Bedaquiline

Specific Binding to Subunit c of ATP Synthase

Research has clearly demonstrated that this compound targets the c subunit of the mycobacterial ATP synthase. frontiersin.orgdrugbank.commdpi.comresearchgate.netbiorxiv.orgasm.orgnih.govasm.org The c subunits form a transmembrane rotor ring within the F₀ portion of the enzyme. nih.govasm.org Studies, including genetic, biochemical, and structural analyses, have identified the binding site of this compound on the c subunit. mdpi.comasm.orgasm.org Resistance mutations to this compound have been mapped to specific amino acid residues (D28, E61, A63, and I66) of the M. tuberculosis c subunit, further supporting this binding site. mdpi.comasm.org Structural studies using the c subunit of Mycobacterium phlei have shown that this compound binds to a cleft between two c subunits in the c-ring. mdpi.com Multiple this compound molecules can bind to the c-ring simultaneously, and the binding affinity of one molecule can be increased by the complementary binding of another. mdpi.com There is also evidence suggesting that this compound may interact with the epsilon (ε) subunit of the F-ATP synthase, which is involved in coupling c-ring rotation to ATP synthesis. frontiersin.orgmdpi.comasm.orgnih.govasm.org Genetic studies have provided in vivo evidence for this interaction, suggesting it occurs near the tryptophan 16 residue of the ε subunit. asm.org

Disruption of Mycobacterial Energy Metabolism and pH Homeostasis

By binding to the ATP synthase, this compound blocks the proton flow through the enzyme, which is necessary for driving ATP synthesis. nih.gov This inhibition leads to a rapid depletion of intracellular ATP levels in M. tuberculosis. mdpi.comnih.govresearchgate.netpnas.org The disruption of ATP production consequently interferes with the mycobacterium's energy metabolism. nih.govfrontiersin.orgnih.govnih.govresearchgate.netalatorax.org

Beyond ATP depletion, this compound has also been shown to disrupt mycobacterial pH homeostasis. frontiersin.orgnih.govresearchgate.netnih.gov Evidence suggests that this compound can act as a proton/potassium (H+/K+) ionophore, leading to the equilibration of transmembrane pH and potassium gradients. pnas.org This ionophoric activity, potentially enhanced by localization at the F₁F₀-ATP synthase, may create an uncoupled microenvironment, contributing to cell death. pnas.org The collapse of the transmembrane pH gradient, but not the membrane potential, has been observed in a dose-dependent manner upon this compound challenge, and these effects were dependent on binding to the F₁F₀-ATP synthase. researchgate.net This electroneutral uncoupling of respiration-driven ATP synthesis may be a determinant of this compound's bactericidal effects. researchgate.net

Activity against Replicating Mycobacteria

This compound is bactericidal against actively growing M. tuberculosis. wikipedia.orgnih.govnih.gov Studies have shown potent in vitro activity against both drug-sensitive and drug-resistant strains of M. tuberculosis with low minimum inhibitory concentrations (MICs). nih.govmdpi.com For instance, MICs against drug-sensitive strains have ranged from 0.030 to 0.120 µg/ml, demonstrating greater potency than some first-line drugs. nih.gov While some studies indicate this compound is largely bacteriostatic against actively growing Mycobacterium abscessus in certain conditions, it has also shown bactericidal activity against this species at concentrations ≥0.0625 µg/ml in specific media. nih.govbiorxiv.org

Activity against Non-Replicating or Persisting Mycobacteria

A key advantage of this compound is its activity against non-replicating or dormant mycobacteria. researchgate.netjyoungpharm.orgnih.govnih.govmdpi.comnih.govacs.orgijbcp.com These persister cells are often less susceptible to conventional antibiotics and contribute to the lengthy treatment duration and relapse in TB. researchgate.netasm.orgmdpi.com this compound's ability to target ATP synthesis, which is essential for the viability of non-replicating persistent mycobacteria, is crucial for its effectiveness against these difficult-to-treat populations. nih.gov Studies have shown that this compound can kill dormant mycobacteria as a result of disturbed ATP homeostasis. ijbcp.com While some research initially suggested apparent activity against non-replicating M. tuberculosis in vitro could be due to carryover effects, other studies confirm its genuine activity against these forms. asm.orgmdpi.com For example, this compound exhibited a comparable bactericidal effect on metabolically inactive non-culturable M. abscessus cells in one study. mdpi.com

Here is a summary of this compound's activity against different mycobacterial states:

In Vitro Mycobactericidal Activity Studies

In vitro studies have demonstrated this compound's activity against a range of Mycobacterium species. It has shown excellent activity against M. tuberculosis, including multidrug-resistant strains. ersnet.org this compound is bactericidal against M. tuberculosis, with ATP production being inhibited within hours of exposure, leading to cell death within several days. wikipedia.org

Studies have also evaluated the in vitro activity of this compound against various NTM species. This compound has shown moderate to significant activity against several clinically relevant NTM, including Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABc). asm.orgoup.comnih.gov

Research findings on the in vitro activity of this compound against NTM have provided crucial data on minimum inhibitory concentrations (MICs). For M. abscessus complex isolates, MIC values have been reported across various studies. One study found this compound MICs for M. abscessus subsp. abscessus ranging from 0.008 to 0.5 µg/mL, with an MIC50 of 0.06 µg/mL and an MIC90 of 0.12 µg/mL for 76 isolates. asm.orgnih.gov For M. abscessus subsp. massiliense, the MIC range was 0.015 to 0.12 µg/mL, with MIC50 and MIC90 values of 0.12 µg/mL. asm.orgnih.gov Another study on M. abscessus complex reported MIC50 and MIC90 values of 0.5 µg/mL, with a range of 0.125 to 2 µg/mL. mdpi.com Against slowly growing mycobacteria (SGM), this compound exhibited high activity against Mycobacterium avium, with MIC50 and MIC90 values of 0.03 and 16 mg/liter, respectively. asm.orgscispace.com For rapidly growing mycobacteria (RGM), M. abscessus subsp. abscessus and M. abscessus subsp. massiliense appeared more susceptible than Mycobacterium fortuitum, with MIC50 and MIC90 values of 0.13 and >16 mg/liter, respectively, for both subspecies. asm.orgscispace.com

The in vitro activity can be influenced by the growth phase of the bacteria and the testing conditions. While this compound is largely bacteriostatic against actively growing M. abscessus in certain media, it has shown bactericidal activity against nutrient-starved persistent cells and additive bactericidal effects in intracellular infection models. biorxiv.orgasm.org

Data tables summarizing MIC values from various studies provide a clearer picture of this compound's in vitro potency against different mycobacterial species.

These findings highlight this compound's potent in vitro activity against key mycobacterial pathogens, supporting its role in the treatment of drug-resistant infections.

Tissue Penetration and Accumulation Profiles

This compound exhibits extensive distribution to tissues. oup.com Preclinical studies in mice have shown significant distribution to organs such as the lungs and spleen. oup.com Brain uptake in these studies was observed to be low. oup.com In humans, this compound has been detected in sputum. oup.com

This compound is a highly lipophilic compound, which likely contributes to its extensive tissue distribution and long terminal half-life. nih.govmdpi.com This lipophilicity may lead to preferential accumulation in brain tissue, although data on this in humans are limited. nih.gov Studies in healthy rodents indicated that this compound penetrated brain tissue sufficiently to reach therapeutic concentrations. nih.gov However, in clinical cases, this compound was undetectable in the cerebrospinal fluid (CSF) of one patient with central nervous system (CNS) TB, while detected in the CSF of others. nih.gov CSF concentrations were found to be significantly lower than plasma concentrations but similar to the estimated plasma unbound fraction. nih.govasm.org

This compound accumulates in tissues, and its slow release from peripheral tissues contributes to its prolonged terminal elimination phase. asm.orgingentaconnect.com This accumulation is a factor in the drug's unique dosing schedule, which includes a loading phase to rapidly achieve therapeutic concentrations followed by an intermittent maintenance phase to prevent excessive long-term accumulation while maintaining target plasma levels. oup.comingentaconnect.com

Protein Binding Dynamics

This compound is characterized by high plasma protein binding, which is reported to be greater than 99.9% in human plasma at concentrations ≥5 mg/L. drugbank.comoup.comasm.orgresearchgate.netwho.int The active metabolite, M2, also exhibits high plasma protein binding, greater than 99.7% at concentrations of 10 and 30 mg/L. asm.orgresearchgate.net While the specific plasma proteins involved are not fully identified, albumin, being the most abundant plasma protein, is likely implicated. oup.com The high protein binding means that only a small fraction of the drug is unbound and available to penetrate tissues and exert pharmacological activity. nih.govasm.org

Cellular Uptake and Localization within Host Cells (e.g., Macrophages, Polymorphonuclear Cells)

This compound accumulates within cells. asm.org Studies have shown that this compound exhibits significant accumulation in infected THP-1 cells. nih.gov The intracellular bactericidal activity of this compound has been observed to be greater than its extracellular activity in primary peritoneal macrophages and a macrophage-like cell line. europa.eu

Research using nanoparticle formulations of this compound in zebrafish models has provided insights into cellular localization. Following intravenous injection, this compound nanoparticles were rapidly and efficiently taken up by endothelial cells lining the vasculature, rather than primarily by macrophages in blood circulation. uio.norsc.org Electron microscopy has shown this compound nanoparticles located inside vesicles of endothelial cells. uio.norsc.org While studies with fluoroquinolones have demonstrated preferential uptake and accumulation in macrophages and foamy macrophages where Mycobacterium tuberculosis resides, this compound's intracellular localization appears to involve endothelial cells. nih.govelifesciences.org

Studies investigating the relationship between plasma and intracellular concentrations in peripheral blood mononuclear cells (PBMCs) of patients with rifampin-resistant TB showed that this compound concentrations in PBMCs ranged from 16.2 to 5,478 ng/ml over a 6-month treatment period. asm.org Intracellular concentrations of this compound in PBMCs increased from predose to 5 hours post-dose but declined to predose levels by 24 hours. asm.org

Role of Cytochrome P450 Enzymes in this compound Metabolism (e.g., CYP3A4)

The primary enzyme involved in the metabolism of this compound is cytochrome P450 (CYP) isoenzyme 3A4. drugbank.comoup.comasm.orgoup.comeuropa.eunih.govlgmpharma.comnih.govpeerj.comnih.goveuropa.eu CYP3A4 is the major CYP isoenzyme responsible for the in vitro metabolism of this compound and the formation of its main metabolite, M2. drugbank.comeuropa.eunih.goveuropa.eu In vitro studies confirm that the CYP3A4 pathway contributes significantly to this compound metabolism, with one study indicating over 75% contribution to the formation of N-desmethyl-bedaquiline (M2). frontiersin.org

While CYP3A4 is the major enzyme, other CYP isoforms, including CYP1A1, CYP2C8, and CYP2C18, have shown some involvement in this compound metabolism in vitro, defined as a metabolic rate exceeding 10% of that observed with CYP3A4. oup.com Additionally, studies using human hepatocytes and recombinant P450s have found that CYP2C8 and CYP2C19 also contribute to this compound N-demethylation. nih.govnih.gov The Michaelis-Menten constant (Km) values for M2 formation by CYP2C8, CYP2C19, and CYP3A4 were determined to be 13.1 µM, 21.3 µM, and 8.5 µM, respectively. nih.govnih.gov

This compound is not a significant inhibitor of the CYP450 enzymes tested in vitro (CYP1A2, CYP2A6, CYP2C8/9/10, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A4/5, and CYP4A) and does not induce CYP1A2, CYP2C9, or CYP2C19 activities. europa.eu

Co-administration of this compound with moderate or strong CYP3A4 inducers can decrease this compound plasma concentrations, potentially reducing its therapeutic effect. europa.eueuropa.eu For example, co-administration with rifampicin, a strong CYP3A4 inducer, reduced this compound exposure (AUC) by 52% in healthy adults. europa.eueuropa.eu Conversely, co-administration with CYP3A4 inhibitors does not appear to have a clinically relevant effect on this compound exposure, and no dose adjustment is typically needed. europa.eu Short-term co-administration with ketoconazole, a strong CYP3A4 inhibitor, increased mean this compound exposure by 22%, while clarithromycin, another strong inhibitor, increased exposure by 14%. europa.eu

Identification and Characterization of Primary and Secondary Metabolites (e.g., N-monodesmethyl metabolite (M2))

The primary metabolite of this compound is the N-monodesmethyl metabolite, referred to as M2. drugbank.comoup.comeuropa.eunih.govlgmpharma.comnih.goveuropa.eu This metabolite is formed through oxidative metabolism, primarily mediated by CYP3A4. drugbank.comeuropa.eunih.govlgmpharma.compeerj.comeuropa.eu

M2 is considered to be less active than the parent compound, with antimycobacterial activity reported to be 3- to 6-fold lower than this compound. drugbank.comoup.comeuropa.eunih.govlgmpharma.comeuropa.eu Although M2 circulates at lower concentrations in plasma compared to this compound, its intracellular concentrations, particularly in PBMCs, can be considerably higher than those of the parent drug. asm.org The average exposure to M2 in humans is lower than this compound, ranging from 23% to 31%. drugbank.comeuropa.eulgmpharma.comeuropa.eu

In addition to M2, several minor metabolites have been identified in human plasma samples. oup.com M2 can be further N-demethylated to form the N-didesmethyl metabolite (M3). frontiersin.org A novel metabolic pathway producing an aldehyde intermediate has also been identified. nih.govnih.gov

While M2 has lower antimycobacterial activity, it is thought to be a stronger inducer of phospholipidosis and may contribute to QT prolongation observed with this compound use. asm.orgoup.comfrontiersin.org

Plasma and Intracellular Concentrations of this compound and M2 in PBMCs (6-Month Treatment Period) asm.org

Intracellular-Plasma Ratios in PBMCs asm.org

Metabolic Stability Research

This compound primarily undergoes oxidative metabolism in the liver, predominantly catalyzed by the cytochrome P450 (CYP) 3A4 isoenzyme. This process leads to the formation of the main circulating metabolite, N-monodesmethyl metabolite (M2). drugbank.comoup.comasm.orgfda.govnih.govnih.govdovepress.com While M2 retains some antimycobacterial activity, it is generally 3- to 6-fold less potent than the parent compound. oup.comnih.govnih.govresearchgate.net In vitro studies also indicate that other CYP isoforms, including CYP1A1, CYP2C8, and CYP2C19, can contribute to this compound metabolism, although their in vivo relevance is considered less significant compared to CYP3A4 due to lower hepatic expression levels. oup.comasm.orgnih.govdovepress.comnih.govnih.gov A minor N-didesmethyl metabolite (M3) is also formed through further N-demethylation of M2, but it possesses negligible antimycobacterial activity. oup.comasm.org Research has also identified a novel metabolic pathway producing an aldehyde intermediate. nih.gov

Excretion Pathways (e.g., Fecal Excretion)

Based on preclinical studies and confirmed by clinical data, the primary route of elimination for this compound and its metabolites is through feces. drugbank.comfda.govresearchgate.netnih.goveuropa.eu The urinary excretion of unchanged this compound is minimal, accounting for less than or equal to 0.001% of the administered dose in clinical studies, indicating that renal clearance of the parent drug is insignificant. drugbank.comfda.goveuropa.eueuropa.euwho.int Studies on fecal samples have shown that unchanged this compound accounts for a significant portion (75%-85%) of the drug-related material eliminated. oup.comresearchgate.net

Terminal Elimination Half-Life Dynamics

This compound exhibits a notably long terminal elimination half-life. The mean terminal elimination half-life for both this compound and its M2 metabolite is approximately 5.5 months, with a range typically cited between 2 and 8 months. drugbank.comresearchgate.neteuropa.eunih.govwikipedia.org This extended half-life is thought to be a consequence of the slow release of this compound and M2 from peripheral tissues where the drug is extensively distributed due to its lipophilic nature and high protein binding (>99.9%). drugbank.comresearchgate.neteuropa.eunih.govwikipedia.orgresearchgate.net While the terminal half-life is very long, the effective half-life associated with drug accumulation in plasma following multiple dosing is considerably shorter, approximately 24 hours. researchgate.netresearchgate.netwho.int

Impact of Genetic Polymorphisms (e.g., SNP rs319952)

Genetic polymorphisms can play a role in the inter-individual variability observed in this compound pharmacokinetics. Studies have identified single-nucleotide polymorphisms (SNPs) associated with alterations in this compound clearance. For instance, the SNP rs319952 in the AGBL4 gene has been significantly associated with the apparent clearance of this compound. asm.orgnih.govresearchgate.net Research in a Chinese MDR-TB patient population indicated that subjects with the GG allele at SNP rs319952 had a lower apparent clearance (1.4 L/h lower) compared to those with AG or AA alleles. asm.orgnih.gov Another study in a South African cohort found that the CYP3A53 polymorphism (rs776746), which results in nonfunctional CYP3A5 protein, was associated with slower this compound clearance. nih.govoup.com CYP3A53 heterozygosity and homozygosity were linked to 15% and 30% slower this compound clearance, respectively. nih.govoup.com Differences in CYP3A5*3 frequencies across populations may partially explain observed variations in this compound clearance, such as the more rapid clearance reported in individuals of African ancestry. nih.govoup.com

Here is a table summarizing the impact of selected genetic polymorphisms on this compound clearance:

Mutations in atpE Gene and their Impact on ATP Synthase Subunit c

The atpE gene encodes the subunit c of the ATP synthase, the enzyme complex that this compound targets to inhibit energy production in Mtb. nih.govasm.org Mutations in atpE are directly linked to this compound resistance by preventing the drug from binding effectively to its target site on the c subunit. oup.comfrontiersin.org These mutations are typically associated with high-level this compound resistance, leading to significant increases in minimum inhibitory concentrations (MICs). asm.orgfrontiersin.orgasm.org While atpE mutations confer high resistance levels (10–128-fold MIC increase), they are reported to occur at a relatively low frequency in clinical isolates compared to other resistance mechanisms. frontiersin.orgfrontiersin.orgersnet.org Studies have identified specific point mutations within the atpE gene, such as A28V, A63P, I66M, A28P, and G61A, in laboratory-generated mutants. oup.com More recently, substitutions like D28N and A63V have also been identified in clinical isolates associated with increased this compound MICs. oup.com

Mutations in Rv0678 Gene and Role in Efflux Pump Regulation (e.g., MmpS5-MmpL5)

Mutations in the Rv0678 gene represent a major non-target-based mechanism of this compound resistance. oup.comfrontiersin.orgasm.org Rv0678 encodes a transcriptional repressor (MmpR) that regulates the expression of the MmpS5-MmpL5 efflux pump system. frontiersin.orgasm.orgplos.org Mutations in Rv0678 lead to impaired repressor function, resulting in the upregulation of the MmpS5-MmpL5 efflux pump. oup.comfrontiersin.orgasm.org This increased expression of the efflux pump components, MmpS5 and MmpL5, enhances the extrusion of this compound from the bacterial cell, thereby reducing its intracellular concentration and conferring resistance. frontiersin.orgasm.orgplos.org Rv0678 mutations are the most common mutations associated with this compound resistance in clinical isolates. asm.orgfrontiersin.orgasm.orgersnet.orgtandfonline.com These mutations typically confer low-level this compound resistance, causing 2- to 8-fold increases in MICs. oup.comfrontiersin.orgfrontiersin.orgasm.org A wide range of mutations can occur within the Rv0678 gene, including missense mutations, insertions, and deletions, dispersed throughout the gene. frontiersin.orgplos.org High-frequency insertions have been observed at nucleotide positions 286–287 and 198–199 in Rv0678. frontiersin.org Rv0678 mutations are also known to cause cross-resistance to clofazimine. oup.comfrontiersin.orgasm.orgasm.orgresearchgate.net

Mutations in pepQ Gene (Rv2535c)

Mutations in the pepQ gene, also known as Rv2535c, have been identified as another genetic determinant of this compound resistance. frontiersin.orgfrontiersin.orgnih.govresearchgate.net pepQ encodes a putative Xaa-Pro aminopeptidase. nih.govasm.orgresearchgate.net Mutations in pepQ are associated with low-level resistance to this compound, with reported MIC increases up to 4-fold in studies involving mice. frontiersin.orgasm.orgresearchgate.net Similar to Rv0678 mutations, alterations in pepQ can also lead to cross-resistance with clofazimine. oup.comfrontiersin.orgasm.orgresearchgate.net The exact mechanism by which pepQ mutations confer resistance is not yet fully understood, and studies have shown no significant differences in the expression of Rv0678, mmpS5, or mmpL5 in pepQ mutants, suggesting an independent resistance pathway. asm.orgresearchgate.net

Mutations in Rv1979c Gene (Putative Permease)

The Rv1979c gene, encoding a putative permease, has also been implicated in this compound resistance. frontiersin.orgfrontiersin.orgnih.govresearchgate.net While the underlying mechanisms remain unclear, mutations in Rv1979c have been associated with reduced susceptibility to this compound. frontiersin.orgnih.gov This gene is thought to encode a probable amino acid membrane transporter with permease activity. nih.govmdpi.com Studies have reported mutations in Rv1979c in association with clofazimine resistance, and its role in this compound resistance is still under investigation. frontiersin.orgnih.govmdpi.com

Identification of Novel Resistance-Associated Variants (RAVs)

Ongoing research utilizing techniques like whole genome sequencing continues to identify novel resistance-associated variants (RAVs) in Mtb isolates. frontiersin.orgnih.gov Beyond the commonly recognized genes (atpE, Rv0678, pepQ, and Rv1979c), other genes and genetic regions may contribute to this compound resistance. For instance, a study identified a novel gene, glpK, harboring a G572 insertion mutation with a high prevalence in laboratory-selected this compound-resistant mutants, suggesting its involvement in resistance. frontiersin.org Additionally, variants in other efflux pump genes, such as Rv1273c, Rv0507c, and Rv1634c, have been observed in drug-resistant isolates, including those resistant to this compound, warranting further investigation into their role in resistance. aku.edu The identification of novel RAVs is crucial for developing comprehensive molecular diagnostics for this compound resistance. frontiersin.orgnih.govaku.edu

Data Table: Summary of Key Genes Associated with this compound Resistance

Minimum Inhibitory Concentration (MIC) Studies

Minimum Inhibitory Concentration (MIC) studies are fundamental for assessing the susceptibility of M. tuberculosis isolates to this compound. The MIC is defined as the lowest concentration of an antibiotic that inhibits the visible growth of a microorganism nih.gov. Standardized drug susceptibility testing (DST) methods for this compound are crucial for accurate resistance detection and surveillance researchgate.netoup.com.

Different methods, including broth microdilution (BMD) and agar dilution (AD), are used to determine this compound MICs shea-online.orgnih.gov. Studies have established quality control (QC) ranges for this compound MICs using the M. tuberculosis reference strain H37Rv on various media. For instance, on 7H10 and 7H11 agar, the acceptable MIC QC range for H37Rv is typically 0.015 to 0.12 µg/ml, while for 7H9 broth, it is 0.015 to 0.06 µg/ml asm.orgresearchgate.net.

MIC values for susceptible strains generally fall within low concentrations, while resistant strains exhibit higher MICs nih.gov. Mutations in atpE are associated with substantial increases in MICs (10- to 128-fold), whereas Rv0678 mutations typically result in more modest increases (2- to 8-fold) frontiersin.orgoup.comfrontiersin.org.

Data from MIC studies are essential for defining breakpoints that differentiate susceptible isolates from those with reduced susceptibility or resistance. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) has approved a breakpoint of ≤0.25 mg/L for susceptible M. tuberculosis complex isolates nih.govoup.com. However, the interpretation of MIC values, particularly those near the breakpoint or in the intermediate range, can be complex and may require additional genotypic analysis frontiersin.orgersnet.org.

Epidemiological Cut-Off (ECOFF) Value Determination for Mycobacterium abscessus

While this compound is primarily used for M. tuberculosis, studies have also explored its activity against non-tuberculous mycobacteria (NTM), such as Mycobacterium abscessus asm.org. Determining epidemiological cut-off (ECOFF) values is important for distinguishing wild-type isolates from those with acquired resistance mechanisms in a given species.

ECOFF values represent the upper limit of the MIC distribution for susceptible isolates without acquired resistance mechanisms. Establishing ECOFFs for this compound in M. abscessus would help in identifying isolates with intrinsic or acquired resistance to the drug. Research has investigated the activity of this compound against M. abscessus and its potential as a therapeutic agent, but the specific ECOFF values for this species were not detailed in the provided context. Further research is needed to establish standardized ECOFFs for this compound against M. abscessus to guide susceptibility testing and clinical interpretation for this NTM.

Data Table: this compound MIC QC Ranges for M. tuberculosis H37Rv

Data Table: Fold Increase in this compound MIC Associated with Resistance Mutations

Detailed Research Findings on MICs:

A multilaboratory study established this compound MIC QC ranges for M. tuberculosis H37Rv, defining ranges for 7H10 agar, 7H11 agar, and 7H9 broth asm.orgresearchgate.net.

In a study in Korea, the MICs for most susceptible strains were 0.125–0.25 mg/L, and for most resistant strains, they were 0.5–1 mg/L nih.gov.

Acquired resistance, suggested by a fourfold increase in MIC values, was observed in a proportion of patients during clinical studies, often correlating with treatment failure or relapse cdc.gov.

Cross-Resistance with Clofazimine

Cross-resistance between this compound and clofazimine is a critical concern because both drugs are often used together in the treatment of DR-TB frontiersin.orgresearchgate.net. This cross-resistance is primarily mediated by mutations in the Rv0678 gene frontiersin.orgfrontiersin.orgoup.comasm.orgnih.govasm.org.

Mutations in Rv0678 lead to the upregulation of the MmpS5-MmpL5 efflux pump, which is capable of extruding both this compound and clofazimine from the mycobacterial cell frontiersin.orguab.eduoup.comfrontiersin.orgasm.org. This shared efflux mechanism is a major contributor to the observed cross-resistance frontiersin.orguab.eduasm.org. Studies have shown that Rv0678 mutations are associated with low-level cross-resistance to both drugs, resulting in increased MICs for both this compound and clofazimine frontiersin.orgoup.comasm.org.

Mutations in the pepQ gene have also been associated with low-level cross-resistance to this compound and clofazimine frontiersin.orgoup.comfrontiersin.orgnih.gov. While the precise mechanism is not fully elucidated, it is believed to involve a non-target-based mechanism, potentially related to efflux, although not through the MmpS5-MmpL5 pump nih.gov.

The emergence of cross-resistance between this compound and clofazimine highlights the importance of careful consideration when designing treatment regimens and the need for surveillance to detect such resistance patterns frontiersin.orgresearchgate.netoup.com.

Detailed Research Findings on Cross-Resistance:

Clinical and in vitro studies have identified the threat of cross-resistance between this compound and clofazimine frontiersin.orgresearchgate.netoup.com.

Rv0678 mutations have been shown to cause low-level cross-resistance to clofazimine in addition to this compound resistance frontiersin.orgoup.comasm.org.

Mutations in pepQ have been isolated from mice treated with this compound and were associated with low-level resistance to both this compound and clofazimine oup.comfrontiersin.orgnih.gov.

A study in Pakistan reported cases of acquired resistance to this compound during therapy, with specific mutations in Rv0678 emerging that were associated with increased MICs and cross-resistance to clofazimine asm.org.

The this compound Drug Resistance Emergence Assessment in MDR-TB (DREAM) study found that phenotypic cross-resistance between this compound and clofazimine was relatively low in treatment-naïve populations (0.4% in MDR-TB and 1% in pre-XDR-TB/XDR-TB) shea-online.orgnih.gov.

Prevalence of Resistance in Different Geographical Regions and Patient Cohorts

The prevalence of this compound resistance varies depending on the geographical region and patient population studied msf.orgresearchgate.netnih.gov. Factors such as prior exposure to this compound or clofazimine and the extent of resistance to other anti-TB drugs can influence the likelihood of this compound resistance msf.orgmedrxiv.org.

Studies have reported varying rates of this compound resistance. A systematic review and meta-analysis indicated a weighted average prevalence of 5.7%, with acquired resistance reported at 5.4% researchgate.netnih.gov. Geographic differences were observed, with a higher prevalence in South Africa (10.4%) compared to China (2.4%) researchgate.netnih.gov.

In South Africa, surveillance data from 2015–2019 showed a baseline phenotypic this compound resistance prevalence of 3.8% in a large cohort of patients with DR-TB msf.org. This prevalence was significantly higher in patients with previous exposure to this compound or clofazimine (21%) compared to treatment-naïve patients (3.6%) msf.orgmedrxiv.org. More recent surveys in South Africa have reported this compound resistance rates ranging from 3.6% to 10.2% in different provinces medrxiv.org.

The DREAM study, a 5-year surveillance study across 11 countries, assessed the susceptibility of over 5000 MDR-TB isolates from this compound-treatment-naïve patients shea-online.orgnih.gov. The study found low rates of this compound resistance in this population, with susceptible, intermediate, and resistant rates of 97.9%, 1.5%, and 0.6% respectively by broth microdilution, and 98.8%, 0.8%, and 0.4% by agar dilution shea-online.orgnih.gov. The study also indicated no significant changes in resistance rates over the 5-year period shea-online.org.

The prevalence of resistance-associated variants (RAVs) can also differ by M. tuberculosis lineage and geographical region asm.orgnih.gov.

Data Table: Prevalence of this compound Resistance

Molecular Epidemiology of Resistant Strains

Molecular epidemiology studies utilize genetic information to track the spread of resistant strains and understand the evolutionary dynamics of resistance. Whole-genome sequencing (WGS) is a powerful tool for identifying resistance-associated mutations and determining the genetic relatedness of resistant isolates msf.orgresearchgate.netasm.org.

Studies have shown that mutations in Rv0678 are the most common genetic determinants of this compound resistance in clinical isolates frontiersin.orgfrontiersin.orgasm.orgersnet.orgresearchgate.netnih.gov. These mutations are frequently observed in this compound-resistant strains and can include single nucleotide variants (SNVs), insertions, and deletions frontiersin.orgfrontiersin.org. The prevalence of Rv0678 mutations among this compound-resistant isolates can be high, reaching over 65% in some studies researchgate.netnih.gov.

Mutations in atpE, while associated with high-level resistance, are less frequently observed in clinical isolates compared to Rv0678 mutations frontiersin.orgfrontiersin.orgnih.gov. This may be due to potential fitness costs associated with atpE mutations frontiersin.orgnih.gov. However, atpE mutations have been identified in clinical strains and are linked to significant increases in MICs frontiersin.orgnih.gov.

Mutations in pepQ and Rv1979c are also detected in some this compound-resistant isolates, contributing to reduced susceptibility frontiersin.orgnih.govnih.gov.

Molecular epidemiology studies can also reveal the transmission of resistant strains. The presence of identical or closely related resistant isolates in different patients suggests recent transmission msf.org. Understanding the patterns of transmission is crucial for implementing effective infection control measures.

Furthermore, molecular studies can shed light on the emergence of heteroresistance, where a patient harbors a mixed population of susceptible and resistant bacteria asm.orgnih.gov. Detecting heteroresistance is important as it can precede the development of full resistance and impact treatment outcomes asm.orgnih.gov.

Detailed Research Findings on Molecular Epidemiology:

Mutations in Rv0678 are the primary cause of this compound resistance in clinical isolates, typically resulting in low-level resistance frontiersin.orgfrontiersin.orgasm.org.

Mutations in atpE are responsible for high-level this compound resistance but are less common in clinical isolates frontiersin.orgfrontiersin.orgnih.gov.

A meta-analysis reported that mutations in the Rv0678 gene represented a significant proportion of resistance mechanisms, reaching as high as 65.6% researchgate.netnih.gov.

WGS studies have identified various types of mutations in Rv0678, including SNVs, deletions, and insertions, associated with this compound resistance frontiersin.orgfrontiersin.org.

Molecular analysis of isolates from Pakistan showed that acquired resistance to this compound during therapy was associated with the emergence of specific mutations in Rv0678 asm.org.

Studies are ongoing to further classify new and previously unknown resistance mutations and establish databases for interpreting genomic data to predict resistance dzif.de.

Heteroresistance to this compound has been observed, with molecular techniques like WGS being important for its detection asm.orgnih.gov.

Data Table: Genes Associated with this compound Resistance and Their Role

Strategies for Resistance Prevention and Mitigation

Preventing and mitigating the emergence and spread of this compound resistance is crucial for preserving the effectiveness of this vital drug. A multifaceted approach is required, encompassing optimal clinical management, robust surveillance, and timely access to drug susceptibility testing.

Individualized clinical management is paramount, emphasizing the use of the strongest possible regimens to achieve cure, reduce transmission, and minimize the selection for resistance atsjournals.org. This involves ensuring that this compound is used as part of an appropriate combination therapy with other active drugs, as recommended by guidelines wikipedia.orgnih.gov. Using this compound in regimens with an insufficient number of effective companion drugs increases the risk of resistance development ersnet.orgmsf.orgmsf.org.

Addressing factors that contribute to pharmacokinetic mismatch, which can drive resistance, is also important lshtm.ac.uk. While shorter treatment durations with potent new drugs are generally effective and improve patient compliance, minimizing pharmacokinetic variability among patients is a complex, multifactorial challenge lshtm.ac.uk.

Enhanced surveillance for this compound resistance is essential to monitor its emergence and spread oup.comatsjournals.org. This includes routine drug susceptibility testing of M. tuberculosis isolates, particularly for patients receiving this compound-containing regimens or those with a history of prior exposure msf.orgmsf.org. Rapid and reliable drug susceptibility testing is needed to guide personalized treatment regimens nih.gov.

Improving access to rapid drug susceptibility testing, especially for ruling out resistance to companion drugs like fluoroquinolones, is a critical first step, particularly in resource-limited settings ersnet.orgersnet.org. Undetected resistance to companion drugs can lead to the functional monotherapy of this compound, significantly increasing the risk of resistance acquisition ersnet.org.

Research into efflux pump inhibitors, such as verapamil, as potential adjunctive therapies to combat this compound resistance mediated by efflux pumps is also being explored asm.org.

Ultimately, addressing patient-level and healthcare system factors that contribute to resistance amplification, alongside the development of new drugs and effective vaccines, will have a major impact on drug-resistant TB lshtm.ac.uk.

Phenotypic DST Approaches

Phenotypic DST methods determine the minimum inhibitory concentration (MIC) of this compound required to inhibit the growth of M. tuberculosis isolates in vitro. These methods remain the gold standard for drug resistance determination biorxiv.org. Several phenotypic methods have been developed and validated in multilaboratory studies. asm.orgresearchgate.netnih.gov.

Commonly used phenotypic methods include:

Middlebrook 7H11 Agar Proportion (AP) Assay: This method involves inoculating agar plates containing different concentrations of this compound with a standardized suspension of M. tuberculosis. Resistance is determined by comparing the growth on drug-containing plates to that on drug-free control plates asm.orgasm.orgresearchgate.net.

Broth Microdilution (BMD) Assay: This method uses liquid culture media in microtiter plates with serial dilutions of this compound. The MIC is the lowest concentration that inhibits visible bacterial growth asm.orgresearchgate.netresearchgate.net. BMD using dry plates has shown high reproducibility asm.orgresearchgate.netnih.gov.

Mycobacterial Growth Indicator Tube (MGIT) Assay: This automated system uses a liquid medium and a fluorescence-based sensor to detect mycobacterial growth. This compound is added to the tubes at a critical concentration, and growth is compared to a drug-free control asm.orgmsf.orgmsf.orgbiorxiv.orgasm.orgresearchgate.net. The MGIT960 system is a routinely used method for this compound DST biorxiv.org.

Validation studies have established provisional MIC breakpoints and critical concentrations (CCs) for categorizing isolates as susceptible or resistant asm.orgresearchgate.netnih.gov. For example, a this compound MIC susceptibility breakpoint of 0.12 μg/mL for the BMD method and WHO interim CCs of 1 μg/mL for MGIT and 0.25 μg/mL for the 7H11 AP methods have been validated asm.orgresearchgate.netnih.gov. These studies have shown that MGIT960 and BMD using dry plates are among the most reproducible methods asm.orgresearchgate.netnih.gov.

Phenotypic DST can also provide insights into heteroresistance, the presence of mixed susceptible and resistant bacterial populations within a sample biorxiv.orgresearchgate.net. Considering intermediate results in MGIT testing, where growth in drug-containing tubes is delayed rather than completely inhibited, may help detect heteroresistance at low frequencies biorxiv.org.

Molecular DST Approaches (e.g., Whole-Genome Sequencing)

Molecular DST approaches aim to detect genetic mutations associated with this compound resistance. These methods offer the potential for faster results compared to phenotypic methods.

Whole-Genome Sequencing (WGS) has emerged as a powerful tool for analyzing drug-resistant M. tuberculosis strains, including those resistant to this compound msf.orgmsf.orgresearchgate.netnih.gov. WGS allows for the comprehensive identification of genetic variants in known resistance genes such as atpE, Rv0678, and pepQ, as well as the potential discovery of novel resistance mechanisms asm.orgmsf.orgmsf.orgresearchgate.netnih.gov. WGS can also detect heteroresistance by identifying resistant subpopulations at low frequencies within a sample researchgate.net.

While WGS is valuable for understanding resistance mechanisms and for surveillance purposes, predicting phenotypic this compound resistance solely based on genotype can be challenging medrxiv.org. The relationship between specific genetic variants and the level of phenotypic resistance can be variable, particularly for mutations in Rv0678 oup.commedrxiv.org. Furthermore, some phenotypically resistant isolates may not harbor known resistance mutations, suggesting the existence of other, as yet uncharacterized, resistance mechanisms frontiersin.org.

Targeted sequencing of known resistance genes like Rv0678, atpE, and pepQ is also used msf.orgmsf.org. Targeted deep sequencing can detect low-level variants that might be missed by standard WGS msf.org.

Despite the advances in molecular methods, a defined genetic hotspot for this compound resistance that would facilitate the design of simple, rapid molecular diagnostic assays (similar to those for rifampicin) is currently lacking medrxiv.org. Therefore, while molecular methods, particularly WGS, are invaluable research and surveillance tools, phenotypic DST remains crucial for guiding clinical treatment decisions asm.org. A combination of phenotypic testing and WGS data is considered valuable for comprehensive drug resistance surveillance asm.org.

Randomized Controlled Trials (RCTs) and Observational Studies

This compound's approval was initially based on results from phase 2 trials oup.com. Since then, its efficacy has been further evaluated in both randomized controlled trials (RCTs) and numerous observational studies across diverse settings oup.combmj.comd-nb.infoscielo.brjbp.org.brnih.gov. These studies have consistently shown improved treatment outcomes in patients receiving this compound-containing regimens oup.combmj.comscielo.brersnet.org. A systematic review and meta-analysis including 2 RCTs and 6 cohort studies involving over 21,000 subjects found that this compound treatment was associated with higher rates of culture conversion and a significant reduction in all-cause death compared to control groups d-nb.info. Another systematic review and meta-analysis of 29 studies (4 experimental and 25 observational) involving over 3,900 patients reported pooled treatment success rates of 86.1% in experimental studies and 74.7% in observational studies for this compound-containing regimens scielo.brjbp.org.br. More recent meta-analyses continue to support the improved treatment outcomes with this compound-based shorter regimens, synthesizing data from recent clinical trials and observational studies bmj.com.

Sputum Culture Conversion Rates as Surrogate Markers of Efficacy

Sputum culture conversion rates are frequently used as surrogate markers of the effectiveness of tuberculosis treatment muhn.edu.cn. Studies have shown that this compound-containing regimens lead to higher sputum culture conversion rates d-nb.infonih.goversnet.orgseaninstitute.or.idersnet.orgnih.gov. A systematic review and meta-analysis indicated that this compound treatment was associated with higher rates of culture conversion compared to control groups d-nb.info. In a retrospective cohort study in Guinea, a this compound-containing regimen was associated with a higher probability of treatment success patsjournal.org. A study in the Republic of Moldova found that patients on this compound-containing regimens had a higher 6-month sputum culture conversion rate (66.7%) compared to those on non-bedaquiline regimens (40.3%) ersnet.org. Pooled sputum culture conversion rates for this compound-containing regimens have been reported around 75% minervamedica.it. Some studies have shown even higher conversion rates, exceeding 90% at the end of treatment in observational cohorts, even among patients with fluoroquinolone-resistant TB and XDR-TB ersnet.org. Early efficacy, as measured by sputum culture conversion within 6 months, has also been associated with high rates (over 97% at 6 months in one study) and can potentially predict the final cure rate muhn.edu.cn.

Here is a table summarizing some sputum culture conversion data:

Cure Rates and Treatment Success Outcomes

Here is a table summarizing some treatment success and cure rate data:

Impact on Mortality Rates

Reducing mortality is a key objective in the treatment of drug-resistant TB. Studies have indicated that this compound-containing regimens are associated with a reduction in mortality rates bmj.comd-nb.infoersnet.orgnih.govpatsjournal.orgminervamedica.itnih.govdovepress.comnih.govaidsmap.com. A meta-analysis of all-oral this compound-based shorter regimens reported a mortality rate of 5% and found that these regimens significantly reduced mortality compared to control regimens bmj.com. A systematic review and meta-analysis found a significant reduction in all-cause death in the this compound treatment group compared to the control group d-nb.info. A retrospective cohort study in Guinea showed that the this compound-containing regimen was associated with a reduction of all-cause mortality by 38% patsjournal.org. In the Republic of Moldova, this compound-containing regimens led to a lower mortality rate (8.8%) compared to non-bedaquiline regimens (20.2%) ersnet.org. A large retrospective cohort study in South Africa found that this compound-based treatment regimens were associated with a large reduction in mortality in patients with drug-resistant tuberculosis, with a hazard ratio of 0.35 for MDR/RR-TB and 0.26 for XDR-TB compared to standard regimens nih.govaidsmap.com. Another study in South Africa reported that the this compound group had an 8% lower risk of mortality during treatment (17.0%) compared to the injectable group (22.4%) nih.gov. A recent study in Limpopo Province, South Africa, also found that BDQ-based regimens were associated with reduced mortality, with patients on BDQ-containing regimens having a 35% lower risk of mortality dovepress.com.

Here is a table summarizing some mortality rate data:

Rationale for Combination Therapy in DR-TB

The rationale for using this compound in combination regimens for drug-resistant TB is based on several factors. Tuberculosis treatment, particularly for drug-resistant strains, requires multiple antimicrobial agents to effectively kill the Mycobacterium tuberculosis bacteria and prevent the emergence of further resistance jbp.org.br. Drug-resistant TB is characterized by resistance to at least rifampicin and isoniazid (MDR-TB), and potentially fluoroquinolones and injectable agents (XDR-TB) d-nb.info. The complexity of drug resistance limits the number of effective drugs available jbp.org.br. This compound's novel mechanism of action makes it active against strains resistant to existing drugs, making it a crucial component of optimized regimens nih.gov. Combining this compound with other effective drugs helps to increase the likelihood of successful treatment outcomes, reduce treatment failure, and minimize the risk of resistance developing to this compound itself bmj.comd-nb.infojbp.org.br. The WHO recommends this compound as a priority drug (Group A) for MDR-TB patients, to be included in all-oral regimens to replace injectable treatments d-nb.infoseaninstitute.or.id. The formation of treatment regimens incorporating this compound has significantly contributed to improving the efficacy of MDR-TB treatment researchgate.net.

Studies on Optimal Regimen Composition and Duration

Research has explored the optimal composition and duration of this compound-containing regimens for MDR/RR-TB. The duration of this compound use has been a key area of investigation. While initial recommendations suggested this compound use for 24 weeks, evidence has emerged supporting its safe use beyond this period, although data on the relative effectiveness of prolonged use have been limited. who.intnih.gov

Studies have evaluated this compound as part of longer individualized regimens, typically lasting 18–20 months. nih.gov The WHO initially recommended this compound for 24 weeks within these longer regimens. nih.gov However, subsequent assessments indicated that extending this compound use beyond 24 weeks was safe, although conclusive evidence on improved effectiveness with extended duration in these longer regimens was not found, particularly in regimens containing sufficient potent companion drugs. nih.gov This suggests that in certain longer regimens, 6 months of this compound may be sufficient for many patients. nih.gov

Investigation of this compound in Shorter All-Oral Regimens

The development of shorter, all-oral regimens for drug-resistant TB has been a major focus, with this compound playing a central role. These regimens aim to improve treatment completion rates and reduce toxicity associated with longer regimens and injectable drugs. jwatch.orgoup.com

Clinical trials and observational studies have investigated the efficacy of this compound-based shorter regimens, typically lasting 6 to 12 months. bmj.comnih.gov A systematic review and meta-analysis of studies involving this compound-based all-oral regimens up to 12 months in duration reported a pooled treatment success rate of 83%. bmj.comnih.govnih.gov These shorter regimens have demonstrated improved treatment outcomes, including significantly higher treatment success rates and reduced mortality and treatment failure compared to longer oral or injectable regimens. bmj.comnih.govnih.gov

Examples of shorter this compound-containing regimens studied include the 6-month BPaLM regimen (this compound, pretomanid, linezolid, and moxifloxacin) recommended by WHO for eligible patients aged 14 years and older with rifampicin-resistant, fluoroquinolone-susceptible pulmonary TB. jwatch.orgwho.int Another investigated regimen is a 9-month all-oral regimen that includes this compound, levofloxacin or moxifloxacin, clofazimine, pyrazinamide, ethambutol, high-dose isoniazid, and ethionamide or linezolid in the initial phase, followed by a continuation phase. who.intwho.int

Studies like the endTB trial have examined various 9-month all-oral regimens containing this compound in combination with other drugs such as clofazimine, delamanid, linezolid, levofloxacin, moxifloxacin, and pyrazinamide, with several demonstrating noninferiority to standard longer therapy. jwatch.org

Data from studies on shorter regimens:

These studies collectively support the effectiveness of this compound as a cornerstone of shorter, all-oral regimens for drug-resistant TB.

Pediatric Patient Cohorts

Investigating this compound use in children has been crucial due to the specific considerations in this age group. While children were often not included in initial trials, data from compassionate use studies and dedicated pediatric trials have provided valuable evidence. frontiersin.org

Two key phase II trials, TMC207-C211 and IMPAACT P1108, have been evaluating this compound in pediatric patients with DR-TB across different age groups. who.intfrontiersin.org These studies assess pharmacokinetics, safety, tolerability, and anti-mycobacterial activity. who.int

A retrospective cohort study in China comparing an all-oral this compound-containing regimen to an injectable-containing regimen in pediatric MDR/RR-TB patients found significantly higher favorable treatment outcomes (100% vs 83.3%) and cure rates (94.6% vs 63.3%) in the this compound group. nih.gov The median time to sputum culture conversion was also significantly shorter in the this compound group (4 weeks vs 8 weeks). nih.gov

An analysis of a pediatric MDR/RR-TB database, including children aged below 6 years and 6-12 years who received this compound, found that this compound was significantly associated with shorter treatment duration and a lower adjusted odds ratio of injectable TB drug use. who.int In children younger than 6 years, there was no statistically significant difference in successful treatment outcomes between those receiving an all-oral this compound-based regimen and those not receiving this compound (89% versus 97%). who.int

The WHO has conditionally recommended this compound for treating children with MDR-TB aged less than 6 years, with doses adjusted for age and weight. frontiersin.org this compound is now recommended by WHO for the treatment of MDR/RR-TB in children of all ages and is a component of the 9-month all-oral regimen for eligible children under 14 years. who.int

Data on this compound efficacy in pediatric patients:

Patients Co-infected with HIV

The efficacy of this compound in patients co-infected with HIV is an important consideration due to potential drug-drug interactions with antiretroviral therapy (ART) and the impact of HIV on TB outcomes.

Studies have evaluated this compound in HIV-positive TB patients, including those on ART. A prospective study involving patients with HIV/TB co-infection treated with this compound-containing regimens reported a treatment success rate of 67.9%. ersnet.org Sputum negativation was observed in a significant proportion of culture-positive patients by the end of the first few months of treatment. ersnet.org

A retrospective cohort study in South Africa compared treatment outcomes in DR-TB patients, the majority of whom were HIV co-infected and on ART, treated with this compound- and linezolid-containing regimens to historic controls. nih.govingentaconnect.com Patients treated with this compound showed significantly higher TB culture conversion and cure rates, along with significantly lower mortality, compared to the historic controls. nih.govingentaconnect.com Specifically, cure was achieved in 63% of patients in the this compound group. nih.gov

While potential drug-drug interactions, particularly with certain ART medications that are moderate or strong CYP3A4 inducers, have been noted, studies suggest that co-administration with weak CYP3A4 inducers like nevirapine resulted in only a mild decrease in this compound exposure, which was not associated with a reduction in therapeutic effect. europa.eu Co-administration with CYP3A4 inhibitors does not appear to have a clinically relevant effect on this compound exposure. europa.eu Research continues to explore drug-drug interactions between this compound and various ARVs. who.int

Studies indicate that this compound can be effectively and safely combined with ART in patients with HIV/TB co-infection. ersnet.orgtibl-journal.com

Data on this compound efficacy in HIV co-infected patients:

Patients with Hepatic Impairment

The use of this compound in patients with hepatic impairment requires careful consideration due to its metabolism. This compound is primarily metabolized by hepatic enzymes. fda.gov

Current information indicates that this compound has not been studied in patients with severe hepatic impairment, and its use is not recommended in this population. europa.euisciii.es While clinical trials have mainly involved patients with normal renal function, renal excretion of unchanged this compound is insignificant. europa.eu Population pharmacokinetic analysis in TB patients treated with this compound did not find creatinine clearance to influence this compound pharmacokinetic parameters within a range of 40 to 227 mL/min. europa.eu

Further research, including pharmacokinetic evaluations in patients with severe hepatic impairment, is considered important to understand if exposure differs in this population and if dose adjustments are necessary. fda.gov

Patients with Renal Impairment

Studies on this compound in patients with renal impairment are limited, with the drug primarily investigated in individuals with normal renal function europa.eufda.gov. Renal excretion of unchanged this compound is minimal, accounting for less than 0.001% of the administered dose europa.eufda.gov.

In a population pharmacokinetic analysis of MDR-TB patients, creatinine clearance levels ranging from 40 to 227 mL/min did not appear to influence the pharmacokinetic parameters of this compound fda.goveuropa.eu. This suggests that mild or moderate renal impairment is not expected to have a clinically significant impact on this compound exposure, and dose adjustments are generally not required in these patient populations europa.eufda.govnih.gov.

However, caution is advised when administering this compound to patients with severe renal impairment (creatinine clearance < 30 mL/min) or end-stage renal disease requiring haemodialysis or peritoneal dialysis europa.eueuropa.eunih.gov. While this compound concentrations may potentially increase in these patients due to alterations in drug absorption, distribution, and metabolism secondary to renal dysfunction, this compound is highly bound to plasma proteins, making its significant removal by haemodialysis or peritoneal dialysis unlikely fda.goveuropa.eu.

Preclinical studies in cisplatin-induced renal-impaired rats showed that pharmacokinetic parameters of this compound were not markedly altered compared to normal rats, with the exception of a reduction in the area under the curve (AUC) for plasma concentration within the experimental timeframe acs.orgresearchgate.net. Specifically, the AUC0-t decreased from 4984 ± 1174 ng h/mL in normal rats to 3477 ± 228 ng h/mL in renal-impaired rats researchgate.netacs.org.

In Vitro and In Vivo Efficacy against Various NTM Species (e.g., Mycobacterium abscessus, Mycobacterium avium Complex)

In vitro studies have demonstrated that this compound possesses antibacterial activity against various NTM species oup.comoup.comasm.org. This compound exhibits moderate-to-high in vitro activity against NTM asm.org. Minimum Inhibitory Concentration (MIC) studies have reported values of <1 µg/mL for M. intracellulare and M. avium, and <2 µg/mL for M. abscessus researchgate.net. Some studies have found this compound to be more active against M. intracellulare and M. avium than against M. abscessus, with a two-fold higher MIC against M. abscessus researchgate.net. An epidemiological cut-off (ECOFF) value of 0.5 mg/mL has been estimated for Mycobacterium abscessus based on available data oup.comoup.comnih.gov. This compound has shown potent and consistent activity against M. abscessus complex isolates, including M. abscessus subsp. abscessus, massiliense, and bolletii, regardless of biofilm-forming ability, with MIC values ranging from 0.125 to 1 µg/mL mdpi.com.

In vivo studies, particularly in animal models, have also investigated this compound's efficacy against NTM. A meta-analysis of animal studies showed a 1.86× reduction in bacterial load in this compound-treated animals compared to untreated controls within 30 days oup.comoup.comnih.gov. This compound monotherapy has demonstrated bacteriostatic effects in mouse models of Mycobacterium avium and M. abscessus infections asm.org. Combination therapy including this compound has shown enhanced efficacy compared to monotherapy in reducing bacterial burden in mouse models biorxiv.org. For instance, a combination of this compound and clofazimine was more effective than either drug alone or other agents in reducing the bacterial burden of M. abscessus in the lung, spleen, and liver in mice jnjmedicalconnect.com.

Clinical Outcomes in Human NTM Infections (Pulmonary vs. Extrapulmonary)

Clinical data on the efficacy of this compound for treating human NTM infections are more limited compared to its use in TB hra.nhs.uk. Studies in humans have evaluated this compound-including regimens for NTM disease, measuring outcomes such as culture conversion, cure, and relapse-free cure oup.comnih.gov.

In a systematic review and meta-analysis, this compound-including regimens were found to be effective in treating NTM extrapulmonary infections but not pulmonary infections oup.comoup.comnih.govnih.gov. Case series have also reported on the use of this compound for NTM infections. In a UK case series of 17 patients with NTM disease treated with this compound, 9 had pulmonary disease, 3 had single-site extrapulmonary disease, and 5 had disseminated disease bmj.comresearchgate.net. M. abscessus (47%) and MAC (35%) were the most frequent causative species bmj.comresearchgate.net. In this series, symptoms completely resolved in 29% of cases, partially resolved in 35%, and did not change in 12% bmj.comresearchgate.net. Complete radiological resolution was observed in 18%, partial resolution in 24%, and no change in 29% bmj.comresearchgate.net. Persistent culture conversion was achieved in 24% of individuals bmj.comresearchgate.net.

Another retrospective analysis from a large healthcare system involving 31 patients treated with this compound for NTM infection (21 pulmonary, 10 non-pulmonary) reported culture clearance in 45% of patients with pulmonary NTM oup.comatsjournals.org. The non-pulmonary infections included skin/soft tissue, bone/joint, and disseminated disease oup.com.

Case reports have also described the successful use of this compound in combination regimens for multi-drug resistant, rapidly growing NTM soft tissue infections, including M. abscessus and M. immunogenum, after initial treatment failure ersnet.org.

Whole Blood Bactericidal Activity (WBA) Studies

Whole blood bactericidal activity (WBA) is an ex vivo method used to measure the ability of a patient's whole blood, containing the administered drug(s), to kill or inhibit the growth of mycobacteria plos.org.

Studies using ex vivo whole blood cultures of healthy volunteers have examined the mycobactericidal activity of this compound. Single oral doses of this compound produced detectable WBA ex vivo, showing bacterial killing plos.org. The activity gradually increased, reaching a maximal effect plos.org. Plasma concentrations of 355 ng/mL were found to be sufficient for intracellular mycobacteriostasis plos.org.

When this compound was combined with other antimycobacterial agents like rifampin or rifabutin, the combined dosing produced higher maximal bactericidal effects compared to this compound alone plos.org. The combination of rifabutin plus this compound demonstrated sustained intracellular mycobactericidal activity that was greater than the sum of their individual effects plos.orgresearchgate.net.

Data Tables

Risk Factors for Cardiotoxicity and Predictive Markers

Risk Factors and Monitoring Protocols for Hepatic Function

The addition of this compound to antituberculosis regimens has been associated with an increased rate of transient serum liver test abnormalities and instances of clinically apparent liver injury. nih.gov Hepatotoxicity has been consistently identified as a significant adverse effect of this compound. nih.govfrontiersin.org Studies have revealed that approximately 16% of patients on a this compound regimen experienced hepatotoxicity. nih.govfrontiersin.org A retrospective cohort study indicated a higher incidence of liver injury in patients receiving this compound compared to those on conventional therapy. nih.gov

Risk factors associated with unsuccessful treatment outcomes in MDR-TB patients receiving this compound-containing regimens include advanced age (≥60 years), being underweight (BMI < 18.5 kg/m2 ), and hepatitis C coinfection. researchgate.netjournal-jps.comdovepress.com Subgroup analysis in one study indicated a lower risk of this compound-related liver injury in females. nih.gov

Monitoring protocols for hepatic function in patients receiving this compound are crucial. frontiersin.org Ideally, liver tests, including serum bilirubin, ALT, AST, and alkaline phosphatase, should be measured at baseline and monitored monthly. nih.govwho.int More frequent monitoring may be necessary if the patient is symptomatic. sci-hub.se this compound should be discontinued for persistent increases in liver test abnormalities, ALT elevations above 8 times the upper limit of normal, bilirubin elevations more than twice normal, or any symptom or sign of liver injury. nih.gov Routine liver function monitoring, potentially every two weeks, has been shown to detect drug-induced liver injury early. dovepress.com

Network pharmacology approaches have been employed to identify potential biological mechanisms of this compound-induced liver injury. nih.govfrontiersin.org The PI3K-Akt signaling pathway has been identified as containing the highest number of associated genes linked to this compound-induced liver injury. nih.govfrontiersin.org

Impact in Co-Infected Patients (e.g., HIV, Viral Hepatitis)

Managing DR-TB patients co-infected with HIV and viral hepatitis is often complicated by hepatotoxicity. doi.orgersnet.org Chronic viral hepatitis C or B can negatively impact TB treatment by increasing the risk of hepatotoxicity related to TB drugs, potentially affecting drug choices and reducing treatment success rates. who.intnih.gov The global HCV antibody seroprevalence in TB patients is estimated to be higher than in the general population. who.intnih.gov

In a study involving DR-TB patients co-infected with HIV and viral hepatitis (HCV and HBV) treated with this compound or delamanid containing regimens, clinically significant hepatotoxicity was observed in a percentage of patients receiving this compound in a treatment scheme that included nevirapine-based ART. doi.org Schemes with delamanid were associated with less hepatotoxicity in this high-risk group. doi.org

Data on drug-drug interactions between newer HCV treatments (direct-acting antivirals - DAAs) and MDR-TB medications are limited, but current evidence suggests minimal interactions. who.int However, caution is advised, as this compound may increase the risk of liver toxicity, particularly when co-administered with some HCV treatments. who.int Concomitant therapy for HCV and MDR/RR-TB appears feasible and potentially beneficial for co-infected patients, despite limited direct evidence. who.int Some studies suggest that concurrent treatment with DAAs for HCV and MDR TB with this compound and pretomanid containing regimens may be safe and effective, potentially leading to reductions in transaminases. plos.org

For patients co-infected with HIV, this compound is metabolized in the liver by the enzyme cytochrome P450 3A (CYP3A). uct.ac.za Antiretrovirals like nevirapine, efavirenz, and lopinavir/ritonavir (LPV/r) can affect the activity of CYP3A, potentially impacting this compound concentrations. uct.ac.za Nevirapine and efavirenz can increase CYP3A activity, potentially decreasing this compound concentration and risking treatment failure or resistance development. uct.ac.za LPV/r inhibits CYP3A, which could lead to increased this compound concentrations and a higher risk of toxicity. uct.ac.za Co-administration of single-dose this compound and multiple-dose nevirapine in adults did not result in clinically relevant changes in this compound exposure. efda.gov.etwho.int However, efavirenz is a moderate inducer of CYP3A4, and co-administration with this compound may result in reduced this compound exposure and loss of activity, and is therefore not recommended. efda.gov.etwho.int Long-term co-administration of this compound and lopinavir/ritonavir in HIV co-infected patients resulted in a mild increase in mean this compound exposure, but experience has shown this does not necessarily lead to an increase in adverse effects, though careful monitoring is recommended. who.inteuropa.eu

Studies have also investigated the intracellular concentrations of this compound and its metabolite M2 in HIV-positive patients compared to HIV-negative patients, showing decreased intracellular-plasma ratios in HIV-positive individuals. ru.nlasm.org

Cellular and Molecular Basis of this compound-Induced Phospholipidosis

The amphiphilic nature of this compound and its M2 metabolite allows them to penetrate lysosomal membranes. researchgate.net The acidic environment within the lysosome protonates the amine group, trapping the protonated drug molecule inside. researchgate.net This trapped drug can inhibit phospholipases, leading to the inhibition of phospholipid degradation and subsequent phospholipid accumulation characteristic of phospholipidosis. researchgate.net In vitro studies suggest that the M2 metabolite is a more potent inducer of phospholipidosis than the parent drug. ru.nlasm.orgru.nlnih.govfrontiersin.org M2 has been shown to accumulate at higher concentrations intracellularly than this compound, supporting its role as a main inducer of phospholipidosis. asm.orgru.nl

Clinical Relevance and Monitoring

The clinical significance of drug-induced phospholipidosis in humans is currently unknown and remains a subject of debate. efda.gov.etasm.orgnih.govnih.gov While for some drugs, such as amiodarone and fluoxetine, phospholipidosis has been associated with clinically relevant toxicity, it is debated whether this is relevant for other drugs. nih.gov Drug accumulation in tissues associated with phospholipidosis may contribute to the long half-life of this compound. researchgate.netnih.govmdpi.com In animal studies, the cellular changes of phospholipidosis have shown reversibility over weeks to months, but the process in humans is poorly understood. nih.gov

Musculopathy

In preclinical animal studies, skeletal muscle was identified as one of the target organs affected by this compound. efda.gov.et These effects were monitored clinically. efda.gov.et Despite this preclinical finding, clinical trials have not reported events of rhabdomyolysis or myopathy. nih.gov However, some adverse event reporting analyses have included myalgia among the less frequent adverse events reported with this compound. elsevier.es

Pancreatitis

Animal toxicology studies have indicated that this compound can be associated with effects on the pancreas. efda.gov.etwho.intfda.govresearchgate.net In studies conducted in mice, rats, and dogs, accumulation of pigment-laden and/or foamy macrophages, consistent with phospholipidosis, was observed in various tissues, including the pancreas. efda.gov.etfda.govresearchgate.neteuropa.eu Pancreas toxicities, with the N-monodesmethyl metabolite (M2) potentially being a main contributor, were associated with a less-than-dose-proportional increase in plasma exposure and an overproportional tissue uptake of this compound and M2 at high-dose levels in dogs. researchgate.net These findings were slowly reversible upon treatment cessation. fda.gov However, the clinical significance of phospholipidosis in humans is currently unknown. efda.gov.eteuropa.eu

Ototoxicity

While the provided search results mention ototoxicity as a potential adverse effect in the outline, the detailed content regarding the mechanism of this compound-induced ototoxicity is not present in the search results.

Effects on Monocytic Phagocytic System (MPS)

This compound has been associated with effects on the monocytic phagocytic system (MPS). efda.gov.etwho.intfda.govresearchgate.neteuropa.eu Animal toxicology studies across different species (mice, rats, and dogs) have consistently shown the presence of pigment-laden and/or foamy macrophages in various MPS tissues, such as lymph nodes, spleen, and liver. efda.gov.etfda.govresearchgate.neteuropa.eu These observations are consistent with phospholipidosis. efda.gov.etfda.govresearchgate.neteuropa.eu While these findings were observed in animal studies and were slowly reversible upon treatment cessation, the significance of phospholipidosis in humans remains unknown. efda.gov.etfda.goveuropa.eu Effects on the MPS were among the target organ effects noted in animal studies, alongside effects on skeletal muscle, liver, stomach, pancreas, and heart muscle. efda.gov.etwho.int

Interactions Mediated by Cytochrome P450 Enzymes (e.g., CYP3A4 Inducers/Inhibitors)

Co-administration of this compound with strong inducers of CYP3A4 can lead to increased metabolism of this compound, resulting in decreased plasma concentrations and potentially reduced therapeutic efficacy. nih.goveuropa.euuct.ac.za Conversely, co-administration with strong or moderate inhibitors of CYP3A4 can decrease this compound metabolism, leading to higher systemic exposure and a potential increase in the risk of adverse reactions. nih.govuct.ac.za

Studies have investigated interactions with various CYP450-based drugs. For instance, co-administration with rifampin, a strong CYP3A4 inducer, resulted in a significant decrease in this compound exposure (AUC) by 52% in healthy adults. europa.euwikipedia.org This reduction in exposure highlights the potential for loss of efficacy when strong CYP3A4 inducers are used concurrently, and thus, co-administration with moderate or strong CYP3A4 inducers like rifamycins (including rifampicin, rifapentine, and rifabutin), efavirenz, etravirine, carbamazepine, phenytoin, and St. John's wort should be avoided. nih.goveuropa.euwikipedia.org

On the other hand, ketoconazole, a strong CYP3A4 inhibitor, increased this compound exposure (AUC) by 22% in healthy subjects when administered concurrently. nih.govwikipedia.org While this increase was observed, the clinical implications regarding increased adverse effects require careful consideration.

Interactions with other anti-TB drugs metabolized by CYP enzymes, such as isoniazid and pyrazinamide, are not considered significant, and dose adjustments are generally not required during co-administration with this compound. nih.gov

Interactions with Antiretroviral Therapies (ART)

Drug-drug interactions between this compound and antiretroviral therapies (ART) are a significant concern, particularly in patients co-infected with HIV and tuberculosis. uct.ac.za this compound's metabolism by CYP3A4 means that ART drugs affecting this enzyme can influence this compound concentrations. uct.ac.za

Nevirapine and efavirenz are antiretrovirals that can affect CYP3A activity. uct.ac.za Nevirapine is an inducer of CYP3A, but studies have not shown a significant reduction in this compound concentrations when co-administered, suggesting they can likely be used together without dose adjustments. nih.govuct.ac.zawho.intnatap.org However, efavirenz induces this compound metabolism, which may lead to reduced this compound exposure and a potential loss of activity, and therefore, co-administration should be avoided. who.int

Lopinavir/ritonavir (LPV/r), a combination ART drug, is more problematic. nih.govuct.ac.za Ritonavir is a potent inhibitor of CYP3A4, primarily used to boost the levels of other protease inhibitors like lopinavir by slowing their metabolism. wikipedia.orgmims.com LPV/r inhibits the CYP3A enzyme, which can lead to decreased this compound metabolism and consequently higher this compound concentrations in the blood. uct.ac.za A pharmacokinetic study in patients with drug-resistant TB showed that patients on LPV/r had this compound concentrations twofold higher than patients not on antiretrovirals. uct.ac.zaoup.com While a single-dose study showed only a modest increase, significant accumulation of this compound and its metabolite is likely with prolonged concomitant use of LPV/r. nih.gov The clinical effects of this increased exposure are not fully clear, but higher concentrations may increase the risk of toxicities, including QT prolongation and elevated liver enzymes. uct.ac.za Therefore, the combination of this compound and LPV/r should be used with extreme caution and under close monitoring when alternative options are unavailable. nih.govuct.ac.zawho.int

Data on drug-drug interaction studies between this compound and ART are limited, often based on studies in healthy volunteers receiving a single dose of this compound. nih.govuct.ac.za The effects of ART on this compound concentrations during more frequent this compound dosing are not fully known. nih.gov

Interactions with Other QT-Prolonging Medications

This compound can cause dose-related prolongation of the QT interval. wikipedia.orgdrugs.com This effect is thought to be potentially related to the plasma concentrations of the M2 metabolite of this compound. dovepress.com Co-administration of this compound with other medications known to prolong the QT interval can result in additive or synergistic effects, increasing the risk of prolonged QT and potentially serious ventricular arrhythmias, such as torsade de pointes, and sudden death. wikipedia.orgdrugs.comdovepress.com

This increased risk was observed in studies where this compound was used concurrently with other QT-prolonging medications, including ketoconazole and clofazimine. europa.euwikipedia.orgdrugs.comdovepress.com In a study, mean increases in QTc were larger in subjects using clofazimine with this compound compared to those not using clofazimine with this compound. drugs.com Another study noted that the use of this compound combined with fluoroquinolones and/or clofazimine is an independent risk factor affecting the QT interval. asm.org

The mechanism for additive or synergistic QT prolongation when this compound is used with other QT-prolonging medications is probably due to co-inhibition of ATP-dependent K+ channels. dovepress.com

Caution is recommended when this compound is used with other QT-prolonging drugs. wikipedia.orgdrugs.com Monitoring for QT prolongation and arrhythmia development is imperative, especially when combined with other such medications. dovepress.com

Here is a summary of some key drug interactions:

Clinical Impact and Management Strategies for Drug Interactions

This compound, a diarylquinoline antimycobacterial agent, is primarily metabolized by the cytochrome P450 (CYP) 3A4 isoenzyme in the liver oup.comalatorax.orgmims.comnih.govresearchgate.net. This metabolic pathway makes this compound susceptible to drug-drug interactions with substances that either induce or inhibit CYP3A4 activity oup.comalatorax.orgnih.govfda.govtbdrugmonographs.co.uknih.gov. The clinical impact of these interactions can range from reduced this compound efficacy due to decreased exposure to an increased risk of adverse reactions due to elevated this compound levels nih.govfda.gov.

Interactions with CYP3A4 Inducers

Strong CYP3A4 inducers can accelerate the metabolism of this compound, leading to lower systemic exposure and potentially reducing its therapeutic effect nih.govfda.govtbdrugmonographs.co.uk. Studies have shown that co-administration with strong inducers like rifampicin can significantly decrease this compound exposure. For instance, a study involving a single dose of 300 mg this compound and multiple doses of 600 mg rifampicin once daily for 21 days in healthy subjects resulted in a 52% reduction in this compound AUC (90% CI: -57% to -46%) fda.gov. Other rifamycins, such as rifapentine and rifabutin, are also strong CYP3A4 inducers and should be avoided fda.gov. Efavirenz, a moderate CYP3A4 inducer, has also been shown to reduce this compound concentrations, with mathematical modeling predicting a 50% reduction in steady-state concentrations nih.govuct.ac.zaersnet.orgwho.intnih.gov.

The clinical impact of reduced this compound exposure due to CYP3A4 inducers is a concern for treatment efficacy and the potential development of further drug resistance uct.ac.za.

Management Strategies for CYP3A4 Inducers:

Co-administration of strong CYP3A4 inducers, such as rifamycins (e.g., rifampicin, rifapentine, rifabutin), should generally be avoided while a patient is on this compound treatment nih.govfda.govtbdrugmonographs.co.uk.

Avoid co-administration with moderate CYP3A4 inducers like efavirenz who.intmedscape.com. The WHO guidance recommends changing the antiretroviral regimen from efavirenz to an alternative when this compound is initiated who.intnih.gov.

If co-administration with a moderate inducer is unavoidable, evaluate for loss of therapeutic effect and consider dose adjustment of the co-administered drug according to its prescribing information, although dose adjustments for this compound in the face of strong drug interactions are not currently well-established or recommended nih.goversnet.orgmedscape.com. Using a higher dose of this compound is a potential strategy but has not been tested or recommended nih.gov.

Interactions with CYP3A4 Inhibitors

Conversely, strong and moderate CYP3A4 inhibitors can decrease the metabolism of this compound, leading to higher systemic exposure nih.govfda.gov. This increased exposure could potentially elevate the risk of this compound-related adverse reactions nih.govfda.govhiv-druginteractions.org. Ketoconazole, a strong CYP3A4 inhibitor, increased this compound exposure (AUC) by 22% when co-administered with this compound in healthy subjects nih.govfda.gov. Ritonavir, a strong CYP3A4 inhibitor often used as a boosting agent for protease inhibitors, is also expected to increase this compound concentrations uct.ac.zahiv-druginteractions.orghiv-druginteractions.org. A study with single-dose this compound and multiple-dose lopinavir/ritonavir showed a 22% increase in this compound AUC, with a more pronounced effect likely occurring during prolonged co-administration hiv-druginteractions.orghiv-druginteractions.org. The active metabolite of this compound (M2) also contributes to QT prolongation, and its concentrations may increase with CYP3A4 inhibitors, potentially enhancing this risk uct.ac.zahiv-druginteractions.orgdrugbank.com.

The clinical impact of increased this compound exposure is primarily the potential for increased adverse effects, particularly QT prolongation and hepatotoxicity uct.ac.zahiv-druginteractions.orgdrugs.com.

Management Strategies for CYP3A4 Inhibitors:

Avoid the use of strong CYP3A4 inhibitors used systemically for more than 14 consecutive days while on this compound, unless the benefit of the combination outweighs the risk nih.govfda.govhiv-druginteractions.org.

If co-administration with strong CYP3A4 inhibitors (such as ritonavir-boosted regimens or certain azole antifungals like ketoconazole) is necessary, use with caution and only in a closely monitored setting tbdrugmonographs.co.ukhiv-druginteractions.orghiv-druginteractions.org.

Increased clinical monitoring for this compound-related adverse reactions is recommended, including frequent electrocardiogram (ECG) assessment and monitoring of transaminases fda.govhiv-druginteractions.orghiv-druginteractions.org.

Interactions Affecting QT Interval

This compound has a known risk of prolonging the QT interval alatorax.orgmedscape.comdrugbank.comdrugs.comwikipedia.orgnewdrugapprovals.orgsajid.co.zaersnet.org. Co-administration with other drugs that also prolong the QT interval can lead to additive or synergistic QT prolongation, increasing the risk of ventricular arrhythmias, including Torsade de Pointes nih.govtbdrugmonographs.co.ukmedscape.comhiv-druginteractions.orgdrugbank.comdrugs.comersnet.org. Many drugs used in the treatment of drug-resistant tuberculosis, such as fluoroquinolones (especially moxifloxacin), clofazimine, and delamanid, are known to prolong the QT interval nih.govtbdrugmonographs.co.uksajid.co.zaersnet.orgfrontiersin.org. Certain antiretroviral drugs and other medications like macrolides and some antidepressants can also prolong the QT interval tbdrugmonographs.co.ukdrugbank.comersnet.org.

The clinical impact of additive QT prolongation is the increased risk of potentially life-threatening arrhythmias nih.govmedscape.comdrugs.comersnet.org.

Management Strategies for QT Prolongation Risk:

If possible, avoid the use of other QT-prolonging drugs with this compound nih.govmedscape.com.

If co-administration with a QT-prolonging drug is necessary, increase ECG monitoring frequency nih.govmedscape.comdrugs.com. Baseline ECG should be obtained before initiating treatment, and follow-up ECGs should be performed at specified intervals (e.g., 2, 12, and 24 weeks) and as clinically indicated tbdrugmonographs.co.ukmedscape.comdrugs.com.

Monitor baseline serum levels for potassium, calcium, and magnesium and correct any abnormalities, as electrolyte imbalances can increase the potential for arrhythmias nih.govmedscape.comdrugs.com. Follow-up electrolyte monitoring is required if QT prolongation is detected tbdrugmonographs.co.ukmedscape.com.

Discontinue this compound and other QT-prolonging drugs if clinically significant ventricular arrhythmia occurs or if the corrected QT (QTc) interval is ≥500 ms tbdrugmonographs.co.ukmedscape.comdrugs.com. Monitor ECG to confirm the QT interval returns to baseline tbdrugmonographs.co.ukmedscape.com.