Osimertinib

Activity Against Uncommon EGFR Mutations

Tertiary EGFR Mutations

Tertiary mutations in the EGFR gene are a key driver of on-target resistance to this compound. mdpi.commdpi.com These mutations often arise at specific amino acid residues within the EGFR kinase domain, altering the protein's structure and reducing the drug's binding affinity.

The most well-characterized tertiary mutation is the C797S mutation, located in exon 20 of the EGFR gene. nih.govamegroups.org this compound forms an irreversible covalent bond with the cysteine residue at position 797 in the ATP-binding pocket of the EGFR kinase domain. amegroups.orgaacrjournals.org The substitution of this cysteine with a serine (C797S) prevents this covalent binding, thereby conferring resistance to this compound and other irreversible third-generation TKIs. patsnap.comamegroups.orgbiomolther.org The C797S mutation is a common mechanism of acquired resistance, accounting for a significant percentage of cases. nih.gov The allelic context of the C797S mutation in relation to the T790M mutation (whether they are on the same allele, "in cis," or on different alleles, "in trans") has implications for subsequent treatment strategies. biomolther.orgnih.gov

Table 1: Prevalence of C797S Mutation in this compound Resistance

Mutations at the L718 residue, specifically L718Q and L718V, have been identified as another mechanism of acquired resistance to this compound. nih.govaacrjournals.org The L718 residue is located in the P-loop of the EGFR kinase domain, near the ATP-binding site. nih.govamegroups.org The L718Q mutation, which is more frequent and confers a higher level of resistance, is thought to cause steric hindrance that interferes with the binding of this compound. nih.govfrontiersin.org These mutations are often found in patients with an L858R driver mutation and can emerge after treatment with this compound. nih.govdovepress.com In vitro studies have shown that cell lines with L718Q mutations exhibit significant resistance to this compound. aacrjournals.org

Table 2: Characteristics of L718Q/V Mutations

Mutations at the L792 residue, including L792F and L792H, have also been implicated in this compound resistance. mdpi.comnih.gov The L792 residue is situated near both the C797 and T790 residues in the EGFR kinase domain. mdpi.com Structural modeling suggests that mutations at this site can sterically interfere with the methoxy group on the phenyl ring of this compound, disrupting its proper positioning and binding. oncotarget.com The L792H mutation, in particular, is considered a potent driver of resistance. mdpi.com These mutations often occur in cis with the T790M mutation. mdpi.com In vitro functional assays have confirmed that L792F/H mutations can confer an intermediate level of resistance to this compound. nih.gov

Mutations at the G796 residue, such as G796S and G796R, represent another class of tertiary mutations that can lead to this compound resistance. mdpi.comnih.gov The G796 residue is located adjacent to C797 and is considered a "solvent-front" position. nih.govnih.gov Mutations at this site are believed to cause steric interference with the aromatic ring of this compound, preventing its binding to the EGFR kinase domain. oncotarget.comnih.gov The G796R mutation is predicted to have a more significant impact on this compound binding than the G796S mutation. nih.gov These mutations have been detected in patients who have progressed on this compound. frontiersin.org

In addition to the more common tertiary mutations, a number of rarer mutations have been identified in patients with acquired resistance to this compound. nih.gov These include mutations at positions V802, T725, Q791, and P794. nih.govnih.gov

V802F: The V802 residue is located in the first helix adjacent to the hinge region of the EGFR kinase domain. nih.gov

T725M: The T725 residue is on the p-loop, which directly interacts with small-molecule inhibitors like this compound. nih.gov

Q791L/H and P794S/R: The Q791 and P794 residues are located in the hinge region of the EGFR kinase domain, which is crucial for ATP binding. nih.gov

In silico modeling has predicted that these mutations can significantly reduce the binding affinity of this compound to EGFR. nih.govresearchgate.netascopubs.org The acquisition of some of these mutations, such as V802F, during this compound treatment has been confirmed by analyzing pre- and post-treatment samples. researchgate.netnih.gov

Exon 20 Insertions

EGFR Gene Amplification

EGFR gene amplification is another on-target mechanism of acquired resistance to this compound. mdpi.comfrontiersin.orgnih.gov This involves an increase in the copy number of the EGFR gene, leading to overexpression of the EGFR protein. dovepress.commdpi.com The increased level of the target protein can overwhelm the inhibitory capacity of this compound, leading to sustained downstream signaling and tumor growth. mdpi.com

The frequency of EGFR amplification as a resistance mechanism varies across studies, with reported rates ranging from approximately 4% to 29% in patients who have developed resistance to this compound. frontiersin.orgnih.govdovepress.commdpi.com It can occur both in the first-line and second-line settings of this compound treatment. dovepress.com In some cases, EGFR amplification can co-exist with other resistance mutations, such as C797S. nih.gov

RAS/RAF/MEK/ERK Pathway Alterations

KRAS Mutations (e.g., G12D, G12C)

Mutations in the KRAS gene, a key downstream effector in the RAS/RAF/MEK/ERK signaling pathway, are a recognized mechanism of acquired resistance to this compound. mdpi.com These mutations can bypass the need for EGFR signaling to drive tumor proliferation.

Frequency and Types: Acquired KRAS mutations are detected in a subset of patients who progress on this compound. mdpi.com For instance, in the FLAURA and AURA3 clinical trials, KRAS mutations were found in approximately 1-3% of patients with acquired resistance. mdpi.commdpi.com Specific mutations identified include G12D, G12C, G12S, G13D, Q61R, and Q61K. mdpi.commdpi.comasco.org

Research Findings: Preclinical studies have demonstrated that the introduction of KRAS mutations into EGFR-mutant lung cancer cell lines confers resistance to this compound. fortunejournals.com In some clinical cases, KRAS mutations such as G12D and G12C have been identified in patients who developed resistance after an initial response to this compound. asco.orgnih.gov The emergence of these mutations often occurs with the loss of the T790M mutation. nih.gov The development of specific inhibitors for KRAS mutations, such as sotorasib and adagrasib for KRAS G12C, presents potential therapeutic strategies to overcome this resistance mechanism, possibly in combination with this compound. mdpi.commdpi.comnih.gov

Table 1: Selected KRAS Mutations in this compound Resistance

NRAS Mutations

Similar to KRAS, mutations in NRAS, another member of the RAS family of small GTPases, can also lead to acquired resistance to this compound by activating downstream signaling pathways independently of EGFR.

Frequency and Types: NRAS mutations are observed in approximately 3% of patients who develop resistance to this compound. mdpi.comnih.gov A notable mutation is NRAS E63K, which has been identified in preclinical models of this compound resistance. nih.govnih.gov Other mutations like G12V and G12R have also been detected in in vitro studies. mdpi.com

Research Findings: In vitro studies have shown that chronic exposure of EGFR-mutant cells to this compound can lead to the development of NRAS mutations and copy number gains. mdpi.comnih.gov These genetic alterations result in sustained activation of the MAPK pathway, thereby diminishing the efficacy of this compound. nih.gov The combination of this compound with a MEK inhibitor, such as selumetinib, has been shown in preclinical models to overcome resistance mediated by NRAS mutations. mdpi.com

BRAF Mutations (e.g., V600E)

BRAF is a serine/threonine kinase that functions downstream of RAS in the MAPK signaling cascade. Activating mutations in BRAF can serve as a bypass track, promoting cell proliferation and survival despite EGFR inhibition by this compound.

Frequency and Types: The most common acquired BRAF mutation is V600E, which is found in approximately 3% of cases of this compound resistance. mdpi.commdpi.comdovepress.com This can occur in patients treated with this compound in both the first- and second-line settings. mdpi.comnih.gov Other less common mutations like G469A have been identified in preclinical studies. mdpi.com

Research Findings: The BRAF V600E mutation can coexist with other resistance mechanisms, such as MET amplification. mdpi.comnih.gov Preclinical and clinical evidence suggests that combining this compound with BRAF inhibitors (e.g., dabrafenib, vemurafenib) and sometimes a MEK inhibitor (e.g., trametinib) can effectively overcome resistance mediated by the BRAF V600E mutation. mdpi.commdpi.comoaepublish.comnih.gov

PI3K/AKT Pathway Alterations (e.g., PIK3CA Amplification/Mutations, PTEN Loss)

The PI3K/AKT/mTOR pathway is a critical signaling cascade that regulates cell growth, proliferation, and survival. Aberrations in this pathway are a frequent cause of resistance to targeted therapies, including this compound.

Frequency and Types: Alterations in the PI3K/AKT pathway are found in about 4-11% of patients with acquired resistance to this compound. mdpi.com These include activating mutations in the PIK3CA gene (e.g., E545K, E542K), PIK3CA amplification, and loss of the tumor suppressor PTEN. mdpi.commdpi.comaacrjournals.org

Research Findings: PIK3CA mutations often coexist with other oncogenic driver mutations. nih.gov Loss of PTEN function, which normally antagonizes PI3K signaling, leads to pathway activation and contributes to this compound resistance. mdpi.comnih.gov Preclinical studies have shown that introducing activating PIK3CA mutations or knocking out PTEN in EGFR-mutant cell lines confers resistance to this compound. aacrjournals.org This resistance is associated with increased levels of phosphorylated AKT and S6, indicating pathway activation. aacrjournals.org Combining this compound with PI3K or AKT inhibitors has shown promise in preclinical models for reversing this resistance. aacrjournals.org

Oncogenic Fusions (e.g., RET, NTRK)

The formation of oncogenic fusion genes is another mechanism of acquired resistance, creating novel chimeric proteins with constitutive kinase activity that can drive cancer cell growth independently of EGFR.

Frequency and Types: Oncogenic fusions are identified in approximately 4-7% of cases of this compound resistance. nih.gov These can involve various kinases, including RET and NTRK. nih.govamegroups.org Specific fusions reported include RET-ERC1, CCDC6-RET, and NTRK-TMP3. mdpi.comnih.gov

Research Findings: The emergence of these fusions under the selective pressure of this compound highlights the genomic plasticity of tumors. aacrjournals.org Case reports have demonstrated that combining this compound with a selective inhibitor targeting the fusion partner can lead to clinical responses. mdpi.com For example, combining this compound with a RET inhibitor like selpercatinib has shown efficacy in patients with acquired RET fusions. mdpi.com

Table 2: Examples of Oncogenic Fusions in this compound Resistance

Activation of AXL Signaling

AXL is a receptor tyrosine kinase that, when activated, can promote cell survival and proliferation through pathways such as PI3K/AKT and MAPK. mdpi.com

Research Findings: Overexpression and activation of AXL have been identified as a mechanism of both intrinsic and acquired resistance to this compound in preclinical models. mdpi.comaacrjournals.orgoncotarget.com In some this compound-resistant cell lines, AXL expression is upregulated, and this can be induced by the drug itself over time. nih.govfrontiersin.org AXL activation can occur alone or in conjunction with other resistance mechanisms like MET amplification. frontiersin.org The combination of this compound with AXL inhibitors, such as cabozantinib or ONO-7475, has been shown to suppress the growth of AXL-overexpressing resistant cells in vitro and in vivo. aacrjournals.orgaacrjournals.org

SRC Family Kinases (SFKs) and Focal Adhesion Kinase (FAK) Signaling

SRC family kinases and focal adhesion kinase are non-receptor tyrosine kinases involved in cell adhesion, migration, and proliferation. researchgate.net

Research Findings: Studies have shown that SFK and FAK signaling can sustain AKT and MAPK pathway activity even under continuous EGFR inhibition by this compound. researchgate.netnih.govaacrjournals.org In this compound-sensitive cells, treatment with the drug can lead to increased autophosphorylation of FAK. aacrjournals.org Furthermore, phosphoproteomic analysis of this compound-resistant cells has revealed that mutual phosphorylation of FAK and Src is a key resistance mechanism. researchgate.net The knockdown of FAK reduces Src phosphorylation, and vice versa. researchgate.net Combined inhibition of SFK and FAK has demonstrated potent effects in inhibiting growth, inducing apoptosis, and delaying acquired resistance in preclinical models. researchgate.netaacrjournals.org The SFK inhibitor dasatinib, for example, has been shown to enhance the effects of this compound. researchgate.net This suggests that targeting the SFK/FAK axis is a promising strategy to overcome this compound resistance. nih.govamegroups.org

YES1 Amplification

Amplification of the YES1 gene, which encodes a member of the Src family of tyrosine kinases, has been identified as a mechanism of acquired resistance to EGFR inhibitors, including this compound. pnas.orgnih.gov This resistance pathway is independent of the primary EGFR target.

Cell clones with activated YES1 expression have demonstrated resistance to all three generations of EGFR TKIs. pnas.org The mechanism involves the activation of downstream signaling pathways that bypass the EGFR inhibition by this compound. Studies have shown that both pharmacologic and siRNA-mediated inhibition of YES1 can resensitize resistant cells to EGFR inhibitors. pnas.orgresearchgate.net

Genomic sequencing of clinical samples from patients with acquired resistance to EGFR inhibitors has revealed YES1 amplification in a subset of cases. pnas.orgnih.gov In some of these cases, YES1 amplification was the only identifiable resistance mechanism. nih.gov Furthermore, pre-inhibitor tumor samples from some of these patients did not show YES1 amplification, indicating that this is an acquired alteration. nih.gov YES1 amplification has also been observed in ALK fusion-positive lung cancer patients who have developed resistance to ALK TKIs, suggesting a broader role for this mechanism in TKI resistance. nih.gov

CDCP1 Overexpression

Overexpression of the CUB domain-containing protein 1 (CDCP1) has emerged as a novel mechanism of acquired resistance to this compound. nih.gov This resistance is often mediated through the activation of the AXL/CDCP1/SRC/AKT signaling pathway. nih.govresearchgate.net

In this compound-resistant lung cancer cell lines, a marked increase in the expression of CDCP1 and SRC has been observed, alongside reduced expression of EGFR family proteins. researchgate.net Interestingly, this compound treatment itself can induce the expression of CDCP1 in a time-dependent manner. nih.gov

The functional consequence of CDCP1 overexpression is the activation of downstream signaling pathways that promote cell growth and survival, thereby circumventing the inhibitory effect of this compound. Silencing of CDCP1 has been shown to restore sensitivity to this compound and is associated with reduced activation of SRC and AKT. nih.gov The combined silencing of both CDCP1 and AXL further enhances this sensitization. nih.gov Clinical relevance is supported by the observation of increased CDCP1 expression in tumor samples from lung cancer patients who have developed resistance to this compound. nih.gov

Combination with Chemotherapy (e.g., Platinum-Pemetrexed)

The addition of platinum-pemetrexed chemotherapy to this compound has been explored as a strategy to enhance treatment efficacy in EGFR-mutated non-small cell lung cancer (NSCLC).

Preclinical Rationale: Preclinical studies have suggested that combining this compound with chemotherapy agents like pemetrexed or cisplatin could help delay the onset of drug resistance. mdpi.com One proposed mechanism involves the ABCB1 protein, which can cause chemoresistance by pumping drugs out of cells. mdpi.com this compound has been shown to counteract this effect in laboratory settings. mdpi.com

Clinical Findings: The phase 3 FLAURA2 trial investigated the combination of this compound with platinum-pemetrexed chemotherapy as a first-line treatment for patients with advanced EGFR-mutated NSCLC. The study demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for the combination therapy compared to this compound alone. onclive.comtargetedonc.com

Specifically, the FLAURA2 trial reported a median PFS of 25.5 months for the combination arm, compared to 16.7 months for the this compound monotherapy arm. targetedonc.com At 24 months, 57% of patients in the combination group were progression-free, versus 41% in the monotherapy group. targetedonc.com The combination also showed a benefit in delaying disease progression in the central nervous system (CNS). ascopubs.org Patients receiving the combination were 42% less likely to experience disease progression or death compared to those on this compound alone. ascopubs.org

Further analysis of the FLAURA2 trial data showed that the combination therapy led to long-term, clinically meaningful survival outcomes even after disease progression. oncnursingnews.com Patients on the combination had a 27% lower risk of needing a subsequent treatment and a 30% lower risk of a second progression event. oncnursingnews.com The median time to a second progression was 30.6 months with the combination versus 27.8 months with this compound alone. oncnursingnews.com

Similarly, the OPAL study, a phase 2 trial, also showed excellent efficacy for the combination of this compound with platinum-based chemotherapy in previously untreated EGFR-mutated advanced non-squamous NSCLC. nih.gov The study reported an objective response rate (ORR) of 90.9% and a median PFS of 31.0 months. nih.gov

Clinical Trial Data for this compound and Chemotherapy Combination

Combination with Anti-Angiogenic Agents (e.g., VEGF Inhibitors, Ramucirumab)

Combining this compound with agents that inhibit angiogenesis, the formation of new blood vessels, is another promising strategy. The vascular endothelial growth factor (VEGF) pathway is a key driver of angiogenesis.

Preclinical and Clinical Rationale: Preclinical research has indicated that dual inhibition of the EGFR and VEGF pathways can postpone the development of resistance to EGFR TKIs. ascopubs.orgmedpagetoday.com In EGFR-mutated NSCLC, the activated EGFR pathway can increase VEGF production, which in turn can contribute to resistance against EGFR inhibitors. ascopubs.org

Clinical Findings: The randomized phase 2 RAMOSE trial evaluated the combination of this compound with ramucirumab, a VEGF receptor 2 (VEGFR2) monoclonal antibody. The interim analysis showed a significant improvement in PFS for the combination therapy. ascopubs.orgnih.gov The median PFS was 24.8 months for the this compound plus ramucirumab arm, compared to 15.6 months for the this compound monotherapy arm. ascopubs.orgnih.gov This benefit was observed across various patient subgroups. ascopubs.org

In contrast, the OSIRAM-1/TORG1833 study, another phase 2 trial, did not show a PFS advantage for the combination of this compound and ramucirumab. ascopubs.org The median PFS was 20.0 months for the combination and 24.0 months for this compound alone. ascopubs.org Similarly, a study combining this compound with bevacizumab, another VEGF inhibitor, did not show a significant improvement in PFS. targetedonc.com The differing outcomes in these trials might be related to the duration of exposure to the VEGF inhibitor. ascopubs.org

A phase 1 study (JVDL) of this compound plus ramucirumab in patients with T790M-positive EGFR-mutant NSCLC who had progressed on a prior EGFR TKI found the combination to be tolerable with encouraging antitumor activity. nih.gov

Clinical Trial Data for this compound and Anti-Angiogenic Agent Combination

Combination with MET-Targeting Agents (e.g., Savolitinib, Tepotinib, Capmatinib)

MET amplification is a known mechanism of acquired resistance to this compound, occurring in a significant percentage of patients. nih.govnih.gov Therefore, combining this compound with a MET inhibitor is a logical approach to overcome this resistance.

Clinical Findings with Savolitinib: The phase 2 FLOWERS/CTONG2008 trial investigated this compound plus savolitinib as a first-line treatment for patients with de novo MET-aberrant, EGFR-mutant advanced NSCLC. The combination showed a significantly higher objective response rate (ORR) of 90.5% compared to 60.9% for this compound alone. ascopost.commedscape.com

The TATTON trial (Part B and D) studied the combination in patients with MET-amplified, EGFR-mutant NSCLC who had progressed on a prior EGFR TKI. nih.gov The combination demonstrated promising antitumor activity. nih.govamegroups.org The SACHI phase 3 trial also showed that savolitinib plus this compound significantly improved PFS compared to chemotherapy in patients with MET-amplified NSCLC after progression on a first-line EGFR TKI. onclive.com

Clinical Findings with Tepotinib: The phase 2 INSIGHT 2 study evaluated the combination of tepotinib and this compound in patients with EGFR-mutated NSCLC with MET amplification who had progressed on first-line this compound. nih.govonclive.com The combination demonstrated a confirmed ORR of 50.0% and was found to be a potential chemotherapy-sparing option. onclive.combeaconhospital.com.my

Clinical Findings with Capmatinib: Preclinical data has suggested that combining this compound with capmatinib can overcome MET-mediated resistance. researchgate.net A case report described a patient with metastatic EGFR-mutant NSCLC who developed a MET Y1003N mutation and had a partial response to the combination of this compound and capmatinib. nih.govnih.gov The GEOMETRY-E study was designed to evaluate this combination, but the randomized part was not initiated. clinicaltrials.gov

Clinical Trial Data for this compound and MET Inhibitor Combination

Combination with HER2/HER3 Inhibitors

Aberrations in the HER2 and HER3 signaling pathways can also contribute to this compound resistance. mdpi.com

Preclinical and Clinical Rationale: HER2 amplification is observed in a small percentage of NSCLC cases, but its frequency increases after this compound treatment. mdpi.com HER3, which lacks its own kinase activity, can dimerize with other receptors like HER2 to activate downstream signaling pathways. mdpi.com Preclinical studies have shown that this compound can suppress HER2 phosphorylation and reduce tumor size in models with HER2 involvement. amegroups.org

Combining this compound with anti-HER3 monoclonal antibodies has been explored in preclinical models. This combination was found to engage the immune system to help eliminate tumor cells. nih.gov Specifically, this compound treatment led to an upregulation of HER3, and the addition of an anti-HER3 antibody facilitated tumor cell killing by macrophages. nih.gov

In animal models, a combination of antibodies targeting EGFR (cetuximab), HER2 (trastuzumab), and a subtherapeutic dose of this compound was effective in preventing the onset of resistance. aacrjournals.org This triple combination led to the degradation of EGFR and HER2, enhanced apoptosis, and inhibited key signaling pathways. aacrjournals.org

Combination with MEK/BRAF Inhibitors

Mutations in the downstream RAS/RAF/MEK/ERK signaling pathway, particularly BRAF mutations like V600E, can drive resistance to this compound. mdpi.comupf.edu

Preclinical and Clinical Rationale: The BRAF V600E mutation has been identified as a mechanism of acquired resistance to this compound. upf.edu Preclinical studies have shown that combining this compound with MEK inhibitors like selumetinib or trametinib can restore sensitivity in cells with certain BRAF mutations. upf.edu

Clinical Findings: In patients with both EGFR and BRAF V600E mutations who have progressed on this compound, a triple-targeted therapy of dabrafenib (BRAF inhibitor), trametinib (MEK inhibitor), and this compound has shown efficacy. nih.govoaepublish.com One study reported an objective response rate of 61.5% and a median PFS of 13.5 months in patients with dual EGFR and BRAF V600E alterations treated with a combination of this compound, dabrafenib, and trametinib. mdpi.com Case reports have also documented successful responses to this triple combination. oaepublish.com

Combination with SRC/FAK Inhibitors

The SRC and focal adhesion kinase (FAK) signaling pathways are involved in cell adhesion, migration, and proliferation, and their activation can contribute to TKI resistance. While specific clinical trial data for this compound in combination with SRC/FAK inhibitors is limited in the provided search results, the rationale for such combinations exists within the broader context of overcoming TKI resistance. These pathways are known to be involved in bypass signaling that can circumvent EGFR blockade. Further preclinical and clinical investigation is needed to establish the efficacy of this combination strategy.

MRX-2843 (MERTK Inhibitor)

MERTK, a receptor tyrosine kinase, has been identified as a key player in promoting resistance to this compound. emory.edunih.gov Preclinical studies have shown that the MERTK ligand GAS6 can promote oncogenic signaling in EGFR-mutated NSCLC cells treated with this compound, suggesting a role for MERTK activation in the development of resistance. nih.gov

The first-in-class MERTK inhibitor, MRX-2843, has demonstrated the ability to resensitize this compound-resistant NSCLC cells to the drug. emory.edunih.gov In preclinical models, the combination of MRX-2843 and this compound has been shown to durably suppress tumor growth, even after treatment cessation. emory.edunih.gov This combination therapy is currently being evaluated in a Phase 1b clinical trial for patients with EGFR-mutant NSCLC. emory.edumdpi.com

Mechanism: MERTK activation can drive bypass signaling pathways, allowing cancer cells to survive and proliferate despite EGFR inhibition by this compound. nih.govnih.gov MRX-2843 inhibits this bypass signaling, restoring sensitivity to this compound.

Preclinical Evidence: In vivo studies have shown that the combination of MRX-2843 and this compound leads to durable tumor regression in EGFR-mutant tumor models. nih.gov

Clinical Development: A Phase 1/Ib clinical trial (NCT04762199) is currently recruiting patients to evaluate the safety and efficacy of MRX-2843 in combination with this compound in patients with EGFR-mutant NSCLC. mdpi.com

NXP900 (SRC Kinase Inhibitor)

NXP900 is a novel and selective inhibitor of the SRC family of kinases (SFK), including SRC and YES1. clinicaltrialvanguard.comfirstwordpharma.com It targets both the catalytic and scaffolding functions of SRC kinase, effectively shutting down this signaling pathway. clinicaltrialvanguard.commedpath.com Preclinical studies have demonstrated that NXP900 can overcome resistance to this compound in NSCLC models. medpath.compatsnap.com

The combination of NXP900 and this compound has shown synergistic effects in preclinical models, leading to reduced cancer cell proliferation and increased cell death. clinicaltrialvanguard.com This suggests that NXP900 could prolong the effectiveness of this compound and provide a promising strategy to combat resistance. patsnap.com

Mechanism: Activation of SRC family kinases is a known mechanism of resistance to EGFR inhibitors. researchgate.net NXP900 inhibits this pathway, thereby restoring sensitivity to this compound.

Preclinical Evidence: Preclinical studies have shown that NXP900 can reverse this compound resistance in resistant cell lines and enhance anti-tumor activity when combined with this compound. clinicaltrialvanguard.compatsnap.com

Clinical Development: NXP900 is currently in a Phase 1a dose-escalation study, with plans to initiate a Phase 1b trial combining NXP900 with this compound in EGFR-mutated NSCLC patients. clinicaltrialvanguard.comfirstwordpharma.com

Combination with Farnesyl Transferase Inhibitors (e.g., Tipifarnib)

Farnesyl transferase inhibitors (FTIs), such as tipifarnib, have shown potential in preventing the emergence of resistance to this compound. kuraoncology.com Preclinical studies have demonstrated that tipifarnib can prevent relapse to this compound in both in vitro and in vivo models of EGFR-mutant lung cancer. biorxiv.orgresearchgate.net

The combination of tipifarnib and this compound has been shown to induce an apoptotic response and prevent the emergence of drug-tolerant "dormant" cells, which are a potential source of resistance. kuraoncology.combiorxiv.org

Mechanism: Tipifarnib inhibits the farnesylation of proteins, including those involved in cell signaling and survival pathways that can contribute to this compound resistance. biorxiv.org

Preclinical Evidence: Co-treatment with tipifarnib and this compound has been shown to durably prevent relapse in preclinical models for up to six months without evidence of toxicity. kuraoncology.combiorxiv.org

Clinical Development: Kura Oncology plans to initiate a clinical trial of tipifarnib in combination with this compound in NSCLC. kuraoncology.com

Combination with Hippo Pathway Inhibitors (e.g., TEAD Autopalmitoylation Inhibitor VT3989)

The Hippo signaling pathway has been implicated in resistance to targeted therapies, including this compound. prnewswire.comnih.gov The TEAD family of transcription factors are the major effectors of the Hippo pathway, and their activation is dependent on a process called autopalmitoylation. aacrjournals.org

VT3989 is a first-in-class TEAD autopalmitoylation inhibitor that has demonstrated synergistic activity with this compound in preclinical models of EGFR-mutant NSCLC. prnewswire.combiospace.com The combination of VT3989 and this compound has been shown to enhance anti-tumor activity and delay tumor growth compared to this compound alone. prnewswire.comaacrjournals.org

Mechanism: VT3989 inhibits TEAD autopalmitoylation, which is required for its interaction with YAP/TAZ and subsequent activation of transcription. aacrjournals.org This disruption of the Hippo pathway can overcome resistance to this compound.

Preclinical Evidence: In vivo studies have shown that the combination of VT3989 and this compound significantly delayed the re-emergence of tumors after initial treatment response. prnewswire.com

Clinical Development: VT3989 is currently being evaluated in Phase 1 clinical trials. prnewswire.combiospace.com

Combination with Immunotherapies

Combining this compound with immunotherapies is another promising strategy to overcome resistance. nih.gov The rationale for this approach is based on the potential for this compound to modulate the tumor microenvironment and enhance the efficacy of immune checkpoint inhibitors. mdpi.com

Preclinical studies have shown that combining this compound with anti-PD-L1 antibodies can lead to enhanced anti-tumor activity. nih.gov However, early clinical trial results have been mixed, highlighting the need for further research to identify the optimal combination strategies and patient populations.

Mechanism: this compound may increase the expression of immune checkpoint molecules on tumor cells, making them more susceptible to immunotherapy. mdpi.com

Preclinical Evidence: Some preclinical models have shown synergistic effects when combining this compound with immune checkpoint inhibitors. nih.gov

Clinical Development: The TATTON trial (NCT02143466) is a multi-arm Phase Ib study evaluating this compound in combination with the anti-PD-L1 monoclonal antibody, durvalumab. nih.gov

Combination with Natural Compounds (e.g., Pterostilbene)

Pterostilbene, a natural compound found in blueberries, has shown potential in overcoming this compound resistance in preclinical studies. nih.gov Research indicates that pterostilbene may abrogate the activation of resistance pathways induced by single-agent this compound treatment. nih.govmdpi.com

In preclinical models, the combination of this compound and pterostilbene yielded synergistic effects in EGFR-mutation positive NSCLC cell lines. nih.gov Pterostilbene was found to reverse the this compound-induced phosphorylation of STAT3, YAP1, and CDCP1, which are known to be involved in resistance signaling. nih.gov

Mechanism: Pterostilbene appears to inhibit compensatory signaling pathways that are activated in response to this compound, thereby preventing the development of resistance. nih.gov

Preclinical Evidence: In vitro studies have demonstrated that the combination of pterostilbene and this compound has a synergistic effect in EGFR-mutant NSCLC cell lines. nih.gov

Future Directions: Further in vivo studies are needed to confirm these findings and translate them into clinical applications. nih.gov

Agents Targeting Specific Tertiary EGFR Mutations

The emergence of tertiary mutations in the EGFR gene is a key on-target mechanism of resistance to this compound. The most well-documented of these is the C797S mutation. acs.org The therapeutic strategy for overcoming this resistance often depends on the allelic context of the C797S and T790M mutations. researchgate.netunipr.it

C797S/T790M in trans : When these mutations occur on different alleles, patients may become sensitive to a combination of first- and third-generation EGFR-TKIs, such as gefitinib and this compound. researchgate.netunipr.it

C797S/T790M in cis : When both mutations are on the same allele, the cancer cells acquire resistance to all generations of EGFR-TKIs. unipr.it In this scenario, combination therapies such as brigatinib with cetuximab have shown activity in case reports. researchgate.netnih.gov Other reported combinations in case studies include this compound with anlotinib or afatinib with apatinib. nih.gov

C797S alone and other tertiary mutations : In the absence of T790M, tumors with mutations like C797S, G796S, or others may regain sensitivity to earlier-generation EGFR-TKIs like gefitinib or afatinib. researchgate.netnih.govamegroups.org For instance, a patient with a G796S mutation responded to gefitinib after this compound failure. nih.gov Computational modeling suggests gefitinib has a preferential binding to the EGFR G796S mutant compared to the wild-type EGFR. nih.gov

Fourth-generation EGFR-TKIs are in development to specifically target these resistance mutations. frontiersin.org

Bispecific Antibodies (e.g., Amivantamab)

Amivantamab is a fully human bispecific antibody that targets both EGFR and the mesenchymal-epithelial transition (MET) receptor. mdpi.combinaytara.org This dual-targeting mechanism allows it to overcome resistance driven by both EGFR and MET pathways. binaytara.org MET amplification is a known bypass pathway that can lead to this compound resistance. acs.orgmdpi.com Amivantamab works by blocking ligand binding and inducing the degradation of both EGFR and MET receptors. binaytara.org

The FDA has approved amivantamab for patients with NSCLC harboring EGFR exon 20 insertion mutations who have progressed on chemotherapy. mdpi.com Clinical studies have demonstrated its efficacy in patients who have developed resistance to this compound. cancernetwork.com

Amivantamab in Combination with Lazertinib

The combination of amivantamab with lazertinib, a third-generation EGFR-TKI with central nervous system (CNS) penetration, is a promising strategy to overcome and prevent this compound resistance. mdpi.comtandfonline.comtandfonline.com This combination targets both EGFR-dependent and MET-dependent resistance mechanisms. tandfonline.comesmo.org

The phase 3 MARIPOSA trial compared amivantamab plus lazertinib to this compound alone in the first-line treatment of EGFR-mutated advanced NSCLC. targetedonc.comnih.gov The combination demonstrated a significant improvement in progression-free survival (PFS) compared to this compound. targetedonc.comnih.gov

The MARIPOSA-2 trial investigated amivantamab plus chemotherapy, with or without lazertinib, in patients who had progressed on this compound. cancernetwork.comonclive.com The results showed that both amivantamab-containing regimens improved PFS compared to chemotherapy alone. cancernetwork.com The combination of amivantamab and lazertinib has also shown a lower incidence of acquired MET amplification and EGFR resistance mutations compared to this compound monotherapy. tandfonline.com

Furmonertinib for Exon 20 Insertions

Furmonertinib is a novel, third-generation EGFR-TKI that has shown significant activity against a broad range of EGFR mutations, including exon 20 insertions, which are typically resistant to this compound. nih.govfrontiersin.orgegfrpositive.org.uk Molecular modeling suggests that furmonertinib's unique chemical structure allows for better binding to various EGFR mutants compared to this compound. arrivent.com

In a phase Ib study (FAVOUR), furmonertinib demonstrated promising efficacy in patients with advanced NSCLC harboring EGFR exon 20 insertions. nih.govfrontiersin.org A real-world study also showed that re-challenging with furmonertinib after resistance to this compound or aumolertinib resulted in a disease control rate of 79.5% and a median PFS of 4.7 months. frontiersin.org

Computational Drug Repurposing Tools (e.g., DRAR-CPI)

Computational tools play a crucial role in modern drug repurposing. rjpbr.comeurekaselect.com One such tool is DRAR-CPI (Drug Repositioning Approach based on the Chemical-Protein Interactome). nih.govbio.tools DRAR-CPI analyzes the interaction profiles of a query molecule against a library of drugs with known targets, indications, and adverse reactions. nih.gov By comparing these chemical-protein interactomes, the server can predict potential new indications or adverse effects for the submitted molecule. nih.govresearchgate.net This in silico screening method can efficiently identify existing drugs that may have off-target effects on cancer-related proteins, such as MET. aacrjournals.orgbioengineer.orgeurekalert.org

Fexofenadine as a MET Inhibitor

Using the DRAR-CPI tool, researchers identified fexofenadine, a commonly used antihistamine, as a potential MET inhibitor. eurekalert.orgaacrjournals.orgbioengineer.org Aberrant MET activation is a significant mechanism of acquired resistance to this compound. aacrjournals.org

Preclinical studies have validated this computational finding. eurekalert.orgaacrjournals.org Fexofenadine was shown to inhibit MET kinase activity in cell-free assays and reduce the phosphorylation of MET and its downstream signaling molecules in this compound-resistant NSCLC cell lines with MET amplification. eurekalert.orgaacrjournals.orgresearchgate.net Kinome profiling revealed that fexofenadine's kinase inhibition profile is similar to that of cabozantinib, a known MET inhibitor. eurekalert.orgaacrjournals.orgresearchgate.net

In both cell line and patient-derived xenograft (PDX) models of this compound-resistant NSCLC, the combination of fexofenadine and this compound demonstrated a significant synergistic antitumor effect, effectively overcoming the resistance. eurekalert.orgaacrjournals.orgresearchgate.net These findings support the potential for clinical evaluation of fexofenadine repurposing to overcome this compound resistance in lung cancer. aacrjournals.orgbioengineer.org

Liquid Biopsy (Circulating Tumor DNA)

Cell Line Models (e.g., H1975, PC-9)

Cell line models are fundamental tools in the preclinical evaluation of this compound, providing critical insights into its efficacy and the molecular mechanisms underlying both sensitivity and resistance. Non-small cell lung cancer (NSCLC) cell lines, such as H1975 and PC-9, which harbor specific epidermal growth factor receptor (EGFR) mutations, are extensively used in this research.

The H1975 cell line is characterized by the presence of two EGFR mutations: the L858R mutation in exon 21, which is an activating mutation, and the T790M mutation in exon 20, known as the "gatekeeper" resistance mutation. iiarjournals.orgvghtpe.gov.tw This dual mutation status makes H1975 cells resistant to first and second-generation EGFR tyrosine kinase inhibitors (TKIs) but sensitive to this compound. iiarjournals.org The half-maximal inhibitory concentration (IC50) of this compound in H1975 cells has been reported to be approximately 4.6 nM to 2.15 µM in various studies. iiarjournals.orgoncotarget.com

The PC-9 cell line, on the other hand, carries an EGFR exon 19 deletion, which makes it highly sensitive to EGFR-TKIs, including this compound. oncotarget.commedsci.org The IC50 of this compound for PC-9 cells is approximately 0.016 µM. medsci.org

These cell lines are instrumental in studying acquired resistance to this compound. Researchers establish this compound-resistant cell lines by exposing parental H1975 or PC-9 cells to gradually increasing concentrations of the drug over time. vghtpe.gov.twaacrjournals.org For example, H1975-derived this compound-resistant cells (H1975/OSI) have been shown to have an IC50 value approximately 5.25-fold higher than the parental cells. iiarjournals.org Similarly, this compound-resistant PC-9 cell lines have been developed to investigate diverse resistance mechanisms. nih.gov

Studies using these models have identified several mechanisms of acquired resistance. In H1975-derived resistant cells, upregulation of AXL, a receptor tyrosine kinase, has been observed. aacrjournals.org Other identified mechanisms in various cell lines include MET amplification, epithelial-to-mesenchymal transition (EMT), and activation of bypass signaling pathways like Src-AKT. aacrjournals.orgnih.gov Interestingly, the common C797S resistance mutation was not always detected in these experimentally generated resistant cell lines. aacrjournals.org

The table below summarizes the characteristics of these key cell lines and their use in this compound research.

Patient-Derived Xenograft (PDX) Models

Patient-derived xenograft (PDX) models, which involve implanting patient tumor tissue directly into immunodeficient mice, offer a more clinically relevant preclinical system for evaluating this compound's efficacy. crownbio.com These models are known to better recapitulate the histological and molecular characteristics of the original patient tumor, as well as its response to treatment. crownbio.com

PDX models have been successfully established from patients with NSCLC harboring various EGFR mutations. nih.gov These models have been instrumental in demonstrating the in vivo activity of this compound against tumors with sensitizing EGFR mutations, including those with the T790M resistance mutation. nih.gov For instance, in PDX models with EGFR exon 19 deletions or L858R mutations, this compound treatment has been shown to lead to significant tumor regression. nih.gov

A key application of PDX models is in the study of acquired resistance to this compound. By continuously treating tumor-bearing mice with this compound, researchers can induce the development of resistance in the xenograft tumors. nih.gov This allows for the investigation of resistance mechanisms in a more complex biological environment than cell line models. One study reported the induction of this compound resistance in a PDX model with an L858R mutation, which was associated with epithelial-to-mesenchymal transition (EMT). nih.gov

Furthermore, PDX models are being used to explore biomarkers of response and resistance. clinicaltrial.be Studies have analyzed MET pathway activation in this compound-resistant PDX models, finding that MET amplification and high levels of phosphorylated MET (phospho-MET) expression were predictive of response to a combination of this compound and a MET inhibitor. aacrjournals.orgnih.gov This highlights the utility of PDX models in identifying potential combination therapies to overcome resistance.

The table below provides examples of how PDX models are utilized in this compound research.

In Vitro and In Vivo Studies for Resistance Mechanisms

The emergence of acquired resistance is a significant clinical challenge in this compound therapy. mdpi.com Both in vitro and in vivo studies are crucial for identifying and understanding the diverse mechanisms that drive this resistance. These investigations provide the foundation for developing strategies to overcome or delay the onset of resistance.

In Vitro Studies:

In vitro studies, primarily using cell line models, have been instrumental in uncovering a wide array of resistance mechanisms. These can be broadly categorized as either EGFR-dependent or EGFR-independent.

EGFR-Dependent Mechanisms: These involve alterations to the EGFR gene itself. The most well-documented is the acquisition of tertiary mutations in the EGFR kinase domain, such as the C797S mutation , which prevents the covalent binding of this compound. acs.orgnih.gov Other less common mutations include L718Q, L792H, and G796D . acs.orgaacrjournals.org

EGFR-Independent Mechanisms: These involve the activation of alternative signaling pathways that bypass the need for EGFR signaling. Common mechanisms include:

MET Amplification: This is one of the most frequent bypass tracks, leading to the activation of downstream pathways like PI3K/AKT. mdpi.com

HER2 Amplification: Amplification of the HER2 gene can also drive resistance.

Activation of other Receptor Tyrosine Kinases (RTKs): Upregulation of AXL has been identified in this compound-resistant cell lines. aacrjournals.org

Downstream Pathway Alterations: Mutations in genes like BRAF (V600E), KRAS, and PIK3CA can also confer resistance. mdpi.comnih.gov

Epithelial-to-Mesenchymal Transition (EMT): This phenotypic change can lead to reduced dependence on EGFR signaling. aacrjournals.org

The following table summarizes key resistance mechanisms identified through in vitro studies.

In Vivo Studies:

In vivo studies, utilizing models such as patient-derived xenografts (PDXs), validate the findings from in vitro experiments and provide a more comprehensive understanding of resistance in a complex biological system. nih.gov These models have confirmed that mechanisms like MET amplification and EMT occur in response to this compound treatment in a living organism. nih.gov Furthermore, in vivo models are essential for testing the efficacy of novel therapeutic strategies aimed at overcoming resistance, such as the combination of this compound with MET inhibitors in MET-amplified tumors. aacrjournals.org

Concentration-Dependent Effects

The relationship between this compound exposure and its effects has been studied. A pharmacokinetic/pharmacodynamic analysis predicted a concentration-dependent increase in the QTc interval. europa.eunih.gov Specifically, an analysis suggested a QTc interval prolongation of 14 msec at a dose of 80 mg. drugbank.comnih.gov

While some studies have not found a significant relationship between this compound exposure and efficacy in terms of tumor response, others have observed associations with certain safety endpoints. fda.govaacrjournals.org For instance, the likelihood of experiencing rash and diarrhea has been shown to increase with higher this compound exposure, although severe instances of these side effects are infrequent. fda.govaacrjournals.org One study reported that while there was no link between exposure and efficacy, there was a linear relationship between exposure and the occurrence of rash, diarrhea, and QTc prolongation. nih.gov In contrast, other real-world studies did not find a significant relationship between plasma exposure and dose-limiting toxicity. mdpi.comuniversiteitleiden.nl Interestingly, one retrospective analysis suggested that very high plasma concentrations of this compound might be associated with worse survival, though this was not statistically significant. mdpi.com

Impact on Signaling Pathways

This compound functions by irreversibly binding to specific mutant forms of the EGFR, including those with the T790M, L858R, and exon 19 deletion mutations. drugbank.compatsnap.com This binding blocks the ATP-binding site of the receptor, thereby inhibiting its kinase activity and preventing the activation of downstream signaling pathways that are crucial for cell proliferation and survival. patsnap.compatsnap.com

The primary signaling cascades inhibited by this compound include:

PI3K/AKT Pathway : This pathway is essential for cell growth and survival. patsnap.compatsnap.com

RAS/RAF/MEK/ERK (MAPK) Pathway : This cascade is critical for cell division and differentiation. patsnap.compatsnap.commdpi.com

By blocking these pathways, this compound effectively disrupts the signals that drive tumor growth. patsnap.com Research has also indicated that this compound treatment can lead to the activation of compensatory signaling pathways, such as the STAT3 and Src-YAP1 pathways, which may contribute to the development of resistance. ijbs.comoncotarget.com Specifically, treatment with this compound has been shown to induce the activation of STAT3. ijbs.comoncotarget.com The signal transducer and activator of transcription 3 (STAT3) is a key downstream molecule of EGFR and plays a significant role in various cellular processes. frontiersin.org

Absorption and Distribution

Following oral administration, this compound is absorbed with a median time to peak plasma concentration (Tmax) of approximately 6 to 7 hours. aacrjournals.orgastrazeneca.canih.gov The absolute bioavailability of this compound is approximately 70%. astrazeneca.canih.goveuropa.eu Food does not have a clinically significant impact on its bioavailability. europa.eucancercareontario.ca

This compound exhibits extensive tissue distribution, with a large mean volume of distribution at steady state of 918 L. drugbank.comnih.govnih.gov This indicates significant penetration into tissues. patsnap.com Plasma protein binding of this compound is high, at approximately 95%. drugbank.compatsnap.com

Half-Life

The terminal half-life of this compound is approximately 48 hours. nih.goveuropa.eunih.gov This relatively long half-life contributes to sustained therapeutic concentrations with once-daily dosing. patsnap.com

Steady-State Accumulation

With once-daily administration, this compound reaches steady-state plasma concentrations in about 15 days. aacrjournals.orgeuropa.eunih.gov At steady state, there is an approximate 3- to 4-fold accumulation of the drug compared to a single dose. nih.govsci-hub.se The ratio of the maximum concentration at steady state (Cmax,ss) to the pre-dose concentration at steady state (Cmin,ss) is about 1.6, indicating that circulating plasma concentrations are maintained within a relatively narrow range over a 24-hour dosing interval. europa.eunih.gov

Interactive Data Tables

Pharmacokinetic Parameters of this compound

Mentioned Compounds

Cerebrospinal Fluid (CSF) Penetration

This compound has demonstrated the ability to cross the blood-brain barrier and penetrate the cerebrospinal fluid (CSF), a critical characteristic for treating central nervous system (CNS) metastases in non-small cell lung cancer (NSCLC). esmo.org

Recent pharmacokinetic analyses have provided specific data on this penetration. In one study, the CSF to free plasma ratio of this compound was found to be approximately 22%, indicating effective CNS penetration. esmo.orgascopubs.orgnih.gov For its active metabolite, AZD5104, the plasma-to-CSF ratio was about 16%, with its concentration in the CSF being around 6% of the plasma concentration. ascopubs.org Another study reported a mean CSF penetration rate of 2.5% (±0.3%). nih.gov

A study involving 13 patients and 25 samples revealed mean CSF and plasma concentrations of this compound to be 14.4 ± 2.8 nM and 555.3 ± 51.5 nM, respectively. nih.gov The median values were 8.1 nM (range, 1.6–56.6 nM) for CSF and 483.3 nM (range, 95.4–1267.0 nM) for plasma. nih.gov This resulted in a median CSF penetration rate of 2.0% (range 0.5–6.9%). nih.gov

Further research has shown that at a higher dose, the CSF-to-free plasma ratio for this compound was approximately 16%. ascopubs.org The ability of this compound to achieve significant exposure in the brain is a key aspect of its clinical efficacy against CNS metastases. researchgate.net

Table 1: this compound and Metabolite CSF Penetration

Metabolism and Excretion Pathways

The metabolism of this compound is primarily conducted in the liver, with the main pathways being oxidation and dealkylation. drugbank.comnih.govastrazeneca.ca In vitro studies have identified cytochrome P450 (CYP) enzymes, predominantly CYP3A4 and CYP3A5, as the major enzymes responsible for its Phase I metabolism. astrazeneca.caeuropa.eu

Two pharmacologically active metabolites, AZ7550 and AZ5104, have been identified in human plasma following oral administration of this compound. drugbank.comastrazeneca.ca These metabolites circulate at approximately 10% of the exposure of the parent compound at steady state. drugbank.comnih.govastrazeneca.ca While AZ7550 has a pharmacological profile similar to this compound, AZ5104 is more potent against both mutant and wild-type Epidermal Growth Factor Receptor (EGFR). drugbank.comastrazeneca.ca The plasma half-life of AZ7550 is longer than that of this compound (72 hours vs. 59 hours). iiarjournals.org

This compound and its metabolites are eliminated through both hepatic and renal routes. nih.gov The majority of a dose is excreted in the feces (68%), with a smaller portion eliminated in the urine (14%). drugbank.comnih.gov Unchanged this compound accounts for only about 2% of the eliminated dose. drugbank.comnih.gov In human plasma, parent this compound constituted 0.8% of the total radioactivity, with the two main metabolites contributing 0.08% and 0.07%. astrazeneca.ca

Table 2: this compound Metabolism and Excretion

Population Pharmacokinetic Analysis

Population pharmacokinetic (PopPK) models have been developed to characterize the pharmacokinetic properties of this compound and its active metabolite AZ5104. nih.govnih.gov These analyses have utilized data from clinical studies involving both healthy volunteers and patients with NSCLC. nih.govnih.gov

A one-compartment model with first-order absorption and elimination has been shown to adequately describe the steady-state pharmacokinetic data of this compound. mdpi.com The PopPK models support dose- and time-independent pharmacokinetics for this compound. ascopubs.org

Key pharmacokinetic parameters estimated from these models include a mean oral clearance (CL/F) of 14.2 to 14.3 L/h and a mean volume of distribution at steady state (V/F) of 986 L. nih.govnih.gov The population-estimated mean half-life of this compound is approximately 48 hours. drugbank.comnih.govnih.gov Following once-daily administration, this compound exhibits an approximate threefold accumulation, reaching steady-state exposures after about 15 days. nih.gov

The interindividual variability (IIV) in clearance and volume of distribution has been reported to be around 40% and 64%, respectively. mdpi.com

Table 3: Population Pharmacokinetic Parameters of this compound

Impact of Covariates on Exposure

Population pharmacokinetic analyses have investigated the influence of various patient characteristics (covariates) on the exposure of this compound. nih.goveuropa.eu Covariates that have been evaluated include body weight, serum albumin, ethnicity, age, sex, smoking status, and markers of hepatic and renal function. nih.goveuropa.euamegroups.org

Among the tested covariates, body weight was identified as having the largest effect on this compound clearance. nih.govnih.govjst.go.jp Specifically, within a body weight range of 43 to 90 kg, the area under the curve at steady state (AUCss) for this compound ranged from -20% to +30% compared to the median body weight of 62 kg. nih.govjst.go.jp For the metabolite AZ5104, the AUCss ranged from -40% to +50% across the same body weight range. nih.gov

Serum albumin and ethnicity were also identified as statistically significant covariates affecting the pharmacokinetics of this compound. nih.govnih.gov However, despite the statistical significance, none of these covariates, including body weight, were found to have a clinically relevant impact on this compound exposure, and no dose adjustments are currently recommended based on these factors. nih.govnih.goveuropa.eu Other factors such as age and sex have not been shown to affect the pharmacokinetics of this compound. amegroups.org

Table 4: Impact of Covariates on this compound Exposure