Ibrutinib

Synthetic Routes and Reaction Conditions: The synthesis of ibrutinib involves several key steps:

Condensation and Methoxidation: 4-benzyloxybenzoyl chloride is reacted with malononitrile and dimethyl sulfate to produce 4-benzyloxyphenyl (methoxy)vinylidenedicyanomethane.

Pyrazole Cyclization: The intermediate is then subjected to pyrazole cyclization with 1-(3R-hydrazino-1-piperidino)-2-propylene-1-ketone to form 1-[(3R)-[3-(4-benzyloxyphenyl)-4-nitrile-5-amino-1H-pyrazole]-1-piperidino]-2-propylene-1-ketone.

Pyrimidine Cyclization: Finally, pyrimidine cyclization occurs to yield this compound

Industrial Production Methods: Industrial production of this compound typically involves large-scale synthesis using the aforementioned steps, with optimization for yield and purity. The process may include additional purification steps such as recrystallization and chromatography to ensure the final product meets pharmaceutical standards .

Types of Reactions:

Oxidation: this compound can undergo oxidation reactions, particularly at the phenoxyphenyl moiety.

Reduction: Reduction reactions may target the nitrile group present in the molecule.

Substitution: Nucleophilic substitution reactions can occur at the piperidine ring.

Common Reagents and Conditions:

Oxidation: Common oxidizing agents include hydrogen peroxide and potassium permanganate.

Reduction: Reducing agents such as lithium aluminum hydride and sodium borohydride are used.

Substitution: Conditions often involve the use of strong nucleophiles like sodium hydride or potassium tert-butoxide

Major Products: The major products formed from these reactions depend on the specific conditions and reagents used. For example, oxidation may yield hydroxylated derivatives, while reduction can produce amine derivatives .

Chronic Lymphocytic Leukemia (CLL)

Ibrutinib has been extensively studied and approved for use in both frontline and relapsed/refractory settings for CLL:

• Frontline Therapy : The RESONATE-2 trial demonstrated that this compound monotherapy significantly improved progression-free survival (PFS) compared to chlorambucil, with a median PFS of 8.9 years versus 1.3 years .
• Combination Therapy : The E1912 trial showed that the combination of this compound and rituximab (IR) provided superior outcomes compared to fludarabine, cyclophosphamide, and rituximab (FCR), particularly in patients with both mutated and unmutated immunoglobulin heavy chain variable region (IGHV) genes .

Mantle Cell Lymphoma (MCL)

This compound is also approved for MCL, particularly in patients with relapsed or refractory disease:

• First-Line Treatment : The SHINE trial revealed that this compound combined with bendamustine-rituximab significantly reduced the risk of disease progression or death by 25% compared to placebo plus bendamustine-rituximab in older patients .
• Long-Term Efficacy : Data from the trial indicated a median PFS of 6.7 years for patients receiving the this compound combination regimen .

Case Study 1: this compound in Elderly Patients with CLL

A cohort study involving elderly patients with untreated CLL showcased that those receiving this compound experienced significant improvements in overall survival (OS) and quality of life compared to traditional therapies. Many patients reported sustained remission over extended follow-up periods, underscoring the drug's long-term efficacy .

Case Study 2: Combination Therapy in MCL

In a clinical setting, a patient diagnosed with MCL received a combination therapy regimen involving this compound and rituximab after failing previous treatments. The patient achieved a complete response (CR) within six months, demonstrating the effectiveness of this approach in managing resistant forms of MCL .

Safety Profile

This compound is generally well-tolerated; however, it is associated with specific adverse effects including:

• Lymphocytosis : A common occurrence during treatment, often resolving over time .
• Cardiovascular Events : Increased risk of atrial fibrillation has been noted, necessitating monitoring during therapy .
• Gastrointestinal Issues : Diarrhea and nausea are frequently reported but manageable with supportive care.

Comparative Efficacy

The following table summarizes key findings from pivotal clinical trials comparing this compound to standard therapies:

Ibrutinib exerts its effects by irreversibly binding to the cysteine-481 residue in the active site of Bruton’s tyrosine kinase. This binding inhibits the kinase activity of BTK, thereby blocking the B-cell receptor signaling pathway. This inhibition leads to reduced proliferation and survival of malignant B cells . Additionally, this compound affects other kinases such as C-terminal Src kinases, contributing to its therapeutic effects .

Efficacy Comparison with Similar Compounds

Ibrutinib vs. Acalabrutinib (Second-Generation BTK Inhibitor)

• PFS and OS: In the ELEVATE-RR trial, acalabrutinib demonstrated non-inferior PFS (HR = 1.00, 95% CI: 0.79–1.27) compared to this compound in relapsed/refractory CLL, with a median PFS of 38.4 months for both . However, this compound showed a higher overall response rate (ORR) in some real-world studies (88.5% vs. ~81% for acalabrutinib) .
• Key Trials: ELEVATE-RR: Non-inferiority of acalabrutinib with fewer cardiovascular adverse events . ALPINE Trial (Indirect Comparison): this compound underperformed in cross-trial matching-adjusted indirect comparisons (MAIC), though methodological limitations apply .

This compound vs. Zanubrutinib (Second-Generation BTK Inhibitor)

• Preclinical Data : Zanubrutinib induced G1 cell cycle arrest in HER2-positive breast cancer models but required higher concentrations than this compound to achieve similar effects .
• Clinical Efficacy: No head-to-head trials exist, but zanubrutinib showed comparable BTK occupancy and ORR in early-phase studies .

This compound vs. Chemo-Immunotherapy Regimens

• Bendamustine-Rituximab (BR) : Adjusted HRs from RESONATE and HELIOS trials favored this compound (PFS HR = 0.13; OS HR = 0.45) .
• Obinutuzumab + Chlorambucil : Matching-adjusted indirect comparisons showed this compound’s superior PFS (HR = 0.45, 95% CI: 0.28–0.71) in older/unfit CLL patients .

This compound vs. Anti-CD20 Monotherapy (Ofatumumab)

• RESONATE Trial : this compound reduced risk of progression/death by 79% (PFS HR = 0.21) and improved OS (HR = 0.29) in relapsed/refractory CLL .

Table 1: Key Efficacy Outcomes Across Trials

Cardiovascular Toxicity

• This compound : Higher incidence of atrial fibrillation (6–16%) and hypertension (24%) in long-term follow-up .
• Acalabrutinib : Lower rates of atrial fibrillation (3.2% vs. 13.3% with this compound) and hypertension in ELEVATE-RR .

Infections and Bleeding

• Both this compound and acalabrutinib have similar infection rates (~50–60%), but this compound is associated with more grade ≥3 bleeding events (4% vs. 2%) .

Table 2: Adverse Event Rates in Key Trials

Pharmacokinetics and Drug Interactions

• Plasma Protein Binding : Both this compound and acalabrutinib exhibit >95% binding, limiting free drug availability .
• CYP Interactions : this compound inhibits CYP2C9 (IC₅₀ = 9.7 µM), posing higher drug-drug interaction risks than acalabrutinib .
• Half-Life : this compound’s half-life (4–6 hours) is shorter than acalabrutinib’s (~8 hours), requiring once-daily dosing .

Resistance Mechanisms

Both this compound and acalabrutinib share resistance pathways, including mutations in BTK (C481S) and PLCγ2. Upregulation of miR-494/495 drives resistance by suppressing PTEN, enhancing PI3K/AKT signaling .

Real-World Effectiveness

• First-Line CLL : Adjusted HRs for this compound vs. chlorambucil showed 4.3-fold PFS improvement (HR = 0.23) and 2.5-fold OS benefit (HR = 0.40) .
• Relapsed/Refractory CLL : Real-world cohorts confirmed 4.8-fold PFS (HR = 0.21) and 3.4-fold OS (HR = 0.29) advantages over physician’s choice regimens .

Ibrutinib is a potent, irreversible inhibitor of Bruton's tyrosine kinase (BTK), primarily used in the treatment of B-cell malignancies such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Its biological activity is characterized by its mechanism of action, pharmacokinetics, and clinical efficacy, which are crucial for understanding its therapeutic potential and optimizing treatment regimens.

This compound exerts its effects by covalently binding to the cysteine residue (Cys481) in the BTK enzyme, leading to the inhibition of B-cell receptor (BCR) signaling pathways. This inhibition results in decreased survival and proliferation of malignant B-cells. Additionally, this compound affects other signaling pathways, including those involving NF-κB, which further contributes to its anti-tumor activity .

Pharmacokinetics and Dose Optimization

Clinical studies have demonstrated that this compound maintains significant biological activity even at reduced doses. A pilot study indicated that after an initial cycle at 420 mg/day, doses could be safely reduced to 280 mg/day or even 140 mg/day without losing BTK occupancy or downstream signaling efficacy. Specifically, BTK occupancy remained above 95% at these lower doses, suggesting effective therapeutic outcomes while potentially reducing adverse effects .

Table: Pharmacokinetic Data Summary

Clinical Efficacy

This compound has been shown to significantly improve progression-free survival (PFS) in patients with CLL compared to traditional therapies. The RESONATE-2 trial established its role as a frontline therapy, demonstrating superior outcomes compared to chlorambucil . Furthermore, studies combining this compound with rituximab have indicated enhanced remission rates and lower residual disease levels in patients .

Case Study: this compound in CLL Treatment

A notable case involved a patient treated with this compound who initially presented with high-risk CLL. Following treatment initiation at 420 mg/day, the patient achieved a complete response within six months. Subsequent dose adjustments to 140 mg/day maintained disease control with minimal side effects. This case exemplifies the potential for dose optimization while retaining therapeutic efficacy .

Adverse Effects and Management

While generally well-tolerated, this compound is associated with adverse effects such as atrial fibrillation and bleeding risks. Monitoring and managing these side effects are critical components of treatment protocols. Studies suggest that lower doses may mitigate these risks without compromising efficacy .