Population pharmacokinetic analysis of pirtobrutinib, a non-covalent BTK inhibitor, in patients with hematological malignancies from the Phase 1/2 BRUIN study
Abstract
Purpose: This study aimed to characterize the pharmacokinetics (PK) of pirtobrutinib, a highly selective and noncovalent Bruton's tyrosine kinase (BTK) inhibitor, in adult patients with hematological malignancies using data from the Phase 1/2 BRUIN study (NCT03740529).
Methods: Pirtobrutinib was administered as monotherapy at doses ranging from 25 to 300 mg once daily (QD). PK samples were collected at multiple time points, including intensive sampling on Cycle (C) 1 Day (D) 1, C1D8, C2D1, and C4D1 for Phase 1 dose-escalation, and sparse sampling on C1D8 and C4D1 for Phase 1 dose-expansion and Phase 2. Population PK (popPK) analysis used nonlinear mixed-effects modeling.
Results: Overall, 4487 evaluable pirtobrutinib concentrations obtained from 595 patients were included in the popPK analysis. Pirtobrutinib PK was well characterized by a 2-compartment model with linear clearance and 4-transit compartments for absorption. The mean elimination half-life was estimated to be 18.8 h. At the recommended Phase 2 dose (200 mg QD), the steady-state mean maximum drug concentration was 6460ng/mL, the mean minimum was 2260ng/mL, and the mean area under the concentration-time curve was 91300ng*h/mL. Pirtobrutinib disposition was significantly affected by body weight, renal function, and serum albumin, but not by formulation, cancer type, age, sex, race, ethnicity, or mild hepatic impairment.
Conclusion: With the proposed starting dose of 200 mg QD, most patients (96%) were expected to…
How strong is the evidence?
Evidence Hub reads this as a clinical trial, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 595 participants or records.
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