Talazoparib Formulation Bridging in Cancer Patients-Challenges and the Critical Role of Model-Informed Drug Development in Approval Despite Failed Bioequivalence

Abstract

Talazoparib is a poly(ADP-ribose) polymerase inhibitor approved for the treatment of breast and prostate cancer. Commercialization of a soft gelatin capsule (SGC) formulation developed post-approval required a bioequivalence (BE) and food effect (FE) study to bridge SGC with the initial commercial hard capsule (HC) formulation. Study execution and meeting BE criteria are challenging due to high variability in C_max, potentially higher C_max for SGC based on dissolution data, and the need to perform BE/FE assessment at steady state in cancer patients. Model-informed drug development (MIDD) was used to facilitate an efficient/feasible study design. Semi-mechanistic pharmacokinetic (PK)/pharmacodynamic (PD) modeling and simulations showed that AUC, instead of C_max, drove hematologic events, the main side effects of talazoparib. This supported a BE study powered for AUC equivalence only. Population PK simulation showed that following a 28-day treatment in the first period, 14 days in subsequent periods is sufficient for steady-state BE/FE assessments. Study results showed AUC met BE criteria while C_max was 37% higher for SGC relative to HC, which was deemed not clinically significant based on the PK/PD model. FE on SGC formulation was consistent with FE on HC formulation reported previously. The safety profile of the two formulations was generally consistent with the known safety profile. The totality of data (AUC equivalence, lack of impact of C_max on safety, observed safety data) supported bridging of the two formulations although C_max failed to meet BE criteria. MIDD was critical in study design optimization and supported approval of the SGC formulation. Trial Registration: ClinicalTrials.gov Identifier: NCT04672460.

Keywords: MIDD; PARP inhibitor; PK/PD modeling; bioequivalence; cancer.

FIGURE 1

Comparison of the dissolution profile of the talazoparib soft gel capsule with hard shell capsule batches in 0.01M HCl with paddles at 75 rpm.^a HCl, hydrochloric acid; rpm, revolutions per minute. ^aThe dissolution media for the hard shell capsules include 0.2% sodium dodecyl sulfate to aid the dispersion of the drug from the excipients.

FIGURE 2

Study schema. D1, Day 1; D21, Day 21; D28, Day 28; P1, period 1; P2, period 2; P3, period 3; PK, pharmacokinetic; QD, once daily.

FIGURE 3

Simulated PK and PD profiles after treatment with talazoparib 1 mg once daily (a) PK profile, (b) PD profile, hemoglobin count, (c) PD profile, neutrophil count, (d) PD profile, platelet count. ^aPatient 1 represents a population‐typical talazoparib PK profile (reference); patient 2 has 22% higher C_max and the same AUC (at steady state vs patient 1); patient 3 has a 52% higher C_max and the same AUC (at steady state vs patient 1); patient 4 has a 17% higher C_max and 25% higher AUC (at steady state vs patient 1). ^bAdapted from figures in previous publication [10].