Pharmacokinetics of cabozantinib tablet and capsule formulations in healthy adults

Abstract

Cabozantinib capsules (COMETRIQ) are approved for the treatment of patients with progressive metastatic medullary thyroid cancer. Cabozantinib tablets are investigational drug products considered to be potentially preferred pharmaceutical dosing forms. Two phase I open-label single-dose studies in healthy individuals were carried out to characterize the plasma pharmacokinetics of cabozantinib capsule and tablet formulations: a two-way crossover bioequivalence study (n=77) comparing the tablet formulation and the marketed capsule formulation at the approved 140 mg dose and a dose-proportionality study (n=21 per treatment arm) evaluating the 20, 40, and 60 mg tablet strengths. In the bioequivalence study, plasma exposure [area under the plasma concentration-time curve (AUC0-t and AUC0-inf)] values were similar (<10% difference) for both formulations and the 90% confidence intervals (CIs) around the ratio of geometric least-squares means (GLSM) were within the accepted bioequivalence limits of 80-125%. However, the GLSM for Cmax was 19% higher for the tablet formulation and the upper 90% CI for the ratio of GLSM (131.65%) was beyond the 80-125% range. Thus, the tablet and capsule formulations failed to fulfill the bioequivalence study acceptance criteria. In the dose-proportionality study, single doses of the 20, 40, and 60 mg cabozantinib tablet strengths showed dose-proportional increases where the 95% CIs for the slopes of the ln-transformed Cmax, AUC0-t, and AUC0-inf values versus ln-transformed cabozantinib dose included the value of 1. These findings indicate that cabozantinib plasma exposures increased proportionally with increasing cabozantinib dose over the 20-60 mg tablet strength dose range.

A population pharmacokinetic model of cabozantinib in healthy volunteers and patients with various cancer types

“…The popPK analysis was conducted using data from nine clinical studies of cabozantinib including two phase I studies in HVs [7], a phase I study in cancer patients with advanced malignances [8], phase II studies in patients with GB [18] and CRPC [19, 20], and phase III studies in patients with RCC [14], MTC [9], or CRPC [15]. The results of most of these studies have been previously published; and a summary of the study designs, dosages, and PK sampling schemes is presented in Table 1.…”

“…(Reference)DesignPatient populationCabozantinib dosePlanned pharmacokinetic samplingXL184-001 [8]Phase 1, nonrandomized, open-label FIH studyMixed malignancies140- or 200-mgDays 1 and 19: pre-dose, 0.5, 1, 2, 4, 8, and 24 hDay 5: pre-dose and 4 hDays 15 and 29: pre-doseXL184-010 [7]Phase 1, crossover BE study of tablet and capsuleHealthy volunteer140-mgPre-dose, 0.5, 1,2,3, 4, 5, 6, 8, 10, 12, 14, 24, 48, 72, 120, 168, 240, 288, 336, 408, and 504 hXL184-020 [7]Phase 1, PK of tabletHealthy volunteer20-, 40-, 60-mgPre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 48, 72, 120, 168, 240, 288, 336, 408, and 504 hXL184-201 [18]Phase 2, multicenter, open labelProgressive glioblastoma multiforme140-mg QDEach Cycle 28 daysCycle 1: pre-dose, and 4 h on Days 1 and 15Cycle 2: pre-dose and 4 h on Days 29 and 43Cycle 3 and beyond: pre-dose on day 1XL184-203 [19, 20]Phase 2, randomized discontinuation studyCastration-resistant prostate cancerRDT: 100-mg QDNRE: 40- or 100-mg QDRDT: pre-dose after “even” weeks after week 12 lead-in, or early termination or adverse eventNRE; pre-dose week 1 day 1; pre-dose end of week 3 and 6, 12, 18, and 24, unscheduled, early termination or adverse eventXL184-301 [9]Phase 3, randomized, double-blind, placebo-controlledMetastatic medullary thyroid cancer140-mg QDCycle 1, day 1: pre-dose and 2, 4, and 6 hCycle 2, day 29: pre-dose and 2, 4, and 6 hXL184-306 [NCT01522443]Phase 3, randomized, double-blind, controlled versus prednisoneCastration-resistant prostate cancer60-mg QDWeek 1 day 1, Week 4 day 1Week 7 day 1, Week 13 day 1XL184-307 [15]Phase 3, randomized, double-blind, controlled versus prednisoneCastration-resistant prostate cancer60-mg QDEnd of Week 3 and End of Week 12XL184-308 […”

“…Structural models evaluated were one- and two-compartment disposition models with first-order elimination, first-order absorption, and absorption lag time. The previous reports indicated that the concentration–time profile showed multiple peaks suggesting enterohepatic recirculation or multiple absorption sites [7, 21]; therefore, other models were considered such as dual lagged first-order absorption models or transit compartment models with increasing number of transit compartments.…”

“…The cabozantinib tablet formulation (Cabometyx) and capsule formulation (Cometriq) were not bioequivalent following a single 140-mg dose in HVs [7]; the geometric least-squares mean (GLSM) for maximal plasma concentration ( C max ) was 19% higher for the tablet formulation and the upper 90% confidence interval for the GLSM ratio for C max (131.65%) slightly exceeded the 125% bioequivalence acceptance limit. However, the GLSM values for tablet and capsule formulations were similar (< 10% difference) for both area under the plasma concentration–time curve (AUC 0− t and AUC 0−∞ ) measures, and the 90% CIs were 100–115% around the GLSM ratios.…”

Cabozantinib for the treatment of renal cell carcinoma

“…Tablets (CABOMETYX; Exelixis, Inc.) and capsules (COMETRIQ; Exelixis, Inc.) are not bioequivalent, nor interchangeable. Following a single 140-mg dose, a 19% increase in the C max of the tablet formulation compared to the capsule formulation was observed; the difference in the AUC was less than 10% [30]. …”