Steven Lacy

Pharmacokinetic (PK) drug interaction studies of cabozantinib: Effect of CYP3A inducer rifampin and inhibitor ketoconazole on cabozantinib plasma PK and effect of cabozantinib on CYP2C8 probe substrate rosiglitazone plasma PK

Cabozantinib is a small‐molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. In vitro data indicate that (1) cytochrome P450 (CYP) 3A4 is the primary CYP isoenzyme involved in the metabolism of cabozantinib, and (2) CYP2C8 is the CYP isoenzyme most potently inhibited by cabozantinib with potential for in vivo inhibition at clinically relevant plasma exposures. Pharmacokinetic (PK) drug–drug interactions (DDIs) were evaluated clinically between cabozantinib and (1) a CYP3A inducer (rifampin) in healthy volunteers, (2) a CYP3A inhibitor (ketoconazole) in healthy volunteers, and (3) a CYP2C8 substrate (rosiglitazone) in patients with solid tumors. Compared with cabozantinib given alone, coadministration with rifampin resulted in a 4.3‐fold higher plasma clearance (CL/F) of cabozantinib and a 77% decrease in cabozantinib plasma AUC0–inf, whereas coadministration with ketoconazole decreased cabozantinib CL/F by 29% and increased cabozantinib AUC0–inf by 38%. Chronic coadministration with cabozantinib resulted in no significant effect on rosiglitazone plasma Cmax, AUC0–24, or AUC0–inf. In summary, chronic use of strong CYP3A inducers and inhibitors should be avoided when cabozantinib is administered, and cabozantinib at clinically relevant exposures is not anticipated to markedly affect the PK of concomitant medications via CYP enzyme inhibition.

Metabolism and Disposition of Cabozantinib in Healthy Male Volunteers and Pharmacologic Characterization of Its Major Metabolites

Metabolism and excretion of cabozantinib, an oral inhibitor of receptor tyrosine kinases, was studied in 8 healthy male volunteers after a single oral dose of 175 mg cabozantinib l-malate containing 14C-cabozantinib (100 µCi/subject). Total mean radioactivity recovery within 48 days was 81.09%; radioactivity was eliminated in feces (53.79%) and urine (27.29%). Cabozantinib was extensively metabolized with 17 individual metabolites identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in plasma, urine, and feces. Relative plasma radioactivity exposures (analyte AUC0-t/total AUC0-t for cabozantinib+major metabolites) were 27.2, 25.2, 32.3, 7, and 6% for cabozantinib and major metabolites monohydroxy sulfate (EXEL-1646), 6-desmethyl amide cleavage product sulfate (EXEL-1644), N-oxide (EXEL-5162), and amide cleavage product (EXEL-5366), respectively. Comparable relative plasma exposures determined by LC-MS/MS analysis were 32.4, 13.8, 45.9, 4.9, and 3.1%, respectively. These major metabolites each possess in vitro inhibition potencies ≤1/10th of parent cabozantinib against the targeted kinases MET, RET, and VEGFR2/KDR. In an in vitro cytochrome P450 (CYP) panel, cabozantinib and EXEL-1644 both inhibited most potently CYP2C8 (Kiapp = 4.6 and 1.1 µM, respectively). In an in vitro drug transporter panel, cabozantinib inhibited most potently MATE1 and MATE2-K (IC50 = 5.94 and 3.12 µM, respectively) and was a MRP2 substrate; EXEL-1644 inhibited most potently OAT1, OAT3, OATP1B1, MATE1, and OATP1B3 (IC50 = 4.3, 4.3, 6.1, 16.7, and 20.6 µM, respectively) and was a substrate of MRP2, OAT3, OATP1B1, OATP1B3, and possibly P-gp. Therefore, cabozantinib appears to be the primary pharmacologically active circulating analyte, whereas both cabozantinib and EXEL-1644 may represent potential for drug-drug interactions.

Evaluation of the effect of food and gastric pH on the single-dose pharmacokinetics of cabozantinib in healthy adult subjects

Cabozantinib is a small molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Cabozantinib exhibits a pH‐dependent solubility profile in vitro. Two phase 1 clinical pharmacology studies were conducted in healthy subjects to evaluate whether factors that may affect cabozantinib solubility and gastric pH could alter cabozantinib bioavailability: a food effect study (study 1) and a drug–drug interaction (DDI) study with the proton pump inhibitor (PPI) esomeprazole (study 2). Following a high‐fat meal (study 1), cabozantinib Cmax and AUC were increased (40.5% and 57%, respectively), and the median tmax was delayed by 2 hours. Cabozantinib should thus not be taken with food (patients should not eat for at least 2 hours before and at least 1 hour after administration). In the DDI study (study 2), the 90% confidence intervals (CIs) around the ratio of least‐squares means of cabozantinib with esomeprazole versus cabozantinib alone for AUC0–inf were within the 80%–125% limits; the upper 90%CI for Cmax was 125.1%. Because of the low apparent risk of a DDI, concomitant use of PPIs or weaker gastric pH‐altering agents with cabozantinib is not contraindicated.

Pharmacokinetics of cabozantinib tablet and capsule formulations in healthy adults.

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.

Effect of Renal and Hepatic Impairment on the Pharmacokinetics of Cabozantinib

Cabozantinib is a tyrosine kinase inhibitor approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Two clinical pharmacology studies were conducted to characterize single‐dose pharmacokinetics (PK) of cabozantinib in renally or hepatically impaired subjects. Study 1 enrolled 10 subjects, each with mild or moderate impairment of renal function; 12 healthy subjects were matched to the moderate group for age, sex, and body mass index (BMI). Study 2 enrolled 8 males each with mild or moderate hepatic impairment; 10 healthy males were matched to the moderate group for age, BMI, and ethnicity. All subjects received one 60 mg cabozantinib oral capsule dose followed by PK sampling over 21 days. Plasma concentration and protein binding were determined by liquid chromatography tandem mass spectrometry and equilibrium dialysis, respectively. PK parameters were computed using noncompartmental methods. Geometric least squared mean (LSM) ratios for plasma cabozantinib AUC0‐∞ for impaired to normal organ function cohorts were (1) approximately 30% and 6% higher in subjects with mild and moderate renal impairment, respectively, and (2) approximately 81% and 63% higher in subjects with mild and moderate hepatic impairment, respectively. The percentage of unbound drug was slightly higher in both moderately impaired cohorts. No deaths or discontinuations due to adverse events occurred in either study. Cabozantinib should be used with caution in subjects with mild or moderate renal impairment. Subjects with mild or moderate hepatic impairment administered cabozantinib should be monitored closely for potential treatment‐emergent drug toxicity that may necessitate a dose hold or reduction.

Clinical Pharmacokinetics and Pharmacodynamics of Cabozantinib

Cabozantinib inhibits receptor tyrosine kinases involved in tumor angiogenesis and metastasis. The capsule formulation (Cometriq®) is approved for the treatment of progressive metastatic medullary thyroid cancer at a 140-mg free base equivalent dose. The tablet formulation (Cabometyx™, 60-mg free base equivalent dose) is approved for the treatment of renal cell carcinoma following anti-angiogenic therapy. Cabozantinib displays a long terminal plasma half-life (~120 h) and accumulates ~fivefold by day 15 following daily dosing based on area under the plasma concentration-time curve (AUC). Four identified inactive metabolites constitute >65 % of total cabozantinib-related AUC following a single 140-mg free base equivalent dose. Cabozantinib AUC was increased by 63–81 % or 7–30 % in subjects with mild/moderate hepatic or renal impairment, respectively; by 34–38 % with concomitant cytochrome P450 3A4 inhibitor ketoconazole; and by 57 % following a high-fat meal. Cabozantinib AUC was decreased by 76–77 % with concomitant cytochrome P450 3A4 inducer rifampin, and was unaffected following administration of proton pump inhibitor esomeprazole. Cabozantinib is a potent in vitro inhibitor of P-glycoprotein, and multidrug and toxin extrusion transporter 1 and 2-K, and is a substrate for multidrug resistance protein 2. No clinically significant covariates affecting cabozantinib pharmacokinetics were identified in a population pharmacokinetic analysis. Patients with medullary thyroid cancer with low model-predicted apparent clearance were more likely to dose hold/reduce cabozantinib early, and had a lower average dose through day 85. However, longitudinal tumor modeling suggests that cabozantinib dose reductions from 140 to 60 mg/day did not markedly reduce tumor growth inhibition in medullary thyroid cancer patients.

Population pharmacokinetic/pharmacodynamic modeling of tumor growth kinetics in medullary thyroid cancer patients receiving cabozantinib.

Nonlinear mixed effects models were developed to describe the relationship between cabozantinib exposure and target lesion tumor size in a phase III study of patients with progressive metastatic medullary thyroid cancer. These models used cabozantinib exposure estimates from a previously published population pharmacokinetic model for cabozantinib in cancer patients that was updated with data from healthy-volunteer studies. Semi-mechanistic models predict well for tumors with static, increasing, or decreasing growth over time, but they were not considered adequate for predicting tumor sizes in medullary thyroid cancer patients, among whom an early reduction in tumor size was followed by a late stabilization phase in those receiving cabozantinib. A semi-empirical tumor model adequately predicted tumor profiles that were assumed to have a net growth rate constant that was piecewise continuous in the regions of 0–110 and 110–280 days. Emax models relating average concentration to average change in tumor size predicted that an average concentration of 79 and 58 ng/ml, respectively, would yield 50% of the maximum possible tumor reduction during the first 110 days of dosing and during the subsequent 110–280 days of dosing. Simulations of tumor responses showed that daily doses of 60 mg or greater are expected to provide a similar tumor reduction. Both model evaluation of observed data and simulation results suggested that the two protocol-defined cabozantinib dose reductions from 140 to 100 mg/day and from 100 to 60 mg/day are not projected to result in a marked reduction in target lesion regrowth.

Population exposure–response analysis of cabozantinib efficacy and safety endpoints in patients with renal cell carcinoma

BackgroundIn the phase III METEOR trial, tyrosine kinase inhibitor cabozantinib significantly improved progression-free survival (PFS), objective response rate (ORR), and overall survival compared to everolimus in patients with advanced renal cell carcinoma (RCC) who had received prior VEGFR inhibitor therapy. In METEOR, RCC patients started at a daily 60-mg cabozantinib tablet (Cabometyx™) dose but could reduce to 40- or 20-mg to achieve a tolerated exposure.Objectives and methodsExposure–response (ER) models were developed to characterize the relationship between cabozantinib at clinically relevant exposures in RCC patients enrolled in METEOR and efficacy (PFS and tumor response) and safety endpoints.ResultsCompared to the average steady-state cabozantinib concentration for a 60-mg dose, exposures at simulated 40- and 20-mg starting doses were predicted to result in higher risk of disease progression or death [hazard ratios (HRs) of 1.10 and 1.39, respectively], lower maximal median reduction in tumor size (− 11.9 vs − 9.1 and − 4.5%, respectively), and lower ORR (19.1 vs 15.6 and 8.7%, respectively). The 60-mg exposure was also associated with higher risk for selected adverse events (AEs) palmar-plantar erythrodysesthesia syndrome (grade ≥ 1), fatigue/asthenia (grade ≥ 3), diarrhea (grade ≥ 3), and hypertension (predicted HRs of 2.21, 2.01, 1.78, and 1.85, respectively) relative to the predicted average steady-state cabozantinib concentration for a 20-mg starting dose.ConclusionER modeling predicted that cabozantinib exposures in RCC patients at the 60-mg starting dose would provide greater anti-tumor activity relative to exposures at simulated 40- and 20-mg starting doses that were associated with decreased rates of clinically relevant AEs.

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

PurposeAn integrated population pharmacokinetic (popPK) model was developed to describe the pharmacokinetics (PK) of tyrosine kinase inhibitor cabozantinib in healthy volunteers (HVs) and patients with various cancer types and to identify any differences in cabozantinib PK across these populations.MethodsPlasma concentration data used to develop the popPK model were obtained from nine clinical trials (8072 concentrations from 1534 HVs or patients) of cabozantinib in HVs and patients with renal cell carcinoma (RCC), medullary thyroid carcinoma (MTC), glioblastoma multiforme, castration-resistant prostate cancer, or other advanced malignancies.ResultsPK data across studies were adequately characterized by a two-compartment disposition model with dual first- and zero-order absorption processes and first-order elimination. Baseline demographic covariates (age, weight, gender, race, and cancer type) were generally predicted to have a small-to-moderate impact on apparent clearance (CL/F). However, MTC cancer type did show an approximately 93% higher CL/F relative to HVs following chronic dosing, resulting in approximately 40–50% lower predicted steady-state cabozantinib plasma concentrations.ConclusionThis popPK analysis showed cabozantinib CL/F values to be higher for patients with MTC and may account for the higher dosage required in this patient population (140-mg) to achieve plasma exposures comparable to those in patients with RCC and other tumor types administered a 60-mg cabozantinib tablet dose. Possible factors that may underlie the higher cabozantinib clearance observed in MTC patients are discussed.