Cabozantinib exposure-response analyses of efficacy and safety in patients with advanced hepatocellular carcinoma.

Cabozantinib, a multi-kinase inhibitor, is approved in the United States and European Union for treatment of patients with hepatocellular carcinoma following prior sorafenib treatment. In the Phase III CELESTIAL trial, hepatocellular carcinoma patients receiving cabozantinib showed longer overall survival (OS) and progression-free survival (PFS) than those receiving placebo. The approved cabozantinib (Cabometyx®) dose is 60 mg once daily with allowable dose modifications to manage adverse events (AE). Time-to-event Cox proportional hazard exposure-response (ER) models were developed to characterize the relationship between predicted cabozantinib exposure and the likelihood of various efficacy and safety endpoints. The ER models were used to predict hazard ratios (HR) for efficacy and safety endpoints for starting doses of 60, 40, or 20 mg daily. Statistically significant relationships between cabozantinib exposure and efficacy and safety endpoints were observed. For efficacy endpoints, predicted HR were lower for OS and PFS at 40 and 60 mg relative to the 20 mg dose: HR for death (OS) are 0.84 (40 mg) and 0.70 (60 mg); HR for disease progression/death (PFS) are 0.73 (40 mg) and 0.62 (60 mg). For safety endpoints, predicted HR were lower for palmar-plantar erythrodysaesthesia (PPE), diarrhea, and hypertension at 20 or 40 mg relative to the 60 mg dose: HR for PPE are 0.31 (20 mg) and 0.66 (40 mg); HR for diarrhea are 0.61 (20 mg) and 0.86 (40 mg); HR for hypertension are 0.46 (20 mg) and 0.76 (40 mg). The rate of dose modifications was predicted to increase in patients with lower cabozantinib apparent clearance. OS and PFS showed the greatest benefit at the 60 mg dose. However, higher cabozantinib exposure was predicted to increase the likelihood of AE and subsequent dose reductions appeared to decrease these risks.

Ketamine and norketamine stability in whole blood at ambient and 4°C conditions.

A study was implemented to describe the pharmacokinetics (PK) of ketamine (K) and its metabolite norketamine (NK) in critically ill adults. Conducting studies in these subjects is hindered by the immediate need to process and freeze samples obtained in a busy intensive care setting. The ability to store unprocessed samples at room temperature for an extended time period would overcome this barrier. Stability and blood to plasma partitioning of K and NK were investigated in whole blood for up to 120 h at room temperature and 4°C. Whole blood was spiked with K and NK (1000 ng/mL each). Blood samples were aliquoted at different time points (0-120 h), extracted and analyzed using a validated high-performance liquid chromatography tandem mass spectrometry assay. The study demonstrated the stability of both K and NK in whole blood up to 120 h. These in vitro studies suggest that the concentrations of K and NK measured in the PK samples are reliable. The established stability results were successfully employed to investigate K and NK pharmacology studies in critically ill adults.

Cabozantinib exposure-response analysis for the phase 3 CheckMate 9ER trial of nivolumab plus cabozantinib versus sunitinib in first-line advanced renal cell carcinoma.

PURPOSE: In the phase 3 CheckMate 9ER trial, intravenous nivolumab (240 mg every 2 weeks) plus oral cabozantinib (40 mg/day) improved progression-free survival (PFS) versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC). To support cabozantinib dosing with the combination, this exposure-response analysis characterized the relationship of cabozantinib exposure with clinical endpoints. METHODS: Dose modification was allowed with cabozantinib (holds and reductions) to manage adverse events (AEs). The population pharmacokinetics analysis was updated and used to generate individual predicted cabozantinib exposure measures. Kaplan-Meier plots and time-to-event Cox proportional hazard (CPH) exposure-response models characterized the relationship of cabozantinib exposure with PFS, dose modifications, and selected AEs. RESULTS: Kaplan-Meier plots showed no clear difference in PFS across cabozantinib exposure quartiles. Cabozantinib exposure did not significantly affect the hazard of PFS in the CPH base model nor in the final model. In contrast, baseline albumin and nivolumab clearance had a significant effect on PFS. There was no significant relationship between cabozantinib clearance and risk of dose modification, but a significant relationship was identified between cabozantinib exposure and Grade ≥ 1 palmar-plantar-erythrodysesthesia and Grade ≥ 3 diarrhea in the exposure-response analysis. CONCLUSION: To optimize individual cabozantinib exposure, these data support the dose modification strategies in CheckMate 9ER for cabozantinib in patients with advanced RCC when combined with nivolumab.

Updated Population Pharmacokinetic Model of Cabozantinib Integrating Various Cancer Types Including Hepatocellular Carcinoma.

An integrated population pharmacokinetic (PPK) model was used to evaluate the effects of liver dysfunction on the pharmacokinetics (PK) of cabozantinib in patients with hepatocellular carcinoma and to determine whether clinical dosage adjustment may be necessary in this population. An integrated PPK model previously developed in healthy volunteers and patients with various cancer types was updated with cabozantinib concentration data from hepatocellular carcinoma patients in phase 2 and 3 studies (total 2023; hepatocellular carcinoma 489 patients). Covariate effects of cancer type including hepatocellular carcinoma population and liver dysfunction per the National Cancer Institute Organ Dysfunction Working Group criteria were evaluated (normal 1425; mild liver dysfunction 558; moderate/severe liver dysfunction 15/1 patients). With hepatocellular carcinoma patients, PK parameter estimates and covariate effects were similar to the previous PPK model (2 compartments with first- and zero-order absorption and first-order elimination). Only medullary thyroid cancer had appreciable PK differences from healthy volunteers. PK parameter estimates were similar with and without addition of liver dysfunction covariates. Patients with mild liver dysfunction were predicted to have minimal differences in apparent clearance of cabozantinib relative to patients with normal liver function. Therefore, no initial cabozantinib dosage adjustment is recommended for cancer patients with mild liver dysfunction. The small sample size for patients with moderate and severe liver dysfunction limited dosing recommendations in these subpopulations. The results from this PPK analysis were different from those of the single-dose hepatic impairment study in healthy volunteers and more reflective of exposure in cancer patients following daily cabozantinib dosing.