Population Pharmacokinetics of Ceritinib in Adult Patients With Tumors Characterized by Genetic Abnormalities in Anaplastic Lymphoma Kinase.

Ceritinib is a second-generation selective and potent oral anaplastic lymphoma kinase (ALK) inhibitor approved for ALK-positive advanced non-small cell lung cancer previously treated with crizotinib. Population pharmacokinetic (PK) analysis was performed to describe the PK of ceritinib and was used to evaluate the covariate effects on systemic exposure at its label dose (750 mg orally once daily). Ceritinib concentration-time data from 4 clinical studies were described by a 1-compartment model with delayed first-order absorption and time-dependent elimination. The apparent clearance at steady state (CL/Fss ) was determined to increase with body weight and albumin but decrease with an increase in alanine aminotransferase. Japanese ethnicity appeared to significantly influence the apparent fractional turnover rate of the inhibited metabolic enzyme (kout ). No dose adjustment was necessary in patients with lower body weight or with preexisting mild hepatic impairment. The ceritinib steady-state exposure (AUCss ) at 750 mg increased by 8% (90% prediction interval [PI], 2-16) in non-Japanese Asians and 31% (90%PI, 17-44) in Japanese patients compared with that in white patients. Other covariates including sex, age, baseline Eastern Cooperative Oncology Group performance status, baseline total bilirubin, baseline estimated glomerular filtration rate, prior crizotinib treatment, and concomitant use of proton pump inhibitors had no statistically significant effect on ceritinib PK parameters. In conclusion, the nonlinear PK of ceritinib was described using a population-based approach in patients with ALK-positive tumors. None of the covariates assessed in this study were considered clinically relevant and therefore do not warrant dose adjustment.