title: Population Pharmacokinetics of Ceritinib in Adult Patients With Tumors Characterized by Genetic Abnormalities in Anaplastic Lymphoma Kinase.
abstract: 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.
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Vanessa Q
authors.initials: VQ
authors.lastname: Passos
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Pai-Hsi
authors.initials: PH
authors.lastname: Huang
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Yvonne Y
authors.initials: YY
authors.lastname: Lau
mesh_terms: D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy; D006801:Humans; D008297:Male; D008954:Models, Biological; D009154:Mutation; D011743:Pyrimidines / Q000493:pharmacokinetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D013450:Sulfones / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D013450:Sulfones; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C586847:ceritinib
keywords: NSCLC; anaplastic lymphoma kinase; ceritinib; population pharmacokinetic analysis