SeungHwan Lee, Seonghae Yoon, Jangsoo Yoon, Jaeseong Oh, Kyung-Sang Yu, In-Jin Jang
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
Objectives: CKD-516 is a newly developed vascular disrupting agent and its active metabolite, S-516 has a potent cytotoxicity against cancer cells. The aim of this study was to develop a population pharmacokinetic model of intravenous CKD-516 in patients with advanced solid tumor.
Methods: CKD-516 concentration-time data were obtained from two independent phase I studies. Subjects of the first study received CKD-516 intravenously once-weekly for 3 weeks and plasma samples for pharmacokinetic analysis were taken for 24 hours after the first dose. Subjects of the second study received twice-weekly for 3 weeks and plasma samples were taken for 24 hours after the first and last doses. Population pharmacokinetic model was developed using NONMEM®, version 7.2.
Results: A total of 205 concentrations of CKD-516 and 346 concentrations of S-516 from 44 subjects were included in population analysis. Pharmacokinetics of CKD-516 and S-516 was best described using a two-compartment model with an additional metabolite compartment. In covariate analysis, dose group and body surface area (BSA) had a significant effect on rate constant of formation (k13) and clearance (CLM) of S-516, respectively. The population mean estimate of central volume (V1), peripheral volume (V2), clearance (CL) and inter-compartmental clearance (Q) of CKD-516 was 11.8 L, 146 L, 61.1 L/h and 25.8 L/h, respectively. The value of k13, CLM and BSA effect on CLM of S-516 was 0.0775 /h or 0.122 /h (only in subjects with 5.0mg/m2/day dose once-weekly), 0.294 and -1.18, respectively. Most of the data were within 5th and 9th percentile in visual predictive check (VPC), which indicated that the model had acceptable predictive performance for CKD-516 and S-516 pharmacokinetics.
Conclusions: A two-compartment model an additional metabolite compartment adequately characterized the pharmacokinetics of CKD-516 and S-516. Application of the population pharmacokinetic model may help decision makings in clinical development of CKD-516.
Reference: PAGE 24 (2015) Abstr 3451 [www.page-meeting.org/?abstract=3451]
Poster: Drug/Disease modeling - Oncology