Population Pharmacokinetics of a Novel Proton Pump Inhibitor, Drug Y, in Healthy Volunteers
SoJeong Yi, In-Jin Jang, MD, PhD, Kyung-Sang Yu, MD, PhD
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
Objectives: A new proton pump inhibitor (Drug Y) is under clinical development for management of gastroesophageal reflux disease. The aim of this study was to characterize pharmacokinetics of Drug Y by population approach following single and multiple oral doses in healthy volunteers.
Methods: In the first-in-human study of Drug Y, healthy volunteers were administered orally single or multiple dose of Drug Y (single dose, 30 to 800 mg; multiple dose, 100 mg once daily for 7 days). The effect of food on the pharmacokinetics was evaluated following single dose of Drug Y 600 mg. Nonlinear mixed effects modeling methodology was implemented in the population pharmacokinetic analysis using NONMEM® (version 6.2). After the Drug Y model was developed, food effets on drug absorption were investigated as categorical covariates. The first-order conditional estimation (FOCE) method was used to fit the plasma concentration-time data. Standard goodness-of-fit diagnostics and posterior predictive checks were used to evaluate the adequacy of the model fit and predictions.
Results: A two compartment model with first-order absorption, absorption lag time, and first-order elimination characterized the pharmacokinetics in 1175 concentrations of Drug Y from 63 healthy volunteers. Population mean estimates (standard error) of oral clearance (CL/F), central volume of distribution (V/F), inter-compartment clearance (Q), and peripheral volume of distribution (V2) were 473 (47.6) L/h, 99.1 (19.8) L, 269 (47.5) L/h, and 5930 (1470) L, respectively. Diagnostic plots results stratified by dose suggest that pharmacokinetic parameters are dose-independent within the dose range tested (30 to 800 mg). At fed status, relative oral bioavailability, absorption rate constant (ka), and absorption lag time were increased compared to those at fast status. Most of the data were within 5th and 95th percentile in visual predictive check, which indicated that the model describes the pharmacokinetics of Drug Y adequately.
Conclusions: The pharmacokinetics of Drug Y was characterized adequately by a two-compartment model with first-order elimination, and food intake affect absorption of Drug Y. This model can be used for modeling and simulation and to predict Drug Y exposure in patients.