Population Pharmacokinetic Model Development for Long-Acting Intramuscular Injection of Drug X in Healthy Subjects
Yu Kyong Kim (1), Euitae Kim (2), Jae-Yong Chung (3), Seonghae Yoon (3)
(1) Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea, (2) Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam. Republic of Korea, (3) Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of Korea
Objectives: Drug X, a new long-acting intramuscular (IM) injection formulation for the chronic disease, is currently under development in hope to improve patient compliance by extending the dosing frequency compared to that of the currently available once daily oral formulation. Population pharmacokinetic (PK) analysis was carried out for characterisation of drug X after IM injection in healthy subjects.
Methods: A nonlinear mixed effect modelling for population PK analysis was performed with 608 concentrations from 20 healthy subjects, who received 35, 70 or 140 mg of single IM injection of drug X. The first-order conditional estimation with interaction estimation method implemented in NONMEM (version 7.3.0) [1] was used, followed by standard goodness-of-fit diagnostics and visual predictive check for qualification evaluation of the model predictions.
Results: One-compartment with two independent first-order absorptions with lag time and combined error model best described the PK of drug X. The typical population estimates (intrasubject variabilities shown as coefficient of variation, CV%) of the apparent clearance (CL/F), volume of distribution (Vd/F), the primary (Ka1) and secondary (Ka2) absorption rate constants, and the lag time of secondary absorption were 9.01 L/h (21.8%), 1270 L (27.2%), 0.0023 h-1(17.0%), 0.0113 h-1 (47.6%) and 352 h (fixed to 0.0%), respectively.
Conclusions: A population PK model of drug X was developed and such model predictions may contribute towards selection of dose for the phase II clinical study.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2015. Icon Development Solutions, Gaithersburg, Maryland, USA.
