Hyangki Choi (1), Yookhwan Noh (1), Jong-Lyul Ghim (1), Kumagai Yuji (2), Jae-Gook Shin (1)
(1) Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea, (2) Department of Clinical Pharmacology, Kitasato University East Hospital, Kanagawa, Japan
Objectives: To develop population PKPD models describing the relationship between moxifloxacin and corrected QT interval prolongation in Korean and Japanese.
Methods: Population pharmacokinetic (PK) and pharmacodynamic (PD) modeling of moxifloxacin was developed from pooled data from Korean male (n=10), female (n=10) and Japanese male (n=10), female (n=9) volunteers. The PK modeling used plasma concentrations of the moxifloxacin and the PD modeling used QT interval prolongation adjusted for circadian variation. The models were developed using NONMEM and evaluated via visual predictive check (VPC).
Results: Data were fitted by 2-compartment model with first-order absorption elimination. There was no statistically significant covariate for each model parameter. The typical point estimates of PK were ke ,elimination rate constant = 0.03 h(-1), V2 ,volume of central compartment = 96.9L, and V3 ,volume of peripheral compartment = 302L. The typical point estimates of PD were Emax ,maximum difference of corrected QT interval from baseline = 30msec , EC50 ,median effective concentration = 5.81 ug/mL, and BASE value ,predose corrected QT interval = 397msec.
Conclusions: The final PK-PD model of moxifloxacin adequately described the observed QT interval prolongation in healthy Korean and Japanese subjects. The model developed in this study could be applied in guiding further clinical development of moxifloxacin in Korea and Japanese population.
References:
[1] Vladimir Piotrovsky. Pharmacokinetic-Pharmacodynamic Modeling in the Data Analysis and Interpretation of Drug-induced QT/QTc Prolongation. AAPS Journal (2005) 7(3): 609-624.
Reference: PAGE 23 () Abstr 3201 [www.page-meeting.org/?abstract=3201]
Poster: Drug/Disease modeling - Safety