A Bayesian approach for population pharmacokinetic modeling of alcohol in Japanese Subjects
Asuka Nemoto (1), Matsuura Masaaki (1), Kazue Yamaoka(1)
Teikyo University School of Public Health
Objectives: To explore significant covariates for the population pharmacokinetic analysis of alcohol by incorporating external data using a Bayesian method, and estimate effects of the covariates.
Methods: Blood alcohol concentration (BAC) data that were previously obtained from 34 Japanese subjects with limited sampling times [1] were re-analyzed. Characteristics of the data were that the concentrations were obtained from only the early part of the time-concentration curve. The data were analyzed using a Markov chain Monte Carlo Bayesian estimation with NONMEM 7.3. Informative priors were obtained from the external study [2]. Namely, a 1-compartment model with Michaelis-Menten elimination, which includes subject characteristics (body weight, sex and the genotype for ADH1B) as covariates, was fitted to our data. Age and the genotype of ALDH2 were investigated in an additional covariate modeling. Uninformative priors were used for scale factors of age on population mean pharmacokinetic (PM-PK) parameters and for the change in the PM-PK parameter values for the genetic variant of ALDH2. Predicted concentration was simulated using estimated values for PM-PK parameters and the area under the time-BAC curve (AUC) was calculated.
Results: The typical value for the apparent volume of distribution was estimated to be 49.3L in subjects with ALDH2*1/*1 (the wild-type) and was 20.4 L smaller in subjects with ALDH2*1/*2 (the genetic variant). The AUC for the subjects with ALDH2*1/*2 was calculated 1.34 times higher than the subjects with ALDH2*1/*1. Age was shown to be positively correlated with the absorption rate and shown to be negatively correlated with the apparent volume of distribution.
Conclusions: A population pharmacokinetic model for alcohol was updated. A Bayesian approach allowed interpretation of significant covariates relationships, even if the current dataset is not informative about all parameters. This is the first study reporting an estimate of the effect of the ALDH2 genotype in a PPK model.
References:
[1] Nemoto A, Terada M, Hayashi T, Hamada C, Matoba R. Population pharmacokinetic analysis of alcohol concentration after beer consumption in fasted Japanese subjects. Int J Clin Pharmacol Toxicol. 2016;5:225-230
[2] Seng KY, Limenta LMG, Heng D, Lee EJD. Population pharmacokinetics and pharmacogenetics of alcohol in Chinese and Indians in Singapore. J Clin Pharm Ther. 2013;38:141–149
