Pharmacokinetic and Pharmacodynamic Model for Drug Induced Transient Transaminitis
Ricardo Nalda-Molina, Amelia Ramon-Lopez, BelÚn Valenzuela, Bernardo Miguel-Lillo, Maria Jose Duart, Arturo Soto-Matos
University of Miguel Hernandez and Pharmamar S.A.
Objectives: Reversible transient elevations in transaminases have been observed after the administration of several drugs. A previously developed semimechanistic pharmacokinetic and pharmacodynamic (PKPD) model was applied to evaluate the time course of alanine aminotransferase (ALT) elevation after drug X administration following different dosing schedules 
Methods: The drug was administered to 475 patients as monotherapy (dose range: 1x-100x mg) as 1- or 24-h infusions on days 1, 8, and 15 every 28 days; 3- or 24-h infusions on days 1 and 15 every 28 days; 1-h infusions daily for five consecutive days every 21 days; or, 3- or 24-h infusions every 14 days. Sequential PKPD modeling was performed with covariate evaluation on model parameters. A precursor-dependent PKPD model described the temporal relationship between ALT elevation and drug concentrations. The transfer process of ALT from hepatocytes to plasma was stimulated by drug concentration through a log-linear model with a mixture model. A feedback loop on the production rate of ALT in the hepatocytes was driven by the ALT plasma concentration. Posterior predictive check on grade ≥ 3 toxicity was used as model validation technique. Simulations were undertaken to assess the influence of the dose and schedule on grade ≥ 3 toxicity.
Results: Baseline ALT is 45.7% of the upper limit of normality (ULN), and the half life of ALT is 12 days. In approximately 12.5% of subjects, the drug effect was about 10-fold higher than that estimated in the rest of the population. Model evaluation showed that the predicted incidence of grade ≥ 3 toxicity was similar to the observed values. Simulations showed that severity of ALT elevation was dose dependent, but no differences in the toxicity were found across the dosing schedule evaluated and the infusion duration.
Conclusions: A previously developed semimechanistic PKPD model manages to describe the transient transaminitis following drug X treatment, including the tolerance development.
 Fetterly GJ, et al. Semimechanistic pharmacokinetic/pharmacodynamic model for hepatoprotective effect of dexamethasone on transient transaminitis after trabectedin (ET-743) treatment. Cancer Chemother Pharmacol. 2007 Oct 9; [Epub ahead of print].