Translational pharmacokinetic–pharmacodynamic modelling; application to cardiovascular safety data for PF-00821385, a novel HIV agent

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • While animal toxicology is routinely used for safety screening of compounds prior to their being tested in man, there is very little in the literature on the quantitative translation of cardiovascular drug effects from animal to man. WHAT THIS STUDY ADDS • This study compares pharmacokinetic–pharmacodynamic analysis of dog and human effects of PF-00821385 on heart rate. • This paper considers how quantitative translational knowledge of drug effects in dogs may be used to optimize future human studies. AIM To assess the translation of pharmacokinetic–pharmacodynamic (PK–PD) relationships for heart rate effects of PF-00821385 in dog and man. METHODS Cardiovascular telemetric parameters and concentration data were available for animals receiving active doses (0.5–120 mg kg−1, n= 4) or vehicle. PF-00821385 was administered to 24 volunteers and pharmacokinetic and vital signs data were collected. PK–PD models were fitted using nonlinear mixed effects. RESULTS Compartmental models with linear absorption and clearance were used to describe pharmacokinetic disposition in animal and man. Diurnal variation in heart and pulse rate was best described with a single cosine function in both dog and man. Canine and human heart rate change were described by a linear model with free drug slope 1.76 bpm µM−1[95% confidence interval (CI) 1.17, 2.35] in the dog and 0.76 bpm µM−1 (95% CI 0.54, 1.14) in man. CONCLUSIONS The preclinical translational of concentration–response has been described and the potential for further interspecies extrapolation and optimization of clinical trial design is addressed.