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

Abstract

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 microM(-1)[95% confidence interval (CI) 1.17, 2.35] in the dog and 0.76 bpm microM(-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.

Figure 1

A visual predictive check (VPC) of the canine pharmacokinetic–pharmacodynamic model's ability to predict the heart rate data. Open circles are the observed data points; the solid grey line represents the 50th quantile of the simulated data, while the short broken black lines represent the 95% prediction interval obtained from the simulations

Figure 3

A visual predictive check (VPC) of the pharmacokinetic–pharmacodynamic model's ability to predict the pulse rate data. Open circles are the observed data points; the solid grey line represents the 50th quantile of the simulated data, while the short broken black lines represent the 95% prediction interval obtained from the simulations. The solid black line represents the 50th quantile of the simulated human data using the slope of drug effect from the canine model

Figure 2

A visual predictive check (VPC) of the human pharmacokinetic model's ability to predict the concentration data. Open circles are the observed data points; the solid grey line represents the 50th quantile of the simulated data, while the short broken black lines represent the 95% prediction interval obtained from the simulations

Figure 4

Observed heart/pulse rate in dogs (open inverted triangle) and humans (closed square) with increasing free concentration. The lines compare the predicted mean rate of change for dogs (short broken line) and humans (solid line)

Figure 5

The difference in maximum and resting heart rate as a function of resting heart rate. H, D and R represent resting heart rates for human, dog and rat, respectively, as predicted by the allometric equations