Pharmacokinetic and pharmacodynamic (PKPD) modeling, together with clinical trial simulation is recognized as one of the emerging technologies that can contribute to improve the drug development process. Over the last years, the field of PK/PD modeling has clearly moved from using empirical functions to characterize data to the utilization of mechanism-based PK/PD models in order to provide better quantitation and prediction of the drug disposition and dynamic, which reflect the essential underlying rules of pharmacology and physiology. The integration of PKPD data and the utilization of mechanism-based PK/PD models are efficient means to generate quantitative information, which not only guides the clinical trial design, but also provides the necessary information to implement a knowledge-based decision making process on drug development strategies. In this way, a quantitative risk-benefit assessment can be obtained via determining the probability of success of a new clinical trial, given certain experimental design.

An example of the implementation of mechanism-based PKPD modeling and simulation techniques to design the first-time-in-man (FTIM) and the proof-of-concept (POC) study of a new erythropoietin receptor agonist (ERA) will be presented. The final objective is to present an strategy to optimize the FTIM/POC study design using in vitro and preclinical data without the support of any human information of the new ERA. Human PK was initially estimated using interspecies allometric scaling on data collected in rat, rabbit, dogs, monkeys. A published PK/PD model derived from healthy volunteers treated with erythropoietin was integrated with the available in vitro and preclinical data.¹ The integrated PK/PD model was used to optimize the design the FTIM and to determine the probability of success of a POC study. The outcome of the simulations was compared to the data collected during the clinical studies.

Reference:
1. Krzyzanski W, Jusko WJ, Wacholtz MC, Minton N, Cheung WK. Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after multiple subcutaneous doses in healthy subjects. Eur J Pharm Sci 2005; 26: 295-306.