A Pharmacokinetic Modeling Approach to Predict the Contribution of Active Metabolites to Human Efficacious Dose

Abstract

A preclinical drug candidate, MRK-1 (Merck candidate drug parent compound), was found to elicit tumor regression in a mouse xenograft model. Analysis of samples from these studies revealed significant levels of two circulating metabolites, whose identities were confirmed by comparison with authentic standards using liquid chromatography-tandem mass spectrometry. These metabolites were found to have an in vitro potency similar to that of MRK-1 against the pharmacological target and were therefore thought to contribute to the observed efficacy. To predict this contribution in humans, a pharmacokinetic (PK) modeling approach was developed. At the mouse efficacious dose, the areas under the plasma concentration time curves (AUCs) of the active metabolites were normalized by their in vitro potency compared with MRK-1. These normalized metabolite AUCs were added to that of MRK-1 to yield a composite efficacious unbound AUC, expressed as "parent drug equivalents," which was used as the target AUC for predictions of the human efficacious dose. In vitro and preclinical PK studies afforded predictions of the PK of MRK-1 and the two active metabolites in human as well as the relative pathway flux to each metabolite. These were used to construct a PK model

Pharmacological Optimization for Successful Traumatic Brain Injury Drug Development

“…This study suggests that the juvenile piglet may serve as an appropriate model for multi-species drug development depending on the specific CYP isoform involved in drug elimination. 48 Prediction of human PK is highly uncertain when the mechanism behind interspecies differences is not understood. No one species behaves similar to human in all aspects of drug disposition.…”

“…Prediction of human dose typically assumes that the pharmacological activity is only from the parent drug molecule without the more complex contribution from an active circulating metabolite. 47,48 Apart from PK assessment in the efficacy species, it is equally important to ensure good PK properties leading to good systemic exposure in the species used for safety assessment. For small molecules, it is recommended to have two species (one rodent and one non-rodent) for safety assessment.…”