Simultaneous Estimation of fm and FG Values Directly from Clinical Drug-Drug Interaction Study Data

During drug development, the design, interpretation and risk assessment of drug-drug interaction (DDI) are generally performed with physiologically-based pharmacokinetic (PBPK) modelling. Critical parameters are the hepatic metabolic fraction (fm) and intestinal availability (FG) which are commonly informed by clinical data. In this study, two methods for the simultaneous estimation of these parameters are proposed which utilize the distinctive changes in substrate’s plasma concentration profiles in response to inhibition of intestinal and hepatic enzymes. The two-dimensional DDI (2D-DDI) method estimates the fm and FG values directly from the ratios of area-under-curve (AUCR) and maximum concentration (CmaxR), while the population PBPK method utilizes the full concentration–time data of a substrate without or with an inhibitor. The utility of both methods was demonstrated for a broad range of > 50,000 virtual and six actual CYP3A substrates. The 2D-DDI method is fast, reliable, and does not require a priori PBPK model development. The population PBPK method can estimate the population parameters and inter-individual variabilities of fm and FG and is applicable to more complex DDIs (e.g., multiple pathways/dynamic inhibitor concentration–time profiles) without the need for IV data. Like other approaches, both methods show an increasing uncertainty for substrates with high hepatic extraction and sensitivity to the assumed degree of enzyme inhibition. While both methods were evaluated for CYP3A substrates, the methodology equally applies to other enzymes. Additionally, this study provides guidance for clinical DDI study design to facilitate robust DDI extrapolation necessary to inform drug labels on concomitant medications in lieu of clinical trials.