Combined translational pharmacometrics approach to support the design and conduct of the first‐in‐human study of DWP16001

Abstract

AimsThe objective of this study was to characterize the pharmacokinetics (PK)/pharmacodynamics (PD) of DWP16001, a novel sodium–glucose cotransporter 2 inhibitor, and predict efficacious doses for the first‐in‐human study using various translational approaches.MethodsA mechanistic PK/PD model was developed for DWP16001 using nonlinear mixed‐effect modelling to describe animal PK/PD properties. Using allometry and in silico physiologically based equations, human PK parameters were predicted. Human PD parameters were scaled by applying interspecies difference and in vitro drug‐specific factors. Human parameters were refined using early clinical data. Model‐predicted PK and PD outcomes were compared to observations before and after parameter refinement.ResultsThe PK/PD model of DWP16001 was developed using a 2‐compartment model with first‐order absorption and indirect response. Efficacious doses of 0.3 and 2 mg of DWP16001 were predicted using human half‐maximal inhibitory concentration values translated from Zucker Diabetic Fatty rats and normal rats, respectively. After parameter refinement, doses of 0.2 and 1 mg were predicted to be efficacious for each disease model, which improved the prediction results to within a 1.2‐fold difference between the model prediction and observation.ConclusionsThis study predicted efficacious human doses of DWP16001 using population PK/PD modelling and a combined translational pharmacometrics approach. Early clinical data allowed the methods used to translate in vitro and in vivo findings to clinical PK/PD values for DWP16001 to be optimized. This study has shown that a refinement step can be readily applied to improve model prediction and further support the study design and conduct of a first‐in‐human study.