Vertical Integration of Pharmacogenetics in Population PK/PD Modeling: A Novel Information Theoretic Method

Abstract

To critically evaluate an information-theoretic method for identifying gene–environmental interactions (GEI) associated with pharmacokinetic (PK), pharmacodynamic (PD), and clinical outcomes from genome-wide pharmacogenetic data. Our approach, which is built on the K-way interaction information (KWII) metric, was challenged with simulated data and clinical PK/PD data sets from the International Warfarin Pharmacogenetics Consortium (IWPC) and a gemcitabine clinical trial. The KWII efficiently identified both novel and known interactions for warfarin and gemcitabine. Interactions between herbal supplementation and VKORC1 genotype were associated with warfarin response. For gemcitabine-associated neutropenia, combination treatment with carboplatin and cytidine deaminase (CDA) 208G→A genotypes were identified as risk factors. Gemcitabine disposition was associated with drug metabolism–transporter interactions between deoxycytidine kinase (DCK) and the equilibrative nucleoside transporter (ENT). This novel approach is effective for detecting GEI involved in drug exposure and response and could enable integration of genome-wide pharmacogenetic data into the population PK/PD analysis paradigm.