Integrated application of in vitro models for hepatic drug disposition: exploration of intracellular unbound drug exposure

Drug development is an extremely expensive undertaking due to lengthy and costly clinical trials. Unfortunately, numerous drug candidates with poor pharmacokinetics (i.e. short half-life, high clearance), unfavorable efficacy or unanticipated toxicity still fail in clinical development phases. To reduce attrition rates during late stage drug development, pharmaceutical companies have designed nonclinical evaluation programs which aim to predict pharmacokinetics, efficacy and toxicity prior to first in human dosing. Identification of unfavorable pharmacokinetic drug properties linked to in vivo drug absorption, distribution, metabolism and excretion (ADME) processes, is a cornerstone of nonclinical drug assessment. As the liver constitutes one of the major organs for drug elimination, ADME researchers have been aiming to optimize and implement reliable laboratory models which allow the investigation of hepatic drug eliminating pathways (i.e. drug metabolism, drug transport). Nevertheless, integration of pharmacokinetic information obtained in multiple in vitro models on a myriad of drug eliminating pathways, comprises a major hurdle in the in vitro to in vivo extrapolation (IVIVE) process. Combined with the broad population variability of drug disposition pathways due to age-related changes, disease state, obesity, ethnic differences, genetic polymorphisms and drug-drug interactions, pharmacokinetic predictions may appear impossible. Hence, this doctoral research sought to improve future IVIVE by presenting new insights into the regulation of intrahepatic free drug concentrations and intersystem extrapolation of in vitro pharmacokinetic data. Combination of high-resolution kinetic data from complementary in vitro models proved to be a doorway to the next dimension of pharmacokinetics, namely intracellular drug exposure and distribution. Furthermore, the importance of drug transporters for hepatic vincristine elimination was investigated and projected onto the most vulnerable of patient populations: children.nrpages: 198status: publishe