Uncovering the Effect of Disease State on OATP1B Activity: Learnings from Protein Expression Data and PK Analyses of Transporter Substrates | Dr. Manthena Varma
Attendees will be educated on the need to understand effect of disease state on transport activity and PK of drugs. Emerging modeling approach to predict PK in NASH/Hepatic impairment population will be discussed. Enable model-informed drug development - understanding disease effects.
The liver and kidney play central role in the pharmacokinetics (PK) of drugs and new molecular entities (NMEs). Several solute carriers (SLCs) including OATP1B1/1B3/2B1, NTCP, OAT2 and OCT1 and efflux pumps including MRPs, Pgp, BCRP are highly expressed on the sinusoidal/canalicular membranes and have the potential to dictate hepatic clearance. Similarly, renal transporters (OCT2/OATs/MATEs) are important in the renal elimination of drugs and metabolites. Disease-states such as renal- and hepatic-impairment is associated with multiple pathophysiological and biological changes including variable and non-uniform reduction in metabolic/transporter activity, altered plasma protein binding, hepatic blood flow and portal-systemic shunting, etc. and may lead to altered blood or plasma clearance of drugs eliminated by liver. This presentation will discuss the disease-induced changes in expression and function of OATP1B and other drug transporters along with drug metabolizing enzymes, and the implications on the clinical pharmacokinetics in patient populations. Emphasis will be placed on the proteomics- and/or PBPK-informed translation to predict PK changes in organ impairment.