Development of a Physiologically Based Pharmacokinetic Model for Raltegravir and Prediction of its Interactions with Rifampicin

Conference: AAPS
Software: GastroPlus®
Division: Simulations Plus


Raltegravir (MK-0518; Isentress™), the HIV-1 integrase strand transfer inhibitor is approved for HIV-1 therapy in combination with other antiretroviral agents. The primary route for raltegravir (“RAL”) elimination is glucuronidation, mainly catalyzed by the isoenzyme UGT1A1 with minor contributions from UGT1A3 and UGT1A9. Rifampicin (“RIF”) is included in the preferred regimen for the treatment of tuberculosis (TB) infections, which are common in the HIV patient population. RIF has been shown to induce several drug metabolizing enzymes and transporters and hence is likely to affect the pharmacokinetics (PK) of RAL. The goal of this work was to develop a physiologically based pharmacokinetic (PBPK) model of RAL accounting for all relevant mechanisms for its disposition following oral administration. The effect of RIF administration on RAL PK was predicted and compared with observed drug interactions. The model can be used for quantitative prediction of drug interactions with co-administration of UGT1A1 inducers and inhibitors.

By Joyce S. Macwan, Michael B. Bolger, Viera Lukacova, Grazyna Fraczkiewicz, Walter S. Woltosz

2016 AAPS Annual Meeting & Exposition in Denver, Colorado,  November 13-17, 2016