Clearance Prediction of HIV Protease Inhibitors in Man: Role of Hepatic Uptake

Abstract

The aim of this work was to explore the contribution of the organic anion transporting polypeptide-1B (OATP1B) drug transporters in the hepatic clearance (Cl) of all marketed HIV protease inhibitors (PI) in humans. HIV PI uptake rates in OATP1B1/1B3-transfected Chinese hamster ovary cells were converted to uptake Cl values in human hepatocytes via a relative activity factor, which was determined by comparing uptake of known substrates between OATP1B1/3-transfected cells and human hepatocytes. Metabolic Cl values were determined in human liver microsomes. In vivo hepatic Cl values were calculated either by combining drug uptake and metabolism or based on one of these individual Cl processes and compared with published in vivo hepatic Cl values. Excellent in vitro-in vivo correlation (R(2) = 0.85) was observed when only uptake Cl values were used, but not when only metabolic Cl was used (R(2) = 0.40). The correlation did not improve when both processes were taken into account (R(2) = 0.85). PBPK models confirmed the remarkable sensitivity of predicted exposure to hepatic drug uptake, indicating a key role for OATP1B1/3 in hepatic disposition of several HIV PI in man. This may contribute to the interindividual variability in systemic and hepatic exposure to these drugs in the clinic.

Hepatic Clearance Prediction of Nine Human Immunodeficiency Virus Protease Inhibitors in Rat

“…Finally, when we compared the relative contribution of hepatic uptake transport in the overall clearance for each individual HIV PI in rat and human (see companion paper De Bruyn et al) 1 , a good correlation (R 2 = 0.74) between both species was observed (Fig. 3).…”

“…As reported in the companion paper by De Bruyn et al, clearance predictions with in vitro models derived from human liver tissue allow estimating a safe first-in-human dose to initiate clinical trials. 1 In vivo drug clearance prediction in rats on the contrary, as applied in the present paper, is useful from different perspectives. First of all, accurate knowledge of the pharmacokinetic behavior of drug candidates in preclinical species (as compared with man) supports optimal design of toxicity studies with sensible use of animals.…”

“…Therefore, in vitro uptake data in suspended rat hepatocytes and metabolic data in rat liver microsomes were extrapolated to the hepatic in vivo clearance for all HIV PIs and compared with experimentally determined in vivo blood clearance in rats. The same approach was applied for this series of compounds in man (see companion paper De Bruyn et al) 1 , providing unique data sets for detailed cross-species comparison of pharmacokinetic behavior of these compounds. At the same time, possible species-specific aspects of clearance prediction algorithms (IVIVE) may be identified.…”

MRP2 Inhibition by HIV Protease Inhibitors in Rat and Human Hepatocytes: A Quantitative Confocal Microscopy Study

“…Moreover, their hepatic disposition constitutes a complex interplay between uptake, metabolism and efflux. These drugs are taken up by the Oatp/OATP family, metabolized by CYP3A enzymes and excreted by the efflux transporters Mdr1/MDR1 and Mrp2/MRP2 (Huisman et al, 2002;Liu and Unadkat, 2013;De Bruyn et al, 2016) .…”

Transport-Metabolism Interplay of Atazanavir in Rat Hepatocytes

“…The current study aims to extend application of the Km-method-from calculating the Kp u,u during our previous experiments with verapamil (passive diffusion; Cyp3a1/2)-to atazanavir (active uptake/efflux; Cyp3a1/2) (Nicolaï et al, 2015). Thus, the HIV protease inhibitor atazanavir (ATV) was selected as a model compound since its elimination involves P450-mediated drug metabolism (hCYP3A4/5; rCyp3a1/2) and drug transport by sinusoidal ATP-binding cassette transporters (ABCC1; MRP1) as well as SLC-transporters (SLCO1B1/3) (Swainston Harrison and Scott, 2005;Kis et al, 2010;Wempe and Anderson, 2011;De Bruyn et al, 2015b). This will enable exploration of the interplay between active uptake/efflux transport and intracellular metabolism, which determine the intracellular unbound drug exposure.…”