P12 SEMI-MECHANISTIC MODELLING APPROACH TO ESTIMATE RIFAMPICIN IN VIVO OATP KI USING BIOMARKER COPROPORPHYRIN 1 AND ROSUVASTATIN AS PROBES

Shelby Barnett , Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom
Kayode Ogungbenro , Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom
Karelle Menochet , Investigative ADME, UCB, Slough, United Kingdom
Hong Shen , Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Lawrenceville, NJ
W. Griffith Humphreys , Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Lawrenceville, NJ
Aleksandra Galetin , Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom
Endogenous biomarkers have the potential to be clinically relevant tools for assessing transporter- mediated drug-drug interactions (DDIs). Several endogenous biomarkers have been proposed for the assessment of OATP-mediated DDIs including bilirubin, DHEAS, coproporphyrin bile acids, tetradecanedioate, and hexadecanedioate. In the recent study [1] coproporphyrin 1 (CP1) showed a comparable increase in AUC to rosuvastatin in the presence of a single dose of potent OATP inhibitor rifampicin (4- and 4.8-fold, respectively). The aim of this study was to develop a semi-mechanistic model for CP1 using individual plasma and urine data from 12 subjects to estimate its renal and biliary clearance. In addition, rifampicin and CP1 clinical data were used to estimate rifampicin in vivo OATP Ki with subsequent comparison to in vitro data. Individual plasma rifampicin data and CP1 plasma and urine data in the presence and absence of rifampicin [1] were modelled using nonlinear mixed-effect modelling approach in NONMEM (v7.3). It was assumed that rifampicin only impacted the biliary clearance of CP1 with no change in its renal clearance and CP1 does not undergo enterohepatic circulation. OATP mediated rifampicin interaction with a clinical probe rosuvastatin was also modelled using plasma and urine data obtained in the same subjects as CP1 data. In addition to typical individual parameter estimates, variability in the PK of rifampicin, CP1 and rosuvastatin were estimated. A transit absorption compartment combined with one compartment disposition model, a turn-over model and a two compartment first order absorption and elimination model best described the PK of rifampicin, CP1 and rosuvastatin, respectively. Baseline CP1 plasma concentrations stayed relatively stable across the three occasions investigated, with <25% CV. Modelling of CP1 plasma and urine data +/- rifampicin allowed differentiation of CP1 biliary and renal clearance and identified biliary excretion as the dominant route of CP1 elimination (>85%) under basal conditions. Estimated in vivo OATP Ki corrected for the average fraction unbound in the plasma for rifampicin was 0.14 µM using CP1 interaction data, whereas 0.26 µM was obtained using rosuvastatin. The in vivo rifampicin OATP Ki based on CP1 data was up to 20-fold lower compared to a wide range of in vitro estimates reported in OATP1B1/3 transfected HEK cell with different clinical probes (including rosuvastatin). The findings of the current study, together with marginal inter-individual variability in CP1, confirm its utility as an endogenous biomarker for the identification of potent OATP inhibitors; further studies are required to confirm its application for the assessment of DDI risk associated with medium-weak OATP inhibitors.

[1] Lai Y, Mandlekar S, Shen H, Holenarsipur VK, Langish R, Rajanna P, Murugesan S, Gaud N, Selvam S, Date O, Cheng Y, Shipkova P, Dai J, Humphreys WG, and Marathe P (2016) Coproporphyrins in Plasma and Urine Can Be Appropriate Clinical Biomarkers to Recapitulate Drug-Drug Interactions Mediated by Organic Anion Transporting Polypeptide Inhibition. The Journal of Pharmacology and Experimental Therapeutics 358:397-404.