P83 ASSESSING THE OATP1B1- AND OATP1B3-MEDIATED DRUG-DRUG INTERACTION POTENTIAL OF MAMMALIAN TARGET OF RAPAMYCIN (MTOR) INHIBITOR EVEROLIMUS

Taleah Farasyn , Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK
Khondoker Alam , Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK
Alexandra Crowe , University of Oklahoma Health Sciences Center, Oklahoma City, OK
Sibylle Neuhoff , Simcyp Ltd (a Certara Company), Sheffield, United Kingdom
Oliver Hatley , Simcyp Ltd (a Certara Company), Sheffield, United Kingdom
Xueying Wang , Center for Computational Biology and Bioinformatics, Indiana Univeristy School of Medicine, Indianapolis, IN
Pengyue Zhang , Center for Computational Biology and Bioinformatics, Indiana Univeristy School of Medicine, Indianapolis, IN
Kai Ding , Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
Lang Li , Center for Computational Biology and Bioinformatics, Indiana Univeristy School of Medicine, Indianapolis, IN
Wei Yue , Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK
Purpose Inhibition of hepatic organic anion transporting polypeptides (OATP) 1B1 and OATP1B3 due to drug-drug interactions (DDIs) often leads to increased systemic exposure of OATP substrates statins and statin-induced myopathy. Cases of severe rhabdomyolysis have been reported in cancer patients concurrently using 10 mg everolimus (EVER) and statins. Current studies were designed to test our hypothesis that EVER has the potential to cause OATP1B1- and OATP1B3-mediated DDIs using static R- and dynamic physiologically based pharmacokinetic (PBPK) models and pharmacoepidemiological studies using the US FDA Adverse Events Reporting System (FAERS).

Methods The half-maximal inhibitory concentration (IC50)/inhibition constant (Ki) values of EVER against OATP1B1 and OATP1B3 were determined in human embryonic kidney (HEK) 293-OATP1B1 and HEK293-OATP1B3 stable cell lines in scenarios with or without EVER pre-incubation and with or without 4% bovine serum albumin (BSA) in the HBSS uptake buffer. [3H]-E217G and [3H]-CCK-8 were used as the substrates for OATP1B1 and OATP1B3, respectively. In the presence of BSA, the IC50,unbound was calculated as the product of measured IC50,total and the unbound fraction of EVER in the uptake buffer (fu,inc). The area under the blood concentration-time curve (AUC) ratio [AUCR=1+(fu × Iin,max/IC50)] was calculated based on the US FDA decision tree. A PBPK model of EVER was developed as a perpetrator file. Simcyp simulator was utilized to simulate the OATP1B1- and OATP1B3-mediated DDI of EVER against pravastatin. The FAERS was used for pharmacoepidemiological studies to test our DDI hypothesis that concurrent usage of EVER with metabolically stable statins, pitavastatin, rosuvastatin and pravastatin, leads to a higher risk for myopathy than statins alone.

Results Preincubation with EVER (0.2-10 µM) significantly decreased OATP1B1- and OATP1B3-mediated transport in both scenarios with and without BSA. The fu,inc of 10 µM EVER in 4% BSA-containing HBSS uptake buffer was determined to be 0.22, consistent with reported unbound fraction (0.26) of EVER in human plasma. In the absence of BSA, preincubation with EVER significantly decreased the measured apparent IC50,unbound values against OATP1B1 (0.51 vs. 0.19 µM) and OATP1B3 (0.52 vs. 0.22 µM). In the presence of BSA, preincubation with EVER also significantly decreased the calculated IC50,unbound values against OATP1B1 (0.19 vs. 0.07 µM) and OATP1B3 (0.32 vs. 0.15 µM). Under all experimental conditions, the R-values for EVER against OATP1B1 and OATP1B3 were greater than the US FDA cut-off values of 1.25, ranging 1.38-3.79. Using the calculated IC50,unbound determined in the presence of BSA after EVER preincubation, simulation of multiple doses of EVER (10 mg once daily) against a single dose of pravastatin (40 mg) yielded AUCR and maximum blood concentration (Cmax) ratios of 1.25 and 1.47, respectively. Pharmacoepidemiological studies indicate that concurrent usage of EVER with statins leads to a significantly increased myopathy risk (9.2 vs. 16%, relative risk=1.94, p=0.05).

Conclusions Model prediction and pharmacoepidemiological studies support that EVER has potential to cause OATP-mediated DDIs. The current study highlighted the importance of including an inhibitor pre-incubation step and taking protein binding into consideration in the in vitro transport studies when establishing the in vitro-in vivo correlation of OATP inhibition.