P. Duan,1 P. Zhao,2 L. Zhang2; 1Commissioner’s Fellow, Food and Drug Administration, Silver Spring, MD, 2Office of Clinical Pharmacology, Office of Translational Sciences, CDER, Food and Drug Administration, Silver Spring, MD

BACKGROUND: The disposition of statins varies and involves both metabolizing enzymes and transporters. This makes the DDI assessment complex and a need to have better predictive models. PBPK models have been successful in the prediction of complex DDIs. For the first time, we developed PBPK models for pitavastatin and atorvastatin to predict DDIs involving these 2 statins as victim drugs and understand key determinants of the system.
METHODS: A PBPK model was developed by using SIMCYP V13 for each “substrate” incorporating the contribution from both CYP enzymes and transporters. For perpetrator drugs, SIMCYP built-in or published models were used.
RESULTS: PBPK models described the pharmacokinetics of pitavastatin and atorvastatin, and recovered the exposure change due to OATP1B1 polymorphism or clinical DDIs with several OATP1B1 and CYP inhibitors (Table). However, DDIs with rifampicin and cyclosporine were under-predicted using the “reported” OATP1B1 Ki values. Sensitivity analysis revealed that lowering OATP1B1 Ki by 10-fold improved the prediction, indicating the possible discrepancy between in vitro Ki and “in vivo” Ki.
CONCLUSION: OATP1B1 was important for the disposition of these 2 statins. Ki values of inhibitor drugs on OATP1B1 need to be carefully evaluated with known substrates for better DDI risk assessment.
AUC Ratio (AUCR) resulted from OATP1B1 polymorphism or drug interactions by using PBPK models
OATP1B1 polymorphism or inhibitor drugAtorvastatinPitavastatin
Predicted AUCRPredicted AUCR with adjusted OATP1B1 Ki (10-fold less)Observed AUCRPredicted AUCRPredicted AUCR with adjusted OATP1B1 Ki (10 fold less)Observed AUCR
OATP1B1 polymorphism (c.521 CC vs c.521 TT)1.90 (1.48-2.39)N/A2.44 (1.36-4.69)2.00 (1.67-2.41)N/A3.08 (2.14-4.16)
Gemfibrozil1.55 (1.43-1.63)N/A1.24 (0.99-1.50)1.53 (1.48-1.57)N/A1.25 (1.06-1.50)
Rifampicin2.11 (1.95-2.21)7.77(6.54-8.03)6.80 (4.40-9.20)1.89 (1.69-1.98)5.96 (4.69-6.01)6.74 (4.73-8.74)
Cyclosporine1.87 (1.65-1.99)6.40(4.93-6.82)7.45 (7.41-7.47)1.57 (1.50-1.61)3.33 (2.85-3.41)4.60 (4.00-5.10)
Itraconazole1.73 (1.56-1.83)N/A2.40 (1.50-2.50)N/A
Erythromycin1.99 (1.69-2.05)N/A1.33 (1.06-1.65)
Simeprevir1.79 (1.52-1.89)N/A2.19 (1.72-2.62)
AUCR: It is the ratio between the AUC of statins comparing variant OATP1B1 to wild type or in the presence and absence of an inhibitor drug. The range in the parenthesis is 95% confidence interval of AUCR.