Effect of the Hepatitis C Virus Protease Inhibitor Faldaprevir on the Pharmacokinetics of an Oral Contraceptive Containing Ethinylestradiol and Levonorgestrel in Healthy Female Volunteers

Abstract

Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor. Faldaprevir is known to inhibit P-glycoprotein, CYP3A4, and UDP-glucuronosyltransferase 1A1. This study evaluated the effect of steady-state 240 mg faldaprevir on the pharmacokinetics (PK) of an oral contraceptive containing ethinylestradiol (EE) and levonorgestrel (LNG) in healthy premenopausal women. In period 1, subjects received EE/LNG once daily (QD) for 14 days. Blood samples were taken on days 1, 11, and 12, with intensive PK blood sampling for EE and LNG on day 13. In period 2, subjects received EE-LNG QD and 240 mg faldaprevir QD on days 14 to 21 (240 mg faldaprevir twice daily on day 14). Blood samples were taken on days 14, 19, and 20, with PK profiling samples obtained for EE and LNG on day 21. A total of 15/16 subjects completed the study. Overall, EE and LNG exposure (assessed by the area under the curve) was approximately 1.4-fold higher when EE and LNG were coadministered with faldaprevir than when administered alone. Median t1/2 (terminal half-life in plasma at steady state) values were prolonged for both EE (2.4 h longer) and LNG (4.7 h longer) when EE and LNG were coadministered with faldaprevir. The mean oral clearance and apparent volume of distribution of both EE and LNG were lower (∼ 30%) when EE and LNG were coadministered with faldaprevir. Coadministration of faldaprevir and an oral contraceptive resulted in a moderate increase in exposure to both EE and LNG. However, this increase was not considered clinically meaningful, and no dose adjustment of oral contraceptives was deemed necessary. (This study has been registered at ClinicalTrials.gov under registration number NCT01570244.).

Role of CYP3A in Oral Contraceptives Clearance

“…The magnitude of increase in the exposure (AUC) of EE was not large in the presence of CYP3A inhibitors ( Figure and Table ). Strong CYP3A inhibitors, such as voriconazole and ketoconazole, increased EE exposure by 60% and 40%, respectively .…”

“…Interestingly, two protease inhibitors, telaprevir and boceprevir, which are known strong CYP3A inhibitors, seemed to decrease the AUC of EE by 26% and 28%, respectively . Moderate CYP3A inhibitors, including fluconazole, atazanavir, and faldaprevir, resulted in a 38% to 48% increase in the AUC of EE . No significant effect on the exposure of EE was observed with other moderate (netupitant) or weak CYP3A inhibitors …”

“…The effects of CYP3A inhibitors on the systemic exposure of progestins are presented in Figure and Table . Strong CYP3A inhibitors, voriconazole and indinavir, increased the AUC of NET by 53% and 26%, respectively, whereas two strong CYP3A inhibitors, telaprevir and boceprevir, did not significantly affect the exposure of NET .…”

Effect of Steady‐State Faldaprevir on Pharmacokinetics of Atorvastatin or Rosuvastatin in Healthy Volunteers: A Prospective Open‐Label, Fixed‐Sequence Crossover Study

“…9 In vitro data also suggest that faldaprevir inhibits P-glycoprotein (P-gp), UDPglucuronosyltransferase (UGT1A1), and CYP2C8. 10,11 Faldaprevir is an inhibitor of OATP1B1 and OATP1B3 and a possible inhibitor of OATP1B2, BCRP, and MRP2. 12 HMG-CoA reductase inhibitors, also known as statins, are widely prescribed for the treatment of hypercholesterolemia.…”

“…In vivo data suggest that with a twice‐daily dose of 240 mg in healthy volunteers, faldaprevir is a weak inhibitor of CYP2C9 and a moderate inhibitor of CYP3A, whereas a dose of 120 mg faldaprevir once daily in HCV patients results in weak inhibition of CYP3A . In vitro data also suggest that faldaprevir inhibits P‐glycoprotein (P‐gp), UDP‐glucuronosyltransferase (UGT1A1), and CYP2C8 . Faldaprevir is an inhibitor of OATP1B1 and OATP1B3 and a possible inhibitor of OATP1B2, BCRP, and MRP2 …”