Effect of the hepatitis C virus protease inhibitor faldaprevir on the pharmacokinetics of an oral contraceptive containing ethinylestradiol and levonorgestrel in healthy female volunteers.
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.).
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA john.sabo@boehringer-ingelheim.com fenglei.huang@boehringer-ingelheim.com.
John P
JP
Sabo
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
Benjamin
B
Lang
Boehringer Ingelheim Canada Ltd./Ltée, Burlington, ON, Canada.
Mabrouk
M
Elgadi
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA john.sabo@boehringer-ingelheim.com fenglei.huang@boehringer-ingelheim.com.
Fenglei
F
Huang
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000621:Aminoisobutyric Acids; D019540:Area Under Curve; D001663:Bilirubin / Q000097:blood; D003277:Contraceptives, Oral, Combined / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004338:Drug Combinations; D004347:Drug Interactions; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives; D016912:Levonorgestrel / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D011804:Quinolines; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D055815:Young Adult; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000621:Aminoisobutyric Acids; D001663:Bilirubin; D003277:Contraceptives, Oral, Combined; D004338:Drug Combinations; D004997:Ethinyl Estradiol; D007930:Leucine; D016912:Levonorgestrel; D009842:Oligopeptides; D011392:Proline; D011480:Protease Inhibitors; D011804:Quinolines; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C072593:ethinyl estradiol, levonorgestrel drug combination; C552340:faldaprevir