Lack of Effect of Tenofovir Disoproxil Fumarate on Pharmacokinetics of Hormonal Contraceptives

Study Objective. To assess the potential for a drug-drug interaction between a representative hormonal contraceptive (norgestimate-ethinyl estradiol) and tenofovir disoproxil fumarate (tenofovir DF), a prodrug of tenofovir, when coadministered. Design. Thirty-day, open-label, fixed-sequence, pharmacokinetic drug-drug interaction study Setting. Single clinical phase I center. Participants. Twenty nonpregnant and nonlactating women aged 19-45 years who were taking a norgestimate-ethinyl estradiol oral contraceptive. Intervention. Each woman received norgestimate-ethinyl estradiol alone on study days 1-22, followed by norgestimate-ethinyl estradiol plus tenofovir DF 300 mg once/day for 7 days during two consecutive 28-day contraceptive cycles. Measurements and Main Results. Pharmacokinetic assessments were performed over 24 hours on study days I and 29 (corresponding to matching days [day 211 of the two contraceptive cycles). Serum or plasma concentrations of tenofovir, norgestimate and its active metabolite deacetyl norgestimate, and ethinyl estradiol were measured by high-performance liquid chromatography-tandem mass spectrometry assays. Geometric mean ratios (90% confidence intervals) for the pharmacokinetic parameters for deacetyl norgestimate and ethinyl estradiol were estimated by using analysis of variance and compared with the no-effect criterion for bioequivalence. The tenofovir pharmacokinetic parameters were compared with historical controls. Pharmacokinetic parameters for deacetyl norgestimate and ethinyl estradiol were unaltered by coadministration of tenofovir DE The tenofovir pharmacokinetic parameters in subjects receiving norgestimate-ethinyl estradiol were consistent with historical control data for tenofovir. Conclusion. Tenofovir DF and norgestimate-ethinyl estradiol are not involved in a clinically significant drug-drug interaction; tenofovir DF did not affect the steady-state pharmacokinetics of norgestimate or ethinyl estradiol, including the concentration at the end of the dosing interval. Both drugs were well tolerated when coadministered. Tenofovir DF is unlikely to affect the pharmacokinetics of hormonal oral contraceptives.