Lack of effect of tenofovir disoproxil fumarate on pharmacokinetics of hormonal contraceptives.
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.


METHODS
Thirty-day, open-label, fixed-sequence, pharmacokinetic drug-drug interaction study.


METHODS
Single clinical phase I center.


METHODS
Twenty nonpregnant and nonlactating women aged 19-45 years who were taking a norgestimate-ethinyl estradiol oral contraceptive.


METHODS
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.


RESULTS
Pharmacokinetic assessments were performed over 24 hours on study days 1 and 29 (corresponding to matching days [day 21] 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 DF. The tenofovir pharmacokinetic parameters in subjects receiving norgestimate-ethinyl estradiol were consistent with historical control data for tenofovir.


CONCLUSIONS
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.
Kearney
Brian P
BP
Gilead Sciences, Inc., Foster City, California 94404, USA. bkearney@gilead.com
Mathias
Anita
A
D000225:Adenine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D003280:Contraceptives, Oral, Synthetic / Q000009:adverse effects / Q000493:pharmacokinetics*; D004338:Drug Combinations; D004347:Drug Interactions; D004997:Ethinyl Estradiol / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009644:Norgestrel / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D063065:Organophosphonates / Q000493:pharmacokinetics / Q000494:pharmacology*; D000068698:Tenofovir
D019380:Anti-HIV Agents; D003280:Contraceptives, Oral, Synthetic; D004338:Drug Combinations; D063065:Organophosphonates; C109079:norgestimate, ethinyl estradiol drug combination; D009644:Norgestrel; D004997:Ethinyl Estradiol; D000068698:Tenofovir; D000225:Adenine