RIFAMPIN AND RIFABUTIN EFFECT ON COMBINATION ORAL CONTRACEEPTIVES IN HIV WOMEN

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This is a controlled, randomized, Phase I, drug-drug, interaction study to evaluate the effect of rifampin and rifabutin on pharmacokinetics and pharmacodynamics of systemic combine oral contraceptive therapy. Rifabutin and rifampin are drugs that are used in the HIV-infected patient population for the prevention and treatment of mycobacterial diseases. Rifampin is a known enzyme inducer which enhances the metabolism of drugs which are metabolized via the hepatic p450 microsomal enzymes resulting in lower plasma concentrations. Many heterosexual HIV-infected women choose to use oral contraceptives for contraception. It is possible that the systemic levels of ethinyl estradiol and norethindrone are lowered in the presence of rifampin and rifabutin which may render the oral contraceptive ineffective. Although there is some suggestion that rifabutin may have less of an effect on the cytochrome P450 system, it is possible that rifabutin may have enough of an enzyme inducing effect to alter the efficacy of the commonly used combination oral contraceptive pill. This study will provide the first head to head comparison of the ability of rifabutin and rifampin to induce cytochrome p450 function. In addition, this study will provide a paradigm to simultaneously study both the pharmacokinetic and pharmacodynamic effects of a p450 inducer. This study may also provide information of regulatory relevance in so much as making dosing recommendations in the specific drug labels. The results could have impact on how these drugs are prescribed. PART I: On day 7 of their oral contraceptive pill cycle, subjects will undergo a baseline evaluation of LH and FSH levels and a 24 hour pharmacokinetic profile of ethinyl estradiol (EE) and norethindrone (NE). On day 8, after the 24 hour profile is completed, subjects will start rifabutin 300 mg every 24 hours of rifampin 600 mg every 24 hours for 14 days. on day 21 of their oral contraceptive pill cycle (14th day of rifampin or rifabutin), subjects will again undergo an evaluation of LH and FSH levels and 24 hour pharmacokinetic profile of EE and NE as on day 7. PART II: Following a 6-week wash-out period, on day 7 of their oral contraceptive cycle, subjects will again undergo a baseline evaluation of LH and FSH levels and a 24 hour pharmacokinetic profile of EE and NE. After the 24 hour profile is completed, subjects will then be started on 14 days of rifampin and rifabutin (whichever agent was not given in Part I). Profiles will be repeated again, on the 14th day of rifampin or rifabutin administration (day 21 of the oral contraceptive cycle). The order of administration of rifampin and rifabutin will be randomized. Eleven of 12 pre-menopausal women who have been on a stable daily regimen of ortho-novum 1-35 have completed the study. We expect to complete the study in early February and complete data analysis in May of 1997.