Can Depot Provera (medroxyprogesterone) be used for contraception in patients treated with indinavi

Fråga: Can Depot Provera (medroxyprogesterone) be used for contraception in patients treated with indinavir, saquinavir, ritonavir or nelfinavir? Can these drugs interact at the CYP3A4 level?

Sammanfattning: According to the pharmacokinetics profile of medroxyprogesterone and protease inhibitors, the coadministration of these drugs is likely to result in a pharmacokinetic interaction. So, alternate means of contraception should be used in patients treated with protease inhibitors. Because of the adverse effects profile and the potential for interactions, patients receiving protease inhibitors require careful monitoring.

Svar: Depot medroxyprogesterone acetate has been used world-wide since 1964 as a contraceptive and by 1993 was in use in more than 90 countries (1). Like most of the steroid compounds, it is metabolised by the CYP3A4 (2). Indinavir, saquinavir, ritonavir and nelfinavir belong to the class of drugs known as protease inhibitors. This group of drugs is a quite recent acquisition in the HIV treatment. Protease inhibitors are extensively metabolised by the cytochrome P450 (CYP) enzymes, the most influential CYP isoenzyme involved in their metabolism being CYP3A4, with the isoforms CYP2C9 and CYP2D6 also contributing (3). It has been shown that the HIV protease inhibitors have differential effects on CYP isozymes (4,5). Ritonavir is a very potent inhibitor of CYP3A4 mediated reactions, and it shows also a certain degree of inhibition on CYP2C9 (4). Indinavir and nefilnavir have fewer effects on CYP3A4, and saquinavir affects it even less, but can produce some inhibition of CYP2C9 (4,5). Since CYP3A4 is the most prevalent of all P450 metabolic enzymes, the likelihood of undesirable interactions between protease inhibitors and other drugs metabolised by this pathway is high.

According to a paper published in the AIDS Information Newsletter (6), coadministration of medroxyprogesterone and a protease inhibitor can result in an interaction at the pharmacokinetic level, according to the different inhibitory potential of the protease inhibitors, which can cause a reduction in the medroxyprogesterone levels. It is, however, not clear if that statement is based on any actual observations or if it is a theoretically derived conclusion. An extensive research in the literature, including the database Drugline and Medline, has not revealed any more documentation on interactions between these drugs.