Increased exposure of norethindrone in HIV+ women treated with ritonavir-boosted atazanavir therapy

Abstract

Objective Pharmacokinetics of norethindrone in combination oral contraceptive regimen are well described among HIV+ women treated with ritonavir boosted protease inhibitor therapies; however such characterization is lacking in women using progestin-only contraception. Our objective is to characterize pharmacokinetics of norethindrone in HIV+ women using ritonavir boosted atazanavir treatment during progestin-only contraceptive regimens. Study Design An open-label, prospective, non-randomized trial to characterize the pharmacokinetics of norethindrone in HIV+ women receiving ritonavir boosted atazanavir (n=10;treatment group) and other antiretroviral therapy known to not alter norethindrone levels (n=17;control group) was conducted. Following informed consent, women were instructed to take a single daily fixed oral dose of 0.35 mg norethindrone and 300mg/100mg atazanavir/ritonavir for 22 days. On day 22 serial blood samples were collected by venous catheter at 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours. Whole blood was processed to collect serum and stored at −20°C until later analysis using radioimmunoassay. Pharmacokinetic parameters were estimated using non-compartmental method. Results In the treatment group, compared to the control group, an increase in area under the curve0-24 (16.69hr*ng/mL vs. 25.20hr*ng/mL; p<0.05) and maximum serum concentration (2.09ng/mL vs. 3.19ng/mL; p<0.05), decrease (25-40%) in apparent volume of distribution and apparent clearance, and unaltered half-life were observed. Conclusion(s) Our findings suggest that progestin-only contraceptives, unlike combination oral contraceptives, benefit from drug-drug interaction and achieve higher levels of exposure. Further studies are needed to establish whether pharmacokinetic interaction leads to favorable clinical outcomes.

Current and future contraceptive options for women living with HIV

“…Ritonavir, when combined as a booster with lopinavir, atazanavir, or darunavir, appear to reduce ethinyl estradiol exposure [69–72]. On the other hand, the effect of boosting ritonavir with PIs on progestins appears less clear, though generally the studies indicate higher or insignificantly lower progestin exposures [69,70,72–74]. Cobicistat-boosted PIs have not become widely available in resource-limited settings, but when cobicistat is combined with elvitegravir, ethinyl estradiol exposure was reduced and progestin exposure was increased [75].…”

Drug–Drug Interactions, Effectiveness, and Safety of Hormonal Contraceptives in Women Living with HIV

“…In contrast, norgestimate exposure increased 85% when combined with atazanavir/ritonavir [56]. Similarly, in two studies of a POP in women predominately receiving atazanavir/ritonavir-based ART, the norethindrone exposure was 50% higher in combination with the PIs [57, 58]. Only one study evaluated luteal activity and no participant had evidence of luteal activity, regardless of receipt of lopinavir/ritonavir-based ART [55].…”

Drug interactions between hormonal contraceptives and antiretrovirals

“…1, Tables 3 and 4). Four reports were secondary analyses or subsets of the primary studies and are included with the primary study in the tables [14–17]. The results are presented by outcome assessed, focusing first on the most important clinical outcomes (contraceptive effectiveness, antiretroviral effectiveness, toxicity associated with combined administration), then the pharmacokinetic data (for contraceptives and antiretrovirals), in each case by antiretroviral class and by contraceptive method.…”

“…Ten reports described contraceptive pharmacokinetics among women using protease inhibitors and hormonal contraceptives (Table 3) [17,31,34,37–39,54–57]. …”