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, nonrandomized 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 300 mg/100 mg 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 h. Whole blood was processed to collect serum and stored at -20°C until later analysis using radioimmunoassay. Pharmacokinetic parameters were estimated using noncompartmental method.

Results: In the treatment group, compared to the control group, an increase in area under the curve₀₋₂₄ (16.69 h*ng/mL vs. 25.20 h*ng/mL; p<.05) and maximum serum concentration (2.09 ng/mL vs. 3.19 ng/mL; p<.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.

Implications: Norethindrone-based progestin-only contraceptives, unlike combination oral contraceptives, exhibit greater drug exposure when co-administered with ritonavir-boosted atazanavir regimen and thus may not warrant a category 3 designation by the World Health Organization. Prospective studies are needed to confirm whether pharmacokinetic interaction results in favorable clinical outcomes.

Trial registration: ClinicalTrials.gov NCT01667978.

Keywords: Norethindrone; Pharmacokinetics; Progestin-only contraception; Ritonavir.

Figure 1. Norethindrone serum concentration-time profiles during steady-state

Norethindrone serum concentrations during steady-state were estimated using radioimmunoassay in control group (closed circles) and treatment group (open circles) of women over a 72-hour period. Each data point represents mean ± SD of 17 and 10 women in control and treatment groups, respectively.