Effects of ritonavir-boosted protease inhibitors on combined oral contraceptive pharmacokinetics and pharmacodynamics in HIV-positive women

Abstract

Objective: To assess the pharmacokinetics of combined oral contraceptive (COC) components and prevalence of ovulation in HIV-positive women using ritonavir-containing antiretroviral regimens compared to those using regimens previously found not to interact with COCs or not using any antiretrovirals.

Study design: We conducted a prospective cohort pharmacokinetic pilot study comparing the pharmacokinetics of levonorgestrel (LNG) and ethinyl estradiol (EE) in HIV-positive women taking ritonavir-containing antiretroviral regimens to those in women using non-ritonavir-containing regimens or no antiretrovirals. Participants received COCs containing LNG/EE 150/30 mcg for 21 days. Beginning day 21, we collected serial blood samples over 72 h. The primary outcome was area under the curve (AUC) of LNG, with secondary outcomes including other LNG pharmacokinetic measures, EE pharmacokinetics and ovulation as measured by serum progesterone.

Results: Pharmacokinetic parameters of LNG showed a trend toward increased exposure in women on ritonavir. LNG AUC_last increased by 32.6% (312±60.9 vs. 243±82.6 ng/mL*h, p=.033, n=5) in women taking ritonavir compared to the control group (n=10). The C_max (9.68±1.81 vs. 7.62±2.29 ng/mL) and C_min (4.97±1.15 vs. 3.70±1.29 ng/mL) were also higher in the ritonavir arm. After excluding the inconsistent users (n=2), CL of LNG was reduced in the ritonavir arm (p=.032). EE pharmacokinetic profiles were not different between groups. The progesterone concentrations were similar in women of both groups, and none were consistent with ovulation during the treatment cycle.

Conclusion: Women on ritonavir showed an approximately 30% increase in LNG exposure but no difference in EE exposure.

Implications: The current data suggest that ritonavir does not have a clinically significant impact on oral contraceptive pharmacokinetics.

Keywords: Clearance; Combined oral contraceptives; HIV-positive; Pharmacokinetics; Volume of distribution.

Figure 1.

Flow of screening and enrollment of women taking ritonavir-boosted protease inhibitors or antiretroviral regimens found not to interact with COCs

Figure 2.

Steady-state and washout plasma concentration vs time profiles for LNG (A) and EE (B) in women taking ritonavir-boosted ARV regimens (COCs+ritonavir (RTV), n=5) compared to women taking ARV regimens not interacting with COCs or no ARV medication (COCs, n=10). Data are presented as mean ±SD.

Figure 3.

Boxplot of LNG (A) and EE (B) pharmacokinetic parameters of subjects in participants taking ritonavir-boosted ARV regimens (LNG/EE+Ritonavir (RTV), n=5) compared to women taking ARV regimens not interacting with COCs or no ARV medication (LNG/EE, n=10). Data are presented as boxplot with whiskers from minimum to maximum. Abbreviations of each parameter can be found in Table 2.

Figure 4

Progesterone concentrations during COC cycle 1 in women taking ritonavir (RTV)-boosted ARV regimens (COCs+RTV, n=5) compared to women taking ARV regimens not interacting with COCs or no ARV medication (COCs, n=10). Data are presented as mean ±SD. Sampling times can be off by 1 or 2 days for each visit.