Aims: To assess the effects of the protease inhibitor ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers.
Methods: This was an open-label, single centre study in 23 subjects who received two single doses of oral contraceptive containing 50 microg ethinyl oestradiol on Day 1 (alone) and on Day 29 during concomitant ritonavir. Each subject received 16 days of every 12 h doses of ritonavir from Day 15 through Day 30. Blood samples were collected for serum ethinyl oestradiol concentrations for 48 h after each dose and for plasma ritonavir on Day 29 at 0 and 4 h postdose.
Results: Statistically significant decreases in ethinyl oestradiol mean Cmax (-32%) and mean AUC (-41%), and a statistically significant increase in the mean terminal elimination rate constant (+31%) were observed during concomitant ritonavir. The harmonic mean terminal half-life decreased from 17 h to 13 h during concomitant ritonavir. No statistically significant change was noted in tmax. The ratios of means (95% confidence intervals) for Cmax and AUC were 0.682 (0.612-0.758) and 0.595 (0.506-0.694), respectively. The changes in ethinyl oestradiol pharmacokinetics were consistent with an increase in clearance from enzymatic induction of glucuronidation and/or cytochrome P450 hydroxylation. Mean steady-state ritonavir concentrations of 6.5 and 13.4 microg ml(-1) were observed at 0 and 4 h postdose, respectively.
Conclusions: Considering the extent of the decrease in ethinyl oestradiol concentrations, the use of alternate contraceptive measures should be considered when ritonavir is being administered.
PIP: The protease inhibitor ritonavir has demonstrated broad-spectrum ability against HIV 1 and 2. The present study investigated the drug interaction potential of steady-state ritonavir on single dose ethinyl estradiol pharmacokinetics. 23 healthy women (mean age, 34 years) received an oral contraceptive (OC) containing 50 mcg of ethinyl estradiol and 1 mg of ethynodiol on days 1 and 29, while 500 mg of ritonavir was administered every 12 hours on days 15-30. After administration of a single dose of OC, serum ethinyl estradiol concentrations peaked at 4 hours and declined thereafter, with a typical half-life of 17 hours. Administration of the second OC on day 29, after 16 days of continuous ritonavir, resulted in a 32% lower ethinyl estradiol mean maximum concentration (p 0.001) and a 41% lower mean area under curve (p 0.001) compared with OC administration alone. In addition, the mean terminal elimination rate constant increased by 31% (p 0.001) with concomitant ritonavir. The changes in ethinyl estradiol pharmacokinetics were consistent with an increase in clearance from enzymatic induction of glucuronidation and/or cytochrome P450 hydroxylation. Mean steady-state ritonavir concentrations of 6.5 and 13.4 mcg/ml were observed at 0 and 4 hours post-dose, respectively. The interaction observed in this study is likely to be clinically significant, with an increased risk of OC failure. Thus, use of alternate contraceptive measures should be recommended when ritonavir is being administered.