Effects of Rifabutin and Rifampicin on the Pharmacokinetics of Ethinylestradiol and Norethindrone

Abstract

This open-label, randomized, three-way crossover study of 28 healthy premenopausal women was conducted to compare the impact of concomitant rifabutin and rifampicin on the safety, pharmacokinetics, and pharmacodynamics of the oral contraceptives ethinylestradiol and norethindrone (Ortho-Novum 1/35; Ortho Pharmaceutical, Raritan, NJ). Each participant received oral contraceptives daily for 21 days for the first control cycle, then was randomized to one of two sequences to receive oral contraceptives with concomitant rifampicin and rifabutin at equal doses of 300 mg/day for 10 days. Ethinylestradiol, norethindrone, follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone, rifampicin, and rifabutin (and metabolite) were measured in plasma over the same time frames in all three cycles. Safety was assessed from before the beginning to the end of each cycle. Twenty-two subjects completed all three cycles. Compared with the control cycle, rifabutin and rifampicin significantly altered the disposition of the oral contraceptive. Area under the concentration-time curve from 0 to 24 hours (AUC0-24) and maximum plasma concentration (Cmax) of ethinylestradiol decreased by 64% and 42%, respectively, after coadministration with rifampicin and by 35% and 20%, respectively, after coadministration with rifabutin. The AUC0-24 of norethindrone decreased by 60% and 20% after coadministration with rifampicin and rifabutin, respectively. Unlike progesterone levels, FSH and LH levels increased during coadministration with rifampicin and rifabutin. The incidence of spotting was significantly higher after coadministration with rifampicin (36.4%) and rifabutin (21.7%) than during the control cycle (3.7%). Although both rifampicin and rifabutin affected the pharmacokinetics of ethinylestradiol and norethindrone, the magnitude of this effect was more pronounced with rifampicin. Likewise, the fact that the highest incidence of spotting occurred with rifampicin was consistent with higher metabolic induction by rifampicin. Despite the fact that there was no change in progesterone levels, it is recommended that patients be advised to use additional contraceptive methods while receiving rifabutin or rifampicin with oral contraceptives to prevent inadvertent pregnancy.

Predictive Utility of In Vitro Rifampin Induction Data Generated in Fresh and Cryopreserved Human Hepatocytes, Fa2N-4, and HepaRG Cells

“…For the purposes of parameter estimation, rifampin oral clearance (CL sys /F) was assumed to be 19.2 l/h based on a nonlinear mixed-effects population pharmacokinetic model fitted to data from 261 pulmonary tuberculosis patients (95% confidence interval, 18.4 -20.0 l/h) (Wilkins et al, 2008). This value is comparable to the estimate obtained by a noncompartmental analysis of rifampin pharmacokinetics in 28 healthy women (18.9 Ϯ 5.6 l/h) (LeBel et al, 1998). The free fraction of rifampin in human hepatocytes (f u,h ) was taken from the literature .…”

Drug interactions and hormonal contraception

“…6,7 However, the two earlier studies gave rifampicin for longer (21 days or more) than the later two (10 and 14 days). From a pharmacokinetic perspective, these two later studies were well designed because they measured the effect of rifampicin on the contraceptive steroids at baseline and at steady state, but as far as evaluating their effects on efficacy, they cannot be conclusive.…”

“…From a pharmacokinetic perspective, these two later studies were well designed because they measured the effect of rifampicin on the contraceptive steroids at baseline and at steady state, but as far as evaluating their effects on efficacy, they cannot be conclusive. All that can be said is that giving a short course of a potent enzyme-inducing drug for the first 10 days of one cycle, 6 or for 14 days for the last two weeks of one cycle, 7 probably does not alter efficacy. However, it would not be safe to extrapolate from this to giving the enzyme-inducing drug continuously (as is more likely with rifampicin use clinically).…”

Pharmacokinetic Interaction Study of Ritonavir-Boosted Saquinavir in Combination with Rifabutin in Healthy Subjects

“…Owing to the anticipated increase in rifabutin exposure with concomitant saquinavir-ritonavir treatment, rifabutin was administered once every 3 days rather than daily in groups 1 and 2. Recruitment into group 3 was dependent on whether the group 2 regimen led to exposure of rifabutin or its active moiety (sum of rifabutin and its active metabolite, 25-Odesacetyl-rifabutin) that was within the established rifabutin area under the concentration-time curve from 0 to 24 h (AUC 0-24 ) range between 1.6 Ϯ 0.4 g ⅐ h/ml and 3.4 Ϯ 0.7 g ⅐ h/ml following daily administration of rifabutin at doses of 150 mg (9) or 300 mg (12), respectively. Thus, group 3, if required, was to be dosed either every second or every fourth day based on whether the observed deviations were higher or less than these established limits.…”