It is known that co‐administration of CYP3A inducers may decrease the effectiveness of oral contraceptives containing progestins as mono‐preparations or combined with ethinylestradiol. In a randomized clinical drug‐drug interaction study, we investigated the effects of CYP3A induction on the pharmacokinetics of commonly used progestins and ethinylestradiol. Rifampicin was used to induce CYP3A. The progestins chosen as victim drugs were levonorgestrel, norethindrone, desogestrel, and dienogest as mono‐products, and drospirenone combined with ethinylestradiol. Postmenopausal women (n = 12–14 per treatment group) received, in fixed sequence, a single dose of the victim drug plus midazolam without rifampicin, with rifampicin 10 mg/day (weak induction), and with rifampicin 600 mg/day (strong induction). The effects on progestin exposure were compared with the effects on midazolam exposure (as a benchmark). Unbound concentrations were evaluated for drugs binding to sex hormone binding globulin. Weak CYP3A induction, as confirmed by a mean decrease in midazolam exposure by 46%, resulted in minor changes in progestin exposure (mean decreases: 15–37%). Strong CYP3A induction, in contrast, resulted in mean decreases by 57–90% (mean decrease in midazolam exposure: 86%). Namely, the magnitude of the observed induction effects varied from weak to strong. Our data might provide an impetus to revisit the currently applied clinical recommendations for oral contraceptives, especially for levonorgestrel and norethindrone‐containing products, and they might give an indication as to which progestin could be used, if requested, by women taking weak CYP3A inducers—although it is acknowledged that the exact exposure‐response relationship for contraceptive efficacy is currently unclear for most progestins.

AIMSThe present study was conducted to investigate the influence of the strong CYP3A4 inhibitor ketoconazole (KTZ) on the pharmacokinetics of drospirenone (DRSP) administered in combination with ethinylestradiol (EE) or estradiol (E2). METHODSThis was a randomized, multicentre, open label, one way crossover, fixed sequence study with two parallel treatment arms. A group sequential design allowed terminating the study for futility after first study cohort. About 50 healthy young women were randomized 1 : 1 to 'DRSP/EE' or 'DRSP/E2'. Subjects in the 'DRSP/EE' group received DRSP 3 mg/EE 0.02 mg (YAZ®, Bayer) once daily for 21 to 28 days followed by DRSP 3 mg/EE 0.02 mg once daily plus KTZ 200 mg twice daily for 10 days. Subjects in the 'DRSP/E2' group received DRSP 3 mg/E2 1.5 mg (research combination) once daily for 21 to 28 days followed by DRSP 3 mg/E2 1.5 mg once daily plus KTZ 200 mg twice daily for 10 days. RESULTSOral co-administration of DRSP/EE or DRSP/E2 and KTZ resulted in an increase in DRSP exposure (AUC(0,24 h)) in both treatment groups: DRSP/EE group: 2.68-fold DRSP increase (90% CI 2.44, 2.95); DRSP/E2 group: 2.30-fold DRSP increase (90% CI 2.08, 2.54). EE and estrone (metabolite of E2) exposures were increased~1.4-fold whereas E2 exposure was largely unaffected by KTZ co-administration. CONCLUSIONSA moderate pharmacokinetic drug-drug interaction between DRSP and KTZ was demonstrated in this study. No relevant changes of medical concern were detected in the safety data collected in this study. WHAT IS KNOWN ABOUT THIS SUBJECT• Prior data indicate that the major plasma metabolites of drospirenone are formed without CYP enzymes. Thus, no major CYPmediated drug interactions were expected.• However, in a recent study with a drospirenone-containing combination oral contraceptive, it was observed that coadministration of boceprevir, a CYP3A4 inhibitor, led to an increase in drospirenone exposure. WHAT THIS STUDY ADDS• In this study, a moderate pharmacokinetic interaction between drospirenone and ketoconazole, a strong CYP3A4 inhibitor, was observed (2 to 3-fold increase in DRSP exposure with ketoconazole coadministration).• Ketoconazole also slightly increased the systemic exposure of ethinylestradiol and estrone.• Overall, safety data indicated that these pharmacokinetic interactions are without clinical relevance.

Background and objectivesIn-vitro data suggest that clearance of vilaprisan is mediated by cytochrome P450 3A4 (oxidation) and aldoketoreductases (reduction). To fully understand the elimination and biotransformation pathways of vilaprisan, a selective progesterone receptor modulator, and to quantify the impact of cytochrome P450 3A4 inhibition on the pharmacokinetics of vilaprisan, two clinical studies in healthy postmenopausal women were conducted.MethodsIn study 1, pharmacokinetics, mass balance, and metabolite patterns were determined after single oral administration of 5 mg of [14C]-labeled vilaprisan in six subjects. In study 2, pharmacokinetics were determined after single oral administration of 4 mg of vilaprisan without and with concomitant administration of the strong cytochrome P450 3A4 inhibitor itraconazole (200 mg/day) in 14 subjects. In addition, a microtracer dose of vilaprisan was given intravenously to determine absolute bioavailability, clearance, and volume of distribution.ResultsThe dominant single compound in plasma was vilaprisan. No plasma metabolites exceeding 10% of total drug-related area under the concentration–time curve were detected. The absolute oral bioavailability of vilaprisan was ~ 60%. The mean clearance was ~ 7 L/h and the volume of distribution at steady state was ~ 360 L. Excretion occurred primarily via feces (73.5 ± 3.70% of dose; urine: 13.1 ± 1.71%; total recovery: 86.6 ± 2.81%), mostly in a metabolized form. Only small amounts of the parent drug were found in excreta. When vilaprisan was administered together with itraconazole, exposure to vilaprisan was increased 6.2-fold (90% confidence interval 5.4–7.2).ConclusionsVilaprisan is predominantly metabolized in the liver to a complex variety of metabolites, which are mainly excreted with feces. The pivotal role of cytochrome P450 3A4 in the metabolism of vilaprisan was confirmed.Clinical Trial RegistrationEudraCT numbers 2013-000707-16 (mass balance study) and 2014-004929-41 (drug–drug interaction/microtracer study); NCT02456129 (drug–drug interaction/microtracer study).Electronic supplementary materialThe online version of this article (10.1007/s40262-017-0607-4) contains supplementary material, which is available to authorized users.

Instantaneous heart rate (IHR) of chicks was determined by electrocardiogram measured non-invasively from the day of hatch to day 6 for continuity of investigation of HR fluctuations from embryos and for ascertainment of HR diurnal rhythms. In Experiment I, IHR was determined for 1-h periods twice a day, in daytime and at night, to investigate development of heart rate fluctuations (variability and irregularities). Chick IHR was substantially more arrhythmic than embryonic HR and spontaneous acceleration dominated HR fluctuations. Chick HR fluctuations were categorized into three types; [1] Type I as a widespread baseline HR (20-50 bpm) due to respiratory arrhythmia, with a mean oscillatory frequency of 0.74 Hz (range 0.4-1.2 Hz); [2] Type II as low frequency oscillations of baseline HR, at a mean of 0.07 Hz (range 0.04-0.10 Hz), and [3] Type III as non-cyclic irregularities, dominated by frequent transient accelerations. In Experiment II, continuous measurements of HR were made under conditions of a natural photoperiod, thermoneutrality and with feed available throughout the first week after hatching and circadian rhythms of HR were ascertained. HR was very variable in the daytime (250-500 bpm), due in part to feeding and activity, and decreased to a diurnal low (200-350 bpm) at night when mean HR was relatively stable. HR fluctuations persisted throughout the diurnal cycle.

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