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.

28 November 2011.

This randomized, double‐blind, parallel‐group study in healthy young women investigated the effect of treatment with vilaprisan (0.5, 1, 2, or 4 mg/day for 12 weeks) on ovarian function by assessing the Hoogland score, which is based on the size of follicle‐like structures as determined by transvaginal ultrasound and on estradiol and progesterone serum concentrations. Ovulation inhibition (ie, Hoogland score <6 in treatment weeks 1‐4 and 8‐12) was observed in >80% of the subjects receiving vilaprisan ≥1 mg/day. The effect was dose dependent. With a Bayesian approach, the percentage of subjects with ovulation inhibition was estimated to increase from 37% in subjects receiving 0.5 mg/day vilaprisan to 76%, 86%, and 88% in subjects receiving 1, 2, and 4 mg/day, respectively. Follicle growth was not suppressed during treatment. The majority of subjects receiving ≥1 mg/day had a Hoogland score of 4 (active follicle‐like structures, ie, follicle diameter >13 mm, estradiol >27.2 pg/mL, no progesterone increase) both at beginning and end of treatment. Mean average estradiol as well as mean maximum progesterone concentrations were noticeably decreased during treatment with vilaprisan ≥1 mg/day compared to pretreatment, but estradiol concentrations remained >80 pg/mL. Both hormones returned to pretreatment levels after the end of treatment, indicating a rapid resumption of normal ovarian activity. Amenorrhea occurred in the majority of subjects during treatment at dosages ≥1 mg/day. The adverse events observed in this study confirm the known safety profile of vilaprisan. All in all, the results of this study support the development of vilaprisan for the long‐term treatment of uterine fibroids.

1 Abecarnil (isopropyl-6-benzyloxy-4-methoxymethyl-,-carboline-3-carboxylate), a ,3-carboline with high affinity for benzodiazepine receptors, was tested in healthy male subjects; single doses of abecarnil were given in five dosage levels (1 mg, 5 mg, 10 mg, 20 mg, 40 mg) and in a multiple dose study in four dosage levels (15 mg, 30 mg, 60 mg, 90 mg day-) for 7 days. On two days following multiple dose treatment, placebo was given in single-blind conditions (follow-up). In each dosage level, in both studies drug was given to 10 subjects (7: verum, 3: placebo). 2 Safety and tolerability were evaluated by changes in vital signs, incidence and severity of adverse reactions and biochemical and haematological screening. Drug effects were estimated utilizing a bipolar visual analogue scale (poles: 'sleepy'-'alert') and a psychomotor task, the digit symbol substitution task. The pharmacokinetics of single and multiple doses were also determined in the multiple dose study. 3 Abecarnil was generally well tolerated. In the single dose study the most frequently reported side effects associated with abecarnil at high doses (20 and 40 mg) were dizziness, unsteady gait, and lack of concentration. A decrement in performance on the digit symbol substitution task was also observed in the two high dosage groups 20 mg and 40 mg. Evaluation of visual analogue scale ratings did not reveal a sedative effect even at higher doses. 4 In the multiple dose study the most frequently reported side effects during the treatment period were dizziness, unsteady gait, and lack of concentration. During the follow-up period the most frequently reported side effects were tiredness, headache and in the 90 mg day-1 group insomnia. A dose dependent decrement in performance on the digit symbol substitution task was observed during days 2-7. A dose-proportional increase in Cmax and in AUC values was also found. The terminal half-life of abecarnil was in the range from 5 to 7 h, and was not affected either by dose or by single vs multiple administrations.

The large-scale deployment of automated vehicles on public roads has the potential to vastly change the transportation modalities of today's society. Although this pursuit has been initiated decades ago, there still exist open challenges in reliably ensuring that such vehicles operate safely in open contexts. While functional safety is a wellestablished concept, the question of measuring the behavioral safety of a vehicle remains subject to research. One way to both objectively and computationally analyze traffic conflicts is the development and utilization of so-called criticality metrics. Contemporary approaches have leveraged the potential of criticality metrics in various applications related to automated driving, e.g. for computationally assessing the dynamic risk or filtering large data sets to build scenario catalogs. As a prerequisite to systematically chooseThe research leading to these results is funded by the German Federal Ministry for Economic Affairs and Energy within the projects 'VVM -Verification & Validation Methods for Automated Vehicles Level 4 and 5' and 'SET Level -Simulation-based Development and Testing of Automated Driving', based on a decision by the Parliament of the Federal Republic of Germany.