Search

Background: Elinzanetant is a dual neurokinin-1,3 receptor antagonist in development for the treatment of menopausal vasomotor symptoms. The objectives of these studies were to characterize the mass balance and biotransformation of elinzanetant., Methods: In the clinical evaluation, whole blood, plasma, urine, and feces were collected from healthy fasted male volunteers (n = 6) following a single dose of 120 mg [ 14 C]-elinzanetant oral suspension for analysis of total radioactivity and metabolite profiling. In vitro reaction phenotyping and kinetics experiments on enzymes involved in elinzanetant metabolism were performed., Results: On average, 90.8% of the total radioactivity administered was recovered in excreta over 480 h, mostly via the fecal route (feces 90.4%; urine 0.4%). Elinzanetant was rapidly absorbed and extensively metabolized but remained the main circulating species in plasma, accounting for 39.1% of total radioactivity. Known principal and active metabolites M27, M30/34, and M18/21 accounted for 7.6%, 13.7%, and 4.9% of total radioactivity in plasma, respectively. All other radiolabeled plasma components were each < 3.5%, revealing the oxidation product M30/34 as the only metabolite with relevant exposure (> 10% of total radioactivity). In feces, metabolites resulting from oxidative biotransformation accounted, in sum, for ~ 40% of the dose, while elinzanetant remained the primary drug-related moiety. Results of in vitro experiments indicated that metabolism of elinzanetant was primarily mediated by cytochrome P450 3A4, with minor contribution from uridine 5'-diphospho-glucuronosyltransferase., Conclusions: Elinzanetant is metabolized mainly via oxidative biotransformation mediated by cytochrome P450 3A4, and primarily excreted in feces. The primary oxidation product M30/34 is a major human metabolite of elinzanetant., Trial Registration Number: NCT04654897., Competing Interests: Declarations. Funding: This study was sponsored by NeRRe Therapeutics Ltd. (Stevenage, UK). Competing interests: Marcus-Hillert Schultze-Mosgau, Klaus Francke, Antje Rottmann, and Simone Schulz are employees of Bayer AG, Anna Engelen was an employee of Bayer AG at the time of conducting the study and data evaluation and is now an employee of Boehringer Ingelheim (Germany), Nand Singh is an employee of Quotient Science (Nottingham, UK), Steve Pawsey is an employee of NeRRe Therapeutics Ltd. (Stevenage, UK), and Ruth Lock is a consultant to NeRRe Therapeutics Ltd. and an employee of Aucuba Sciences Ltd (London, UK). Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Approval from the Research Ethics Committee was received on 14 September 2020 (IRAS ID: 285216). Consent to participate: Informed consent was obtained from all individual participants included in the study. Consent for publication: Not applicable. Data Availability Statement: Result summaries of Bayer's sponsored clinical trials in drug development phases 1, 2, 3, and 4 are provided in the Bayer Trial Finder application after marketing authorization approval in line with the position of the global pharmaceutical industry associations laid down in the "Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases". In addition, results of clinical drug trials will be provided on the publicly funded website www.ClinicalTrials.gov and EU Clinical Trials Register in line with the applicable regulations. Bayer commits to sharing upon request from qualified scientific and medical researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials for medicines and indications approved in the United States (US) and European Union (EU) on or after January 01, 2014, as necessary for conducting legitimate research. Code Availability: Not applicable. Author Contributions: Participated in research design: Anna Engelen, Steve Pawsey, Ruth Lock, Simone I. Schulz, Nand Singh, Antje Rottmann, Marcus-Hillert Schultze-Mosgau. Conducted experiments: Anna Engelen, Steve Pawsey, Simone I. Schulz, Nand Singh. Contributed new reagents or analytic tools: Simone I. Schulz, Anna Engelen. Performed data analysis: Anna Engelen, Steve Pawsey, Simone I. Schulz, Nand Singh, Klaus Francke, Antje Rottmann, Marcus-Hillert Schultze-Mosgau. Wrote or contributed to the writing of the manuscript: all authors., (© 2024. The Author(s).)

Elinzanetant is a potent and selective dual neurokin-1 (NK-1) and -3 (NK-3) receptor antagonist that is currently developed for the treatment of women with moderate-to-severe vasomotor symptoms (VMS) associated with menopause. Here, we report the development of a population pharmacokinetic (popPK) model for elinzanetant and its principal metabolites based on an integrated dataset from 366 subjects (including 197 women with VMS) collected in 10 phase I or II studies. The pharmacokinetics of elinzanetant and its metabolites could be well described by the popPK model. Within the investigated dose range of 40-160 mg, the oral bioavailability of elinzanetant was dose independent and estimated to be 36.7%. The clearance of elinzanetant was estimated to be 7.26 L/h and the central and peripheral distribution volume were 23.7 and 168 L. No intrinsic or extrinsic influencing factors have been identified in the investigated population other than the effect of a high-fat breakfast on the oral absorption of elinzanetant. The popPK model was then coupled to a pharmacodynamic model to predict occupancies of the NK-1 and NK-3 receptors. After repeated once-daily administration of the anticipated therapeutic dose of 120 mg elinzanetant, the model-predicted median receptor occupancies are >99% for NK-1 and >94.8% for NK-3 during day and night-time, indicating sustained and near-complete inhibition of both target receptors during the dosing interval., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

In the past, rifampicin was well-established as strong index CYP3A inducer in clinical drug-drug interaction (DDI) studies. However, due to identified potentially genotoxic nitrosamine impurities, it should not any longer be used in healthy volunteer studies. Available clinical data suggest carbamazepine as an alternative to rifampicin as strong index CYP3A4 inducer in clinical DDI studies. Further, physiologically-based pharmacokinetic (PBPK) modeling is a tool with increasing importance to support the DDI risk assessment of drugs during drug development. CYP3A4 induction properties and the safety profile of carbamazepine were investigated in two open-label, fixed sequence, crossover clinical pharmacology studies in healthy volunteers using midazolam as a sensitive index CYP3A4 substrate. Carbamazepine was up-titrated from 100 mg twice daily (b.i.d.) to 200 mg b.i.d., and to a final dose of 300 mg b.i.d. for 10 consecutive days. Mean area under plasma concentration-time curve from zero to infinity (AUC( 0-∞ )) of midazolam consistently decreased by 71.8% (ratio: 0.282, 90% confidence interval (CI): 0.235-0.340) and 67.7% (ratio: 0.323, 90% CI: 0.256-0.407) in study 1 and study 2, respectively. The effect was adequately described by an internally developed PBPK model for carbamazepine which has been made freely available to the scientific community. Further, carbamazepine was safe and well-tolerated in the investigated dosing regimen in healthy participants. The results demonstrated that the presented design is appropriate for the use of carbamazepine as alternative inducer to rifampicin in DDI studies acknowledging its CYP3A4 inductive potency and safety profile., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Overactive adenosine triphosphate signaling via P2X3 homotrimeric receptors is implicated in multiple conditions. To fully understand the metabolism and elimination pathways of eliapixant, a study was conducted to assess the pharmacokinetics, mass balance, and routes of excretion of a single oral dose of the selective P2X3 receptor antagonist eliapixant, in addition to an in vitro characterization., Methods: In this single-center open-label non-randomized non-placebo-controlled phase I study, healthy male subjects (n = 6) received a single dose of 50 mg eliapixant blended with 3.7 MBq [ 14 C]eliapixant as a PEG 400-based oral solution. Total radioactivity and metabolites excreted in urine and feces, and pharmacokinetics of total radioactivity, eliapixant, and metabolites in plasma were assessed via liquid scintillation counting and high-performance liquid chromatography-based methods coupled to radiometric and mass spectrometric detection. Metabolite profiles of eliapixant in human in vitro systems and metabolizing enzymes were also investigated., Results: After administration as an oral solution, eliapixant was rapidly absorbed, reaching maximum plasma concentrations within 2 h. Eliapixant was eliminated from plasma with a mean terminal half-life of 48.3 h. Unchanged eliapixant was the predominant component in plasma (72.6% of total radioactivity area under the curve). The remaining percentage of drug-related components in plasma probably represented the sum of many metabolites, detected in trace amounts. Mean recovery of total radioactivity was 97.9% of the administered dose (94.3-99.4%) within 14 days, with 86.3% (84.8-88.1%) excreted via feces and 11.6% (9.5-13.1%) via urine. Excretion of parent drug was minimal in feces (0.7% of dose) and urine (≈ 0.5%). In feces, metabolites formed by oxidation represented > 90% of excreted total radioactivity. The metabolites detected in the in vitro experiments were similar to those identified in vivo., Conclusion: Complete recovery of administered eliapixant-related radioactivity was observed in healthy male subjects with predominant excretion via feces. Eliapixant was almost exclusively cleared by oxidative biotransformation (> 90% of dose), with major involvement of cytochrome P450 3A4. Excretion of parent drug was of minor importance (~ 1% of dose)., Clinical Trial Registration: ClinicalTrials.gov: NCT04487431 (registered 27 July 2020)/EudraCT number: 2020-000519-54 (registered 3 February 2020), NCT02817100 (registered 26 June 2016), NCT03310645 (registered 16 October 2017)., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aims: We report population pharmacokinetic (popPK) and exposure-response (E-R) analyses for efficacy (induced amenorrhoea [IA]) and safety (unbound oestradiol [E2] concentrations) of the selective progesterone receptor modulator vilaprisan. Results were used to inform the dose for the Phase 3 programme in patients with uterine fibroids., Methods: A popPK model was developed using data from Phase 1 and 2 studies (including ASTEROID 1 and 2). The relationship between vilaprisan exposure (steady-state AUC) and IA after oral administration of 0.5, 1, 2 or 4 mg/day over 3 months was analysed in ASTEROID 1 using logistic regression and qualified in ASTEROID 2 by comparing simulated and observed probability for IA after 2 mg/day. The exposure-E2 relationship was analysed visually., Results: Vilaprisan clearance was 22.7% lower in obese vs non-obese patients. The E-R relationship for IA in ASTEROID 1 was steep and consistent with ASTEROID 2, with a maximum probability (P max ) of 59% (95% CI: 49-68%). The exposure at which 50% of P max is obtained was 36.9 μg*h/L (95% CI: 27.7-48.7 μg*h/L). Simulations showed that 36% of the patients will be below 90% of P max for IA after 1 mg/day compared to 2% after 2 mg/day. E2 levels tended to decrease with increasing exposure. While E2 levels remained largely within the physiologic follicular phase range, the clinical relevance of this decrease will be evaluated in long-term studies., Conclusions: A 2 mg/day dose was selected for Phase 3 as E-R analyses show this dose results in a close to maximum probability for IA, without any safety concerns noted., (© 2021 Bayer AG. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Vilaprisan is a highly potent selective progesterone receptor modulator in development for the treatment of symptomatic uterine fibroids and endometriosis. Its pharmacokinetics are characterized by rapid absorption, almost complete bioavailability, and dose-proportional exposure. The intrinsic factors of age, bodyweight, and race have no clinically relevant effect on the pharmacokinetics and pharmacodynamics of vilaprisan and do not warrant a dose adjustment. Similarly, vilaprisan can be used in patients with mild or moderate renal or hepatic impairment without dose adjustment, but its use is not recommended in patients with severe organ impairment. Vilaprisan has no perpetrator potential on cytochrome P450 (CYP) enzymes or transporters and therefore restrictions in the concomitant use of their substrates are not required. Nonetheless, because it is a sensitive CYP3A4 substrate itself, concomitant use of vilaprisan with strong CYP3A inhibitors or inducers is not recommended. However, there is no risk for QTc prolongation when vilaprisan and a strong CYP3A inhibitor are administered concomitantly, as indicated by a vilaprisan concentration-QTc response analysis across all studies with triplicate electrocardiogram measurements. Furthermore, due to its mode of action, vilaprisan is also not recommended to be used together with progestin-containing oral contraceptives. Vilaprisan shows a steep exposure-response relationship for inducing amenorrhea in patients with uterine fibroids experiencing heavy menstrual bleeding. Based on simulations, a dose of 2 mg/day is expected to induce a maximum bleeding reduction and was thus selected for phase III., (© 2021. The Author(s).)

Background and Objectives: As the prevalence of some gynecological conditions depends on patient characteristics such as race/ethnicity, it is important to study therapies for these conditions in diverse populations. The study described in this article was conducted to investigate the safety, tolerability, and pharmacokinetics of vilaprisan, a selective progesterone receptor modulator, in Japanese women in Japan. It supplements two comparable studies that were conducted in healthy postmenopausal European and Chinese women, respectively., Methods: In this exploratory randomized, placebo-controlled, double-blind, ascending-dose study, five groups of healthy postmenopausal Japanese women received vilaprisan as immediate-release tablets (1, 5, or 15 mg as a single dose or 1 or 5 mg/day for 28 days) or placebo tablets (single dosing: 8 subjects/dose step, thereof 2 subjects randomized to placebo; multiple dosing: 12 subjects/dose step, thereof 4 subjects randomized to placebo). Blood samples for pharmacokinetic profiles were collected over 14-19 days. Safety assessments were based on adverse event data, vital signs, electrocardiograms, clinical laboratory tests, and transvaginal ultrasound examinations., Results: 48 participants were randomized, treated, and analyzed. Vilaprisan was rapidly absorbed, reaching maximum plasma concentrations (C max ) between 1 and 3 h post dose. Post maximum, plasma concentrations rapidly declined, indicating pronounced distribution into tissues. The exposure of vilaprisan increased roughly dose-proportionally: The geometric mean (geometric coefficients of variation) areas under the concentration time curves from time zero to infinity (AUC ∞ ) after single administration of 1, 5, or 15 mg vilaprisan were 67 µg·h/l (34%), 249 µg·h/l (15%), and 788 µg·h/l (37%), respectively. The AUC in the dosing interval after multiple administrations (AUC 24,md ) of 1 mg/day was 76 µg·h/l (59%), and the AUC 24,md after 5 mg/day was 311 µg·h/l (20%). Geometric mean C max values also increased roughly dose-proportionally: They amounted to 6 µg/l (22%), 16 µg/l (33%), and 52 µg/l (27%) after single administration and to 8 µg/l (28%) and 31 µg/l (22%) after multiple administrations of the above doses. Mild adverse events were observed, similar to those observed in other clinical studies of vilaprisan., Conclusions: Overall, vilaprisan was safe and well tolerated. The exposure in Japanese women was similar to that observed in European and Chinese women in separate studies., Trial Registration: 15 Nov 2011 (no registration number assigned)., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

This exploratory, open-label, randomized, 3-period crossover study in 12 healthy postmenopausal women investigated the effects of food intake on the pharmacokinetics of vilaprisan. Single doses of vilaprisan (2 mg) were administered under fasting conditions, after intake of a high-fat, high-calorie meal, and after intake of a moderate-fat, moderate-calorie meal. The intake of food had only a marginal impact on the oral bioavailability of vilaprisan. The mean exposure of vilaprisan (area under the plasma concentration-time curve [AUC]) was increased by approximately 20% when the drug was taken after a meal and not on an empty stomach (point estimate for AUC ratios [%] and 90% confidence interval: high-fat and -calorie meal/fasting 121 [114-128]; moderate-fat and -calorie meal/fasting 118 [111-125]). The rate of absorption was slightly decreased when the drug was taken after a meal as indicated by approximately 10% lower mean maximum concentrations (C max ) of vilaprisan in plasma (C max ratios: high-fat and -calorie meal/fasting 87.9 [75.6-102]; moderate-fat and -calorie meal/fasting 89.4 [76.9-104]) and a prolonged time to C max (fasting: 1.5 hours; fed conditions; ∼4 hours). Overall, the results of this study indicate that vilaprisan can be administered equally well with or without food., (© 2020 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Vilaprisan is a novel selective progesterone receptor modulator for the long-term treatment of uterine fibroids and endometriosis. This study investigated the pharmacokinetics, safety, and tolerability of vilaprisan in healthy Chinese postmenopausal women. Twelve participants received multiple doses of vilaprisan once daily over 14 days as a 2-mg tablet. Plasma vilaprisan concentrations were determined using liquid chromatography-tandem mass spectrometry. The main pharmacokinetic parameters of vilaprisan were assessed with noncompartmental analysis, including maximum observed concentration (C max ), systemic exposure (area under the plasma concentration-time curve), time to reach C max and terminal half-life. Safety assessments include the documentation of adverse events, measurement of clinical/anthropometric parameters and vital signs, electrocardiogram, and physical and gynecologic examination. The participants had a mean age of 53.3 (± 4.2) years and a body mass index of 23.8 ± 2.8 kg/m 2 . Median time to reach C max was 1.5 hours after both single and multiple vilaprisan administration. Mean C max values obtained after multiple dosing (23.3 μg/L [standard deviation (SD) = 6.73]) were 1.92-fold (SD = 0.554) higher compared to single dosing (12.5 μg/L [SD = 3.04]). Mean area under the plasma concentration-time curve in the dosing interval increased with an accumulation factor of 2.98 (SD = 0.767) between single (91.3 μg · h/L [SD = 20.4]) and multiple dosing (276 μg · h/L [SD = 109]). The mean terminal half-life of vilaprisan was 44.5 hours (SD = 10.3) after multiple dosing. Mild to moderate adverse events were observed similar to previous studies. Overall, daily oral administration of the therapeutic dose of 2 mg of vilaprisan over 14 days was safe and well tolerated by all participants., (© 2020 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Aims: The primary objective was to explore whether the suppression of ovarian activity induced by a combined oral contraceptive (COC) is influenced by the simultaneous intake of the selective progesterone receptor modulator (SPRM) vilaprisan (VPR)., Methods: In this exploratory randomized, double-blind, parallel-group study, 71 healthy premenopausal women were randomized (1:1) to receive either 2 mg/d VPR or placebo for 3 months. Concomitantly, a COC (0.15 mg levonorgestrel, 0.03 mg ethinyloestradiol) was administered in a cyclic regimen. Ovarian activity (Hoogland score based on follicle size and hormone concentrations), cervical function (Insler score), bleeding pattern and endometrial thickness/histology were assessed before treatment, in treatment cycle 3 and during follow-up., Results: The known COC-driven suppression of ovarian activity was mildly affected by VPR. COC+VPR group: 22, 0 and 6% of the subjects had Hoogland scores of 4 (active follicle-like structures), 5 or 6 (ovulation). COC+placebo group: 14% of the subjects had a score of 4 and none a score of 5 or 6 (Bayesian analysis for Hoogland score = 4, median difference in response rate: 7.5%; 90% credible interval [-8.5; 23.5%]). COC effects on cervical function were moderately affected (mucus more sperm permeable under COC+VPR). COC withdrawal bleeding, in contrast, was absent in 81% of the subjects receiving COC+VPR vs 0% receiving COC+placebo., Conclusion: The SPRM VPR interfered with the pharmacodynamic effects of the COC. Therefore, full contraceptive effectiveness cannot be assumed without final judgement by a Pearl index study. Women on SPRMs should be advised to use nonhormonal contraception methods., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

This open label, parallel-group study investigated the pharmacokinetics and safety of a single oral 2-mg dose of the novel selective progesterone receptor modulator vilaprisan in participants with impaired renal function compared with age, weight, sex, and race matched controls with normal renal function. Systemic exposure (area under the plasma concentration-time curve [AUC]) and maximum observed concentrations (C max ) were compared among 9 participants with moderate renal impairment and matched controls by ANOVA. An additional 4 participants, each with severe renal impairment or normal renal function, contributed to a linear regression analysis exploring any monotone relationship between individual variables and the estimated glomerular filtration rate. The geometric mean AUC was increased by a factor of 1.35 in renally impaired participants compared to normal controls (not statistically significant: least squares mean, 1.346; 90% confidence interval, 0.918-1.973). C max was similar in participants with moderate renal impairment and normal renal function (least squares mean, 1.026; 90% confidence interval, 0.779-1.351). Considering the overall variability, there was no correlation between renal function (estimated glomerular filtration rate) and C max or AUC of vilaprisan. Single oral administration of vilaprisan 2 mg was well tolerated by all participants, both men and women and irrespective of renal function. The incidence of treatment-emergent adverse events was similar across all groups. Results from this study do not indicate that a dose adjustment will be necessary for vilaprisan when treating patients up to moderate renal impairment., (© 2020 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Aims: The study objective was to evaluate the pharmacokinetics of the selective progesterone receptor modulator vilaprisan in participants with hepatic impairment. Additionally, the safety and tolerability of vilaprisan were investigated., Methods: In this phase 1, open-label, nonrandomised, parallel-group, pharmacokinetic study, men and women with mild or moderate hepatic impairment (Child-Pugh grade A or B) and control participants with normal hepatic function matched by age, weight and sex received a single oral 2 mg dose of vilaprisan. Key pharmacokinetic parameters, relationships between parameters and safety outcomes were measured., Results: Thirty-six participants completed the study: 9 with mild hepatic impairment, 9 with moderate hepatic impairment and 18 matched control participants with normal hepatic function. Vilaprisan reached maximum plasma concentrations after 1-2 hours. Unbound vilaprisan exposure was 1.44-fold higher for participants with mild hepatic impairment vs controls (90% confidence interval: 0.91-2.26), and 1.74-fold higher for participants with moderate impairment vs controls (90% confidence interval: 1.09-2.78). The maximum observed unbound peak concentrations were similar for participants with hepatic impairment and matched controls. Vilaprisan 2 mg was well tolerated and the incidence of treatment-emergent adverse events was similar across cohorts., Conclusion: Only mild increases of <1.75-fold in exposure were observed in participants with mild or moderate hepatic impairment compared with control participants. No safety concern was identified. These data, alongside the excellent safety profile observed in phase 1 and 2 studies, do not indicate that a dose adjustment would be required in patients with mild or moderate hepatic impairment., (© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: The primary aim of the present study was to quantify the effects of rifampicin, a strong cytochrome P450 (CYP) 3A4 inducer, on the pharmacokinetics of the new selective progesterone receptor modulator, vilaprisan. In addition, the effects of rifampicin on the glucuronidation of bilirubin, an endogenous UDP-glucuronosyltransferase family 1 member A1 (UGT1A1) substrate, were explored., Methods: This was an open-label, two-period study in 12 healthy postmenopausal women. Subjects received a single oral dose of vilaprisan 4 mg in each period. In period 2, administration of vilaprisan was preceded and followed by rifampicin 600 mg day -1 . A subtherapeutic dose of midazolam (1 mg) was coadministered with vilaprisan to monitor CYP3A4 induction. Details of the administration and sampling schedule were optimized by means of a physiologically based pharmacokinetic model. Plasma concentrations of vilaprisan, midazolam, and 1'- hydroxy-midazolam were measured and rifampicin-associated changes in the glucuronidation of bilirubin were determined., Results: As predicted by our model, the coadministration of rifampicin was associated with a substantial decrease in exposure to vilaprisan and midazolam - indicated by the following point estimates (90% confidence intervals) for the area under the plasma concentration-time curve from zero to the time of the last quantifiable concentration ratio with or without rifampicin: 0.040 (0.0325, 0.0505) for vilaprisan and 0.144 (0.117, 0.178) for midazolam. Further, it was associated with an increase in bilirubin glucuronidation, indicating that UGT1A1 was induced., Conclusions: The exposure to vilaprisan was reduced by 96%. Such a reduction is likely to render the drug therapeutically ineffective. Therefore, it is recommended that the use of strong CYP3A4 inducers is avoided when taking vilaprisan., (© 2018 The British Pharmacological Society.)

Progesterone plays an important role in the female reproductive system. However, there is also evidence that gynecologic disorders/diseases such as uterine fibroids and endometriosis are progesterone-dependent. Steroidal and non-steroidal selective progesterone receptor modulators (SPRMs) have shown potential for the treatment of such diseases. Steroidal SPRMs, including mifepristone and ulipristal acetate, have proven effective in clinical trials. However, several steroidal SPRMs containing a dimethylamino substituent have been associated with elevated liver enzymes in patients. An earlier drug discovery program identified lonaprisan as a highly selective SPRM that did not show drug-related change in liver enzyme activity. Building on data obtained from that work, here we describe the research program that culminated in the discovery of a novel steroidal SPRM, vilaprisan, which combines an extremely high potency with very favorable drug metabolism and pharmacokinetic properties. Vilaprisan has entered clinical development and is currently undergoing phase 3 clinical trials., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background and Objectives: In-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., Methods: In study 1, pharmacokinetics, mass balance, and metabolite patterns were determined after single oral administration of 5 mg of [ 14 C]-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., Results: The 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)., Conclusions: Vilaprisan 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 Registration: EudraCT numbers 2013-000707-16 (mass balance study) and 2014-004929-41 (drug-drug interaction/microtracer study); NCT02456129 (drug-drug interaction/microtracer study).

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., (© 2017, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Pharmacokinetics (PK) of anastrozole (ATZ) and levonorgestrel (LNG) released from an intravaginal ring (IVR) intended to treat endometriosis symptoms were characterized, and the exposure-response relationship focusing on the development of large ovarian follicle-like structures was investigated by modeling and simulation to support dose selection for further studies. A population PK analysis and simulations were performed for ATZ and LNG based on clinical phase 1 study data from 66 healthy women. A PK/PD model was developed to predict the probability of a maximum follicle size ≥30 mm and the potential contribution of ATZ beside the known LNG effects. Population PK models for ATZ and LNG were established where the interaction of LNG with sex hormone-binding globulin (SHBG) as well as a stimulating effect of estradiol on SHBG were considered. Furthermore, simulations showed that doses of 40 μg/d LNG combined with 300, 600, or 1050 μg/d ATZ reached anticipated exposure levels for both drugs, facilitating selection of ATZ and LNG doses in the phase 2 dose-finding study. The main driver for the effect on maximum follicle size appears to be unbound LNG exposure. A 50% probability of maximum follicle size ≥30 mm was estimated for 40 μg/d LNG based on the exposure-response analysis. ATZ in the dose range investigated does not increase the risk for ovarian cysts as occurs with LNG at a dose that does not inhibit ovulation., (© 2016, The American College of Clinical Pharmacology.)

The BREELIB nebulizer was developed for iloprost to reduce inhalation times for patients with pulmonary arterial hypertension (PAH). This multicenter, randomized, unblinded, four-part study compared inhalation time, pharmacokinetics, and acute tolerability of iloprost 5 µg at mouthpiece delivered via BREELIB versus the standard I-Neb nebulizer in 27 patients with PAH. The primary safety outcome was the proportion of patients with a maximum increase in heart rate (HR) ≥ 25% and/or a maximum decrease in systolic blood pressure ≥ 20% within 30 min after inhalation. Other safety outcomes included systolic, diastolic, and mean blood pressure, HR, oxygen saturation, and adverse events (AEs). Median inhalation times were considerably shorter with BREELIB versus I-Neb (2.6 versus 10.9 min; n = 24). Maximum iloprost plasma concentration and systemic exposure (area under the plasma concentration-time curve) were 77% and 42% higher, respectively, with BREELIB versus I-Neb. Five patients experienced a maximum systolic blood pressure decrease ≥ 20%, four with BREELIB (one mildly and transiently symptomatic), and one with I-Neb; none required medical intervention. AEs reported during the study were consistent with the known safety profile of iloprost. The BREELIB nebulizer offers reduced inhalation time, good tolerability, and may improve iloprost aerosol therapy convenience and thus compliance for patients with PAH.

Objectives: Vilaprisan is a novel, potent, and highly selective progesterone receptor modulator, which might offer a promising option for the treatment of uterine fibroids., Methods and Materials: In this randomized, placebo-controlled, parallel-group phase 1 study, the pharmacokinetics and safety of vilaprisan were investigated in healthy postmenopausal women. Subjects received a single oral dose of vilaprisan (1, 5, 15, or 30 mg) or placebo and - after a wash-out period - daily doses of the same strength over 28 days. Safety assessments included vital signs, ECGs, clinical laboratory tests, and adverse events. Blood samples for pharmacokinetic (PK) profiles were collected over 14 days after single dose (sd) and multiple dose (md; day 28)., Results: Vilaprisan was well tolerated. Mild to moderate adverse events occurred with similar frequency at all dose levels. Following single dose, maximum vilaprisan concentrations were observed 1 - 2 hours post-dose. Terminal half-lives ranged from 31 to 38 hours. Maximum concentrations of vilaprisan (Cmax) and exposure to vilaprisan (AUC) increased roughly dose-proportionally from 3.74 µg/L (1 mg) to 68.6 µg/L (30 mg) and 58.5 µg×h/L to 1,590 µg×h/L, respectively. With daily dosing, accumulation consistent with the long terminal half-life was observed (AUC(0-24)md/AUC(0-24)sd ratios: 1.9 to 3.2). The ratio AUC(0-24)md/AUCsd increased with dose from ~ 1 (1 mg) to 1.5 (30 mg)., Conclusions: Exposure to vilaprisan increased roughly dose-proportionally in the dose range studied and accumulated after multiple dosing as expected based on t1/2, indicating linear pharmacokinetics of vilaprisan in the expected therapeutic dose range.
.

Study Question: What are suitable doses of the aromatase inhibitor anastrozole (ATZ) and the progestin levonorgestrel (LNG), when delivered to the systemic circulation by an intravaginal ring (IVR), for further clinical development as a potential new therapy for the treatment of endometriosis?, Summary Answer: Anticipated targets for pharmacokinetics, pharmacodynamics and safety/tolerability were achieved for both drug components of the IVR at the doses investigated, supporting selection of the doses to be investigated in Phase 2 studies., What Is Known Already: Aromatase is a key enzyme in the biosynthesis of estrogens and is known to increase local levels of estradiol (E2) at extragonadal sites. Up-regulation of aromatase expression has been demonstrated in endometriotic lesions and the use of oral aromatase inhibitors has been shown to reduce endometriosis-associated pelvic pain in small-scale clinical trials., Study Design, Size, Duration: This Phase 1, randomized, multicentre, parallel-group, three-arm, open-label study assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of various IVRs intended for systemic drug delivery. After screening, healthy, ovulating women aged 18-35 years were randomized to use IVRs releasing one of the three ATZ/LNG dose combinations (in vitro nominal daily drug release rates on Day 29: ATZ/LNG 500 µg/20 µg [low dose], ATZ/LNG 1000 µg/30 µg [mid dose] or ATZ/LNG 1500 µg/40 µg [high dose]) for two consecutive 28-day wearing periods without a treatment break., Participants/materials, Setting, Methods: Sixty women were included in the per protocol set. The primary variables were plasma concentrations of ATZ and LNG at the end of each treatment period and the mean size of largest follicle-like structures (FLSs) over 56 days. Serum concentrations of several hormones were also evaluated, with emphasis on E2 levels., Main Results and the Role of Chance: At the end of the first treatment period, geometric mean plasma concentrations of LNG and ATZ, respectively, were 0.228 and 12.5 µg/l for the low dose, 0.269 and 19.8 µg/l for the mid dose and 0.384 and 37.3 µg/l for the high dose; results were similar at the end of the second treatment period. Over the entire treatment period, mean FLS sizes were higher in all three treatment groups than during the pretreatment cycle; more women in the mid- and high-dose groups had FLSs of at least 30 mm (32-45%) than those in the low-dose group (14-24%). Changes in the mean size of FLSs were similar to those reported for low-dose progestin-only oral contraceptives and generally resolved during the 2-month treatment period. Serum E2 levels were decreased, but only one woman in each of the mid- and high-dose groups, and no woman in the low-dose group, had a serum E2 level below 20 pg/ml in both cycles. All ATZ and LNG combinations showed good tolerability., Limitations, Reasons for Caution: This was an exploratory study; no formal power calculation was performed., Wider Implications of the Findings: The results of this first-in-human study of the ATZ/LNG IVR facilitated the selection of ATZ and LNG doses to be investigated in the Phase 2 studies of patients with endometriosis., Study Funding/competing Interest: The study was funded by Bayer Pharma AG. T.R. is an employee of DINOX GmbH, which received funding from Bayer Pharma AG to perform this study. M.-H.S.-M., K.W., R.N., S.K., J.K., H.S. and B.R. are or have been employees of Bayer Pharma AG. H.S. is a named inventor on EP 2 552 404 B1, a patent application relating to this work., Trial Registration Number: EudraCT number: 2011-005620-18., Trial Registration Date: 16 November 2011., Date of First Patient's Enrolment: 14 March 2012., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Study Question: Does administration of vilaprisan (VPR) to healthy women for 12 weeks reduce menstrual bleeding?, Summary Answer: In this 12-week proof-of-concept phase 1 trial, most women (30/33, 90%) who received VPR at daily doses of 1-5 mg reported the absence of menstrual bleeding., What Is Known Already: Vilaprisan (BAY 1002670) is a novel, highly potent selective progesterone receptor modulator that markedly reduces the growth of human leiomyoma tissue in a preclinical model of uterine fibroids (UFs)., Study Design, Size, Duration: In this double-blind, parallel-group study, of the 163 healthy women enrolled 73 were randomized to daily VPR 0.1 mg (n = 12), 0.5 mg (n = 12), 1 mg (n = 13), 2 mg (n = 12), 5 mg (n = 12) or placebo tablets (n = 12) for 12 weeks. Participants were followed up until the start of the second menstrual bleeding after the end of treatment. Trial simulations were used to determine the minimum sample size required to estimate the non-bleeding rate (i.e. self-assessed bleeding intensity of 'none' or 'spotting') using Bayesian dose-response estimation with incorporated prior information. It was estimated that 48 participants in the per-protocol analysis population would be sufficient., Participants/materials, Setting, Methods: Women aged 18-45 years who had been sterilized by tubal ligation were enrolled between November 2011 and May 2012. Participants kept a daily diary of bleeding intensity. Blood and urine samples were taken, and transvaginal ultrasound was performed before treatment, during treatment and follow-up. Endometrial biopsies were obtained during the pretreatment cycle, at the end of the treatment period and during the follow-up phase. The primary outcome was the estimated dose-response curve of the observed non-bleeding rate during Days 10-84 of treatment, excluding the endometrial biopsy day and 2 days after biopsy. Secondary outcomes included return of bleeding during follow-up, size of follicle-like structures and serum hormone levels. Safety assessments included adverse events (AEs), endometrial thickness and histology, laboratory parameters, vital signs and 12-lead electrocardiography., Main Results and the Role of Chance: All 73 randomized participants received at least one dose of study medication and were included in safety analyses; six participants were excluded from the per-protocol analyses. A total of 69 completed the study. Observed non-bleeding rates increased with VPR dose: 0.1 mg (0%; 90% confidence interval [CI]: 0-23.8), 0.5 mg (27.3%; 90% CI: 7.9-56.4), 1 mg (80.0%; 90% CI: 49.3-96.3), 2 mg (100%; 90% CI: 77.9-100), 5 mg (90.9%; 90% CI: 63.6-99.5), compared with 0% (90% CI: 0-22.1) in the placebo group. Maximal non-bleeding rates were reached at doses of 2 mg and higher. Return of menstrual bleeding was observed in all women ≤52 days after VPR discontinuation. No treatment-emergent critical endometrial findings occurred. Follicular growth was not suppressed and minimum average estradiol levels remained above 40 pg/ml. No serious treatment-emergent AEs or study discontinuations due to AEs were reported. Clinically relevant changes in laboratory parameters or vital signs were not evident., Limitations, Reasons for Caution: The results of this small proof-of-concept study will need to be confirmed in larger trials in patients with UFs to establish the potential therapeutic benefits and safety of VPR., Wider Implications of the Findings: The high rates of non-bleeding (80-100% at VPR doses of 1-5 mg) support further evaluation of VPR in patients with UFs and heavy menstrual bleeding., Study Funding/competing Interests: This study was funded by Bayer Pharma AG. B.S., A.K., M.-H.S.M., C.S. and B.R. are employees of Bayer Pharma AG. B.S., A.K. and M.-H.S.M. are listed as inventors of an issued patent related to this work, and received payment for this from Bayer Pharma AG. D.B. is the founder of Biokinetic Europe Ltd, UK, which received funding for this study from Bayer Pharma AG. M.K. is an employee of Nuvisan GmbH, Germany, which received funding for this study from Bayer Pharma AG., Trial Registration Number: Clinicaltrials.gov identifier: NCT01816815., Trial Registration Date: 20 March 2013., Date of First Patient's Enrolment: 28 November 2011., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Isoflavonoids and lignans are diet constituents with chemopreventive properties. We compared the ability of the isoflavonoids genistein and equol, the lignans enterodiol, enterolactone and nordihydroguaiaretic acid (NDGA) and the lignan metabolite methyl p-hydroxyphenyllactate to interfere with mitogenic and tumour promotional signal transduction pathways. Their effects on c-fos mRNA levels after induction by either epidermal growth factor (EGF) or the tumour promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was measured in human breast cancer-derived MDA-MB-468 cells. Of the six agents, only genistein decreased EGF-induced, c-fos transcription (by 63% compared to control at 100 mumol/l). In contrast, both genistein and equol at 100 mumol/l decreased TPA-induced c-fos levels, by 75 and 67%, respectively. NDGA and methyl p-hydroxyphenyllactate did not inhibit TPA mediated c-fos transcription and enterolactone and enterodiol had only a weak inhibitory effect. NDGA at 0.1-10 mumol/l increased c-fos mRNA levels. None of the agents inhibited protein kinase C and only genistein inhibited EGF receptor-linked protein tyrosine kinase obtained from MDA-MB-468 cells, with an IC50 of 60 mumol/l. NDGA and genistein arrested cell colony formation potently, genistein was 15-fold more growth-inhibitory than equol. The results suggest that both genistein and equol interfere similarly with TPA-induced signal transduction pathways. Inhibition by genistein of EGF-induced c-fos mRNA transcription is probably related to its interruption of EGF receptor-linked protein tyrosine kinase, whereas genistein-induced growth arrest is not. If ability to antagonise phorbol ester effects is important for chemopreventive efficacy, equol and genistein might be equi-efficacious chemopreventors, whereas enterolactone, enterodiol and NDGA should be much less potent. If phorbol ester antagonism together with antimitogenic activity determine optimal chemopreventive activity of this type of agent, genistein would be more potent than equol.

The staurosporine analogues CGP 41251, UCN-01 and Ro 31-8220 are specific inhibitors of protein kinase C (PKC). CGP 41251 and UCN-01 exert anti-neoplastic activity against human tumours grown in rodents, and CGP 41251 reverses multidrug resistance. The hypothesis was tested that these agents can induce drug resistance and alter cellular levels of target kinases. Human-derived A549 lung carcinoma cells were exposed for 6 months to CGP 41251, UCN-01 or Ro 31-8220 at gradually increasing concentrations. Cells acquired resistance against these agents, 4.3-fold against CGP 41251 (A549/CGP cells), 4.0-fold against UCN-01 (A549/UCN cells) and 14-fold against Ro 31-8220 (A549/Ro cells). Cells were neither collaterally cross-resistant towards the PKC inhibitors nor resistant against the growth-inhibitory properties of 12-O-tetradecanoylphorbol-13-acetate. However, cross-resistance was observed in A549/CGP cells against staurosporine (13-fold) and in A549/Ro cells against doxorubicin (26-fold). All 3 cell types expressed multidrug resistance-associated protein, and A549/Ro cells expressed P-glycoprotein, as adjudged by Western blot analysis. Phorbol ester-stimulated PKC activity in these cells was decreased by between 57% and 96% compared to wild-type A549 cells. Levels of the PKC isoenzymes alpha and theta in all 3 resistant cell types and of PKC-epsilon in A549/UCN cells were concomitantly reduced. Cells regained drug sensitivity after culture in the absence of drug for 6 (A549/Ro cells), 5 (A549/CGP cells) and 1 (A549/UCN cells) months. Our results suggest the following features of this type of anti-signalling drug: (i) they can induce drug resistance, (ii) they may be potentially useful in combination because of the lack of cross-resistance between them and (iii) they can down-regulate PKC, which may have pharmacological or toxicological consequences.

1. The first example of a P450-dependent N-hydroxylation of an aminoguanidine (amidinohydrazone) is reported for 2-amino-5-chlorobenzophenone amidinohydrazone 1 (G 256) as substrate. 2. The N-hydroxylated metabolite 2 (2-amino-5-chlorobenzophenone N-hydroxyamidinohydrazone NOH-G256) and a further metabolite of 1, the phenol 3, were identified by tlc and ms analysis. 3. The microsomal reduction of an N-hydroxyaminoguanidine (N-hydroxy-amidino-hydrazone) was also demonstrated for the transformation of 2 to 1. 4. Both the N-hydroxylation of the aminoguanidine and the retroreduction of the N-hydroxyaminoguanidine were characterized by quantitative hplc analysis. 5. The conversion of the aminoguanidine 1 to N-hydroxyaminoguanidine 2 may be considered as an analogue of the physiological N-hydroxylation of arginine to N-hydroxyarginine by NO synthases.

The microsomal N-hydroxylation of the strongly basic guanidinium group (debrisoquine) to N-hydroxyguanidine (N-hydroxydebrisoquine) and the retroreduction of the N-hydroxyguanidine are demonstrated for the first time. The reduction of the N-hydroxyguanidine by liver homogenates and hepatocytes is catalysed by a microsomal NADH-dependent system that is strongly inhibited by hydroxylamine or N-methylhydroxylamine. In the presence of these alternate substrates for the reductase the microsomal catalysed N-hydroxylation of debrisoquine is readily characterized. The oxidation was inhibited by antibodies against NADPH cytochrome P450 reductase and the role of the P450 monooxygenase was further verified by studies with partially purified and purified P450 2C3 reconstituted systems. The transformation of N-hydroxydebrisoquine to the corresponding urea derivative was also detected in in vitro experiments with microsomal fractions and enriched P450 fractions as well as with flavin-containing monooxygenase (FMO). Experiments with catalase, superoxide dismutase and H2O2 have shown that the H2O2 or O2-, respectively, formed from the respective enzyme and the substrate, apparently participated in the reaction. Whereas the N-hydroxylation of the guanidine involves the usual monooxygenase activity of cytochrome P450 the resultant N-hydroxyguanidine decouples monooxygenases (cytochrome P450, FMO) and the H2O2 and, above all, O2- thus formed transform the N-hydroxyguanidine further to the corresponding urea derivative. The possibility for the N-hydroxylation of non-physiological guanidines to N-hydroxyguanidines and subsequent oxidative conversion to the respective urea is comparable to the physiological transformation of arginine to citrulline via N-hydroxyarginine with the liberation of nitric oxide (endothelial derived relaxing factor) and could, therefore, contribute to the efficacy of drugs containing guanidine and similar functional groups.