Effect of hepatic impairment on the pharmacokinetics of vilaprisan: An open‐label, single‐dose, parallel‐group study

Chattopadhyay, Niladri; Riecke, Kai; Ligges, Sandra; Zimmermann, Till; Halabi, Atef; Schultze‐Mosgau, Marcus‐Hillert

doi:10.1111/bcp.13992

Cited by 8 publications

(6 citation statements)

References 19 publications

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“…Moderate left ovarian cyst, mild endometrial echo asymmetry, and postmenopausal bleeding were observed in 1 subject. The majority of these safety findings were similar to the findings observed in previous phase 1 5,[11][12][13][18][19][20] and phase 2 6,14 studies. Further PK, safety, and efficacy data from patients including Chinese women will be collected in the phase 3 program that is currently on partial clinical hold to allow for thorough evaluation as a precautionary measure due to preclinical findings in toxicologic long-term studies with vilaprisan in rodents.…”

Section: Safetysupporting

confidence: 88%

Pharmacokinetics and Safety of the Selective Progesterone Receptor Modulator Vilaprisan in Chinese Healthy Postmenopausal Women

Jiang

Chen

et al. 2020

Clinical Pharm in Drug Dev

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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.

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Section: Safetysupporting

confidence: 88%

Pharmacokinetics and Safety of the Selective Progesterone Receptor Modulator Vilaprisan in Chinese Healthy Postmenopausal Women

Jiang

Chen

et al. 2020

Clinical Pharm in Drug Dev

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“…Although the target population for vilaprisan is women with UFs or endometriosis, the study was conducted in both male and female participants because the PK of vilaprisan are similar between both sexes, as previously shown in a clinical study that included female and male participants with hepatic impairment. 9 Eligible participants were 18 to 79 years old with a body mass index of 18 to 40 kg m −2 (inclusive). Participants were excluded from study participation if they had a clinically significant medical abnormality other than renal impairment or its underlying causes, in particular, gastrointestinal, cerebrovascular, cardiovascular, or pulmonary disorders.…”

Section: Participantsmentioning

confidence: 99%

Pharmacokinetics and Safety of the Novel Selective Progesterone Receptor Modulator Vilaprisan in Participants With Renal Impairment

Schultze‐Mosgau

Lasseter

Marbury

et al. 2020

The Journal of Clinical Pharma

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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.

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“…was not identified as a significant covariate in the population PK analysis by Sutter et al [ 23 ] a Furthermore, largely the same VPR exposure was observed in studies with Chinese, Japanese, and mainly Caucasian/White postmenopausal subjects (ESM 3) No dose adjustment based on race or ethnicity is necessary Renal impairment Increase VPR exposure was mildly increased in subjects with moderate renal impairment (eGFR 30–59 mL/min/1.73 m 2 ) compared with healthy controls (estimated AUC ratio 135%) [ 29 ]. No dose adjustment is required for these patients Based on only limited data in subjects with severe renal impairment, VPR is not recommended to be used in this patient population Hepatic impairment Increase Only mild increases of < 1.75-fold in exposure were observed in subjects with mild (Child–Pugh A) or moderate (Child–Pugh B) hepatic impairment compared with control subjects [ 30 ]. No dose adjustment is required in patients with mild or moderate hepatic impairment.…”

Section: Pharmacokinetic (Pk) Propertiesmentioning

confidence: 99%

“…Due to the currently targeted indications, i.e., UFs and endometriosis, almost all studies with vilaprisan were conducted in women. Men were included in only two studies—a PK study in patients with renal impairment [ 29 ] and a PK study in patients with hepatic impairment [ 30 ]. A subgroup analysis within the latter study did not reveal any obvious differences in the vilaprisan exposure levels of men and women with normal hepatic function.…”

Section: Pharmacokinetic (Pk) Propertiesmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of the Selective Progesterone Receptor Modulator Vilaprisan: A Comprehensive Overview

et al. 2021

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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.

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Effect of hepatic impairment on the pharmacokinetics of vilaprisan: An open‐label, single‐dose, parallel‐group study

Cited by 8 publications

References 19 publications

Pharmacokinetics and Safety of the Selective Progesterone Receptor Modulator Vilaprisan in Chinese Healthy Postmenopausal Women

Pharmacokinetics and Safety of the Selective Progesterone Receptor Modulator Vilaprisan in Chinese Healthy Postmenopausal Women

Pharmacokinetics and Safety of the Novel Selective Progesterone Receptor Modulator Vilaprisan in Participants With Renal Impairment

Clinical Pharmacokinetics and Pharmacodynamics of the Selective Progesterone Receptor Modulator Vilaprisan: A Comprehensive Overview

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