Assessment of the safe and efficacious dose of the selective progesterone receptor modulator vilaprisan for the treatment of patients with uterine fibroids by exposure–response modelling and simulation

Abstract

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 (steadystate 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.

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

“…Overall, both covariates, i.e., body weight and BMI, are not considered clinically relevant for vilaprisan as they explain < 5% of the observed variability in the PK of vilaprisan. Further evaluations are warranted that include data from phase III studies to substantiate the findings of the covariate analysis reported by Sutter et al [23]. The current database (N = 414 subjects) was too small for an extensive covariate analysis, and also too homogenous as it included mainly Caucasians (70.8%; 13.8% Asians, 12.6% Blacks or African Americans).…”

“…No major impact of age and menopausal state (pre-or postmenopausal) on vilaprisan exposure was detected. Furthermore, neither was age identified as a significant covariate in the population PK meta-analysis of data obtained in 414 premenopausal women between 21 and 50 years of age [23], and nor were there any marked differences in vilaprisan exposure between healthy postmenopausal women, who were mostly…”

“…As mentioned above, two covariates were identified-body weight as a significant covariate for V2/F and BMI as a significant covariate for CL/F; they explained 1.2% and 4.4% of the V2/F and CL/F variability, respectively [23]. Thus, no dose adjustment based on body size is necessary.…”

“…A population PK meta-analysis showed that the PK of vilaprisan can be described by a linear two-compartment model with first-order elimination from the central compartment and first-order absorption kinetics including a lag time [23]. This population PK analysis was based on the PK data obtained in premenopausal or perimenopausal women between 21 and 50 years of age in two phase I [24,25] and two phase II studies (ASTEROID 1 and ASTEROID 2 trials) [26,27] as described in detail by Sutter et al [23]. The results from the population PK model were consistent with the dense PK data established initially in postmenopausal women.…”

“…The impact of various intrinsic and extrinsic factors on the exposure of vilaprisan was tested in a number of dedicated phase I studies. In addition, a few preselected potential impact factors were tested as covariates during the development of the above-described population PK model for vilaprisan [23]. An overview of the results of these studies and analyses is given in Table 2.…”