Exposure-response analysis of vilaprisan describing uterine fibroid size by population PK/PD modelling
Hauke Rühs (1), Gabriele Sutter (1), Matthias Frei (1), Marcus-Hillert Schultze-Mosgau (1), Dirk Garmann (1) and Bart Ploeger (1)
(1) Bayer AG
Objectives: Vilaprisan is a new highly potent and selective progesterone-receptor-modulator (SPRM) in clinical development. The objective of the analysis was to assess the exposure–response relationship of vilaprisan on uterine fibroids in a Phase 2b dose finding study.
Methods: Data from a Phase 2b study, investigating efficacy and safety of different doses (0.5, 1, 2 and 4 mg) of vilaprisan over a treatment period of 3 months in women with symptomatic uterine fibroids, were analyzed by means of nonlinear mixed-effects modeling using the program NONMEM, version 7.3.0 (Icon Development Solutions, Ellicott City, Maryland USA) [1]. A PK model based on healthy subject data from two Phase 1 studies was applied to the data of the Phase 2b study in order to estimate the Empirical Bayes estimates.
With regard to the dose-exposure-response analysis of fibroid volume, the change in the largest fibroid volume - measured by transvaginal ultrasound - over time was analyzed. First, a model for the change in fibroid volume over time without vilaprisan treatment was developed. Based on this, the drug effect on the change in fibroid volume over time was investigated by testing different effect models, including Emax models.
Results: A total of 267 subjects were available for PK/PD analysis, with 217 subjects on active vilaprisan treatment and further 50 subjects who had received placebo treatment. The fibroid volume without vilaprisan treatment could be described as a constant volume, whereas the fibroid volume under treatment decreased exponentially. In the final model, the first-order rate constant for fibroid volume shrinkage depends on the vilaprisan AUC(0‑24)ss and this relationship was best described by an Emax model with a shape factor of 1. At the highest dose this corresponds to a shrinkage in fibroid volume relative to baseline of 53.0% after 3 months of treatment.All model parameters were estimated sufficiently well.
Conclusions: An exposure-response relationship for vilaprisan could be established by population PK/PD modelling, showing a high exposure driven effect of vilaprisan on uterine fibroid size. At the highest dose a shrinkage in fibroid volume relative to baseline of 53.0% was determined after 3 months of treatment.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
