Pilari, S.
Abbott GmbH & Co. KG
Objectives: Hormone replacement therapy (HRT) is widely used to antagonize low levels of endogenous hormones as e.g. in menopause, hypogonadism, and hypothyroidism. In the determination of the pharmacokinetics and bioequivalence of exogenously administered hormones the levels of endogenous hormones has to be taken into account. Current guidelines recommend the analysis of time matched differences between observations under placebo and active treatment in cross-over studies. However, the exogenous introduction of hormones may lead to a shutdown or down-regulation of the endogenous hormone production that may result in constantly declining endogenous hormone concentrations under active treatment. Not taking into account the dynamics of this hormonal interplay and feedback mechanism thus may lead to a bias in AUC and volume of distribution of exogenously administered hormones. Consequently, bioequivalence may falsely be concluded which increases patient risk.
Methods: Exemplary for Testosterone homeostasis, we develop a mechanism-based semi-physiological model to describe the down-regulation of endogenous Testosterone and its metabolite 5alpha-Dihydrotestosterone (DHT) following oral Testosterone replacement therapy. To distinguish exogenously introduced and endogenously produced Testosterone, we particularly make use of extensive measurements of Testosterone and DHT at baseline (prior to HRT), under treatment, and in the washout period. Our model further incorporates the most relevant processes involved in the maintenance of Testosterone homeostasis, i.e., circadian rhythm of endogenous Testosterone production, binding of Testosterone and DHT to sex hormone binding globulin (SHBG) as well as Testosterone feedback on SHBG levels.
Results/Conclusions: We demonstrate that HRT may lead to a shutdown or down-regulation of endogenous hormones. Current guidelines acknowledge the influence of endogenous hormone levels but do not adequately reflect the importance of the temporal dependency. In order to quantify and predict the impact of HRT on endogenous hormone homeostasis, it is indispensable to extensively collect data prior to HRT, under treatment as well as in the washout phase. Alternatively, the use of radio-labeled hormones or additional enrollment of patients without an endogenous production would make it possible to distinguish exogenous and endogenous hormone levels but are likely beyond the capacities of typical phase I units.
Reference: PAGE 21 (2012) Abstr 2491 [www.page-meeting.org/?abstract=2491]
Poster: Other Drug/Disease Modelling