Development of a mechanistic-based pharmacodynamic model to describe the effect of a prolonged administration of a GnRH agonist on testosterone levels
Elba M. Romero Tejeda, Nieves Vélez de Mendizábal, Iñaki F. Trocóniz
Universidad de Navarra
Objectives: The implementation of PD models to characterize specific processes between drug administration and its effect, are now substantially explored in order to describe the behavior of receptor mediated drug effects. To analyze the performance on the pharmacodynamic (PD) of an agonist, we developed a receptor-mechanism-based PD model able to describe the changes in testosterone concentrations observed after prolonged exposure of a GnRH agonist.
Methods: Pharmacokinetic profiles in order to develop the PD model were simulated from Bayesian predictions parameters previously reported [1]. Structural design of model was developed using the Systems Dynamics framework that combines the power of differential equations with a graphical design and representation of the variables [2]. The model and initial parameters estimates were developed and simulated in the VENSIM (Ventana Systems, Inc., MA, United States.) computing environment.The effect-versus-time data were evaluated during the analysis by the program NONMEM v7. The designed model was compared against models previously described in literature [3]. Performance evaluation between models was done by the exploration of visual predictive check and other statistical evaluation tools [4].
Results: The presence of the agonist in the developed model is responsible of the fractional receptor occupancy increase (R*/RT), enhancing testosterone levels (up-regulation) at the beginning of the treatment. This increase provokes in return a decrease in the number of total receptors. Therefore the number of active receptors drastically diminishes and reduces the synthesis of testosterone (down-regulation). The model includes a positive feedback loop, which is responsible of the recovery of the total receptors once the concentrations of the agonist were cleared from plasma. Such receptor recovery allows testosterone levels to return to homeostasis (recovery). Comparison between models revealed differences at the times of suppression and duration of the testosterone concentration needed to achieve castrate levels, recovering time of testosterone to homeostasis and type of recovery (linear, exponential).
Conclusions: A mechanism-based PD model was successfully developed allowing us to explore the influence of receptors occupancy and the the effect of a prolonged administration of a GnRH agonist on testosterone levels.
References:
[1]PAGE 18 (2009) Abstr 1563 [www.page-meeting.org/?abstract=1563]
[2] E.B.Roberts. Making system dynamics useful: a personal memoir. System Dynamics Review. 23:119-136 (2007)
[3]Tornoe, et al. Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of the hypothalamic-pituitary-gonadal axis following treatment with GnRH analogues. B. J. Clin. Pharmacol. 2007 (jun); 63(6): 648-64
[4] PAGE 18 (2009) Abstr 1604 [www.page-meeting.org/?abstract=1604]
