Modeling a bivariate control system: LH and testosterone response to the GnRH antagonist antide

Abstract

A pharmacodynamic analysis of the input-response relationship between the gonadotropin-releasing hormone antagonist antide and luteinizing hormone (LH) and testosterone concentrations is presented. A control compartmental model is developed using pharmacokinetic and pharmacodynamic data from experiments in which different short intravenous antide infusions were given to healthy male volunteers. Because of the control interdependence between serum LH and testosterone a separation principle similar to one we have used previously to analyze physiological pharmacokinetic data is used for model exploration: testosterone and LH are first modeled separately, conditioning on the other observed response. This reveals that the LH effect on testosterone depends on previous LH exposure and that LH depends not on current but on previous testosterone exposure, resulting in an LH overshoot after antide-induced suppression. Both submodels are combined into one global model, which in addition includes a model for testosterone circadian variation. This model describes the data well and can be used to predict responses for some nonstudied antide dosages. However, the sensitivity of predictions to model assumptions limits the range of valid extrapolation, and this, too, is illustrated.

Pharmacokinetic/Pharmacodynamic Model of the Testosterone Effects of Triptorelin Administered in Sustained Release Formulations in Patients with Prostate Cancer

“…Population PK/PD models have been developed in the past for different antagonists (Fattinger et al, 1996;Pechstein et al, 2000;Tornøe et al, 2007) and different agonists (Gries et al, 1999;Tornøe et al, 2007) of the pituitary receptor. In the case of triptorelin a model developed for LH and testosterone after SR administration of triptorelin at the dose of 3.75 mg has been proposed (Tornøe et al, 2007).…”

Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of the hypothalamic–pituitary–gonadal axis following treatment with GnRH analogues

“…The complex regulatory behaviour of the hypothalamic–pituitary–gonadal (HPG) axis (see Figure 1) has been modelled by others [8–12]. Thus far, only a small number of pharmacokinetic/pharmacodynamic (PK/PD) models of the HPG axis after administration of GnRH analogues have linked the time course of drug concentration to its effect on LH and testosterone [13–15], and even fewer have incorporated the complex regulatory behaviour of the HPG axis [16]. No PK/PD model has described and predicted the response of LH and testosterone after treatment with both a GnRH agonist and a GnRH receptor blocker in one combined model.…”

Pharmacodynamic model of testosterone suppression after intramuscular depot estrogen therapy in prostate cancer

“…The literature value for half-life of testosterone is 0.5 hr or less [6], although estimates of up to 1.6 hr have been reported [7]. We observed a large individual variation of the parameter kout, giving halflives for testosterone in the range of 1-64 hr, and a median value of 8 hr.…”

“…The large interindividual variation in testosterone parameters indicates that a more complex model should also be examined. Furthermore, circadian variation of serum testosterone has been reported [5,7]. With the sampling schedule over several weeks in the present study, such a diurnal effect was not incorporated in our analysis.…”