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

Abstract

The objectives of the current work were to develop a predictive population pharmacokinetic (PK)/pharmacodynamic (PD) model for the testosterone (TST) effects of triptorelin (TRP) administered in sustained-release (SR) formulations to patients with prostate cancer and determine the minimal required triptorelin serum concentration (C TRP_min ) to keep the testosterone levels of the patients below or equal to the level of castration (TST Յ0.5 ng/ml). A total of eight healthy male volunteers and 74 patients with prostate cancer received one or two doses of triptorelin injected subcutaneously or intramuscularly. Five different triptorelin formulations were tested. Pharmacokinetic (serum concentration of triptorelin) and pharmacodynamic (TST levels in serum) data were analyzed by using the population approach with NONMEM software (http://www.iconplc. com/technology/products/nonmem/). The PK/PD model was constructed by assembling the agonist nature of triptorelin with the competitive reversible receptor binding interaction with the endogenous agonist, a process responsible for the initial and transient TST flare-up, and triggering down-regulation mechanisms described as a decrease in receptor synthesis. The typical population values of K D , the receptor equilibrium dissociation constant of triptorelin, and C TRP_min to keep 95% of the patients castrated were 0.931 and 0.0609 ng/ml, respectively. The semimechanistic nature of the model renders the predictions of the effect of triptorelin on TST possible regardless the type of SR formulation administered, while exploring different designs during the development of new delivery systems.

Current challenges in peptide-based drug discovery

“…The situation is less problematic in humans where higher blood volumes are available than in rodents, although the required drug doses in humans are about 12-fold lower than in mice due to differences in the body surface area/weight ratio (Reagan-Shaw et al, 2008). Human serum concentrations of triptorelin, a 10-residue agonist of the gonadotropin-releasing hormone receptor, at 8 ng/mL are already associated with activation of 90% of the receptor population (Romero et al, 2012). In turn, even if the sensitivity of the murine plasma quantification protocol can be increased by a magnitude, later time points will still be missed when highly active peptide drugs are present in the circulation above their IC 50 /EC 50 figures.…”

A Semi-Mechanistic Integrated Pharmacokinetic/Pharmacodynamic Model of the Testosterone Effects of the Gonadotropin-Releasing Hormone Agonist Leuprolide in Prostate Cancer Patients

“…In the phase III study, blood samples for pharmacokinetic and pharmacodynamic assessments were collected from a subset of 28 patients on study days 1, 2, 4, and 8, and at weeks 2,4,8,14,20, and 24 after the first IM administration. Similarly, samples were collected 1, 2, 4, and 8 days and 2, 4, 8, 14, 20, and 24 weeks from the second dose, i.e., study days 169, 170, 171, and 176 and at weeks 26,30,34,40,46, and 48.…”

Time and dose relationships between schisandrin B- and schisandrae fructus oil-induced hepatotoxicity and the associated elevations in hepatic and serum triglyceride levels in mice

“…PD refers to the study of the time course and intensity of therapeutic and adverse effects of a drug, which are related to the receptor binding, postreceptor events, and chemical interactions. In this regard, the approach of PK/PD modeling is adopted to investigate the dose-response relationship for some drugs in vivo 7–9. However, for other drugs, a simpler relationship between the concentration and effect is modeled mathematically to conceptualize receptor occupancy and drug response in an idealized in vitro system 10–12…”