The objective of the current work was to develop a predictive population pharmacokinetic/pharmacodynamic (PK/PD) model for the testosterone (TST) effects of triptorelin administered in sustained-release (SR) formulations to patients with prostate cancer, and to determine the minimum required triptorelin serum concentration (CTRP_min) to maintain the patients castrated (TST≤0.5 ng/mL). A total of 8 healthy male volunteers and 74 prostate cancer patients received one of 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 using the population approach with the NONMEM software. The PK/PD model was constructed resembling the agonist nature of triptorelin together with the competitive reversible receptor binding interaction with the endogenous agonist, a process responsible of the initial and transient TST flare-up, and triggering down-regulation mechanisms described as a decrease in receptor synthesis. The typical population values of KD, the receptor equilibrium dissociation constant of triptorelin, and CTRP_min to keep 95% of the patients castrated were 0.931 ng/mL and 0.0609 ng/mL, respectively. The semi-mechanistic 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 development of new delivery systems.
- Received April 12, 2012.
- Revision received June 11, 2012.
- Accepted June 11, 2012.
- The American Society for Pharmacology and Experimental Therapeutics