Pharmacokinetic/pharmacodynamic model of the testosterone effects of triptorelin administered in sustained release formulations in patients with prostate cancer

J Pharmacol Exp Ther. 2012 Sep;342(3):788-98. doi: 10.1124/jpet.112.195560. Epub 2012 Jun 12.

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 ≤ 0.5 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Antineoplastic Agents, Hormonal / blood
  • Antineoplastic Agents, Hormonal / pharmacokinetics
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Case-Control Studies
  • Chemistry, Pharmaceutical
  • Clinical Trials as Topic
  • Delayed-Action Preparations
  • Down-Regulation / drug effects
  • Humans
  • Injections, Intramuscular
  • Male
  • Models, Biological
  • Orchiectomy
  • Prostatic Neoplasms / blood*
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / surgery
  • Randomized Controlled Trials as Topic
  • Testosterone / blood*
  • Triptorelin Pamoate / administration & dosage*
  • Triptorelin Pamoate / blood
  • Triptorelin Pamoate / pharmacokinetics*

Substances

  • Antineoplastic Agents, Hormonal
  • Delayed-Action Preparations
  • Triptorelin Pamoate
  • Testosterone