Pharmacokinetic/pharmacodynamic model of the testosterone effects of triptorelin administered in sustained release formulations in patients with prostate cancer
| Autor: | Concepción Peraire, Nieves Velez de Mendizabal, Elba Romero, Emma Bascompta, Josep-María Cendrós, Iñaki F. Trocóniz, Rosendo Obach |
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| Rok vydání: | 2012 |
| Předmět: |
Agonist
Male medicine.medical_specialty Adolescent Antineoplastic Agents Hormonal medicine.drug_class Chemistry Pharmaceutical Population Down-Regulation Pharmacology Injections Intramuscular Models Biological Prostate cancer Pharmacokinetics Internal medicine Medicine Humans Testosterone education Randomized Controlled Trials as Topic education.field_of_study Clinical Trials as Topic Triptorelin Pamoate business.industry Prostatic Neoplasms medicine.disease Triptorelin NONMEM Endocrinology Pharmacodynamics Case-Control Studies Delayed-Action Preparations Molecular Medicine business Orchiectomy medicine.drug |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 342(3) |
| ISSN: | 1521-0103 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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