Pharmacokinetic/pharmacodynamic modelling of triptorelin in prostate cancer patients

Resumen

Prostate cancer is very sensitive to hormones, and its pharmacological treatment is mainly based on optimal androgen blockade, reflected as continuous plasma testosterone (TST) levels below the castration limit (0.5 ng/mL). Chemical castration can be achieved by triptorelin (TRP), a synthetic GnRH analogue administered as a sustained release (SR) formulation. The model proposed here defined triptorelin disposition in plasma followed a multi-exponential kinetics described with an open three compartment model evaluated in humans and dogs. Absorption process for all the sustained release formulation studied in both species assuming three simultaneous input mechanisms, two of them represented by first order kinetics and the third one by a zero order process. Main features of the PK/PD model are: (1)Competitive interaction between endogenous GnRH and triptorelin, (2)Down-regulation of the GnRH receptor, (3)Feed-back mechanism at the level of GnRH receptor. The model was applied to compute the pharmacokinetic descriptor CTRP_min, defined as the minimum drug concentration value, independent from the type of formulation administered, required to maintain 95% of the treated patients under the castration limit. CTRP_min for cancer patients was 0.0609 ng/mL. Pharmacokinetics and pharmacodynamics triptorelin behaved very similarly between humans and dogs. Model-based computer simulations showed that a good prediction of the testosterone effects in cancer patients can be obtained linking the pharmacokinetic model and estimates obtained in dogs with the pharmacodynamic-system model selected in humans. The modelling exercise performed in the current investigation highlights the possibilities of incorporating the pharmacometrics approach in drug development, in this case for the particular interest of searching for better sustained release devices.