Coupling complex mechanistic PK/PD modelling with dynamic system analysis to obtain relevant clinical/biological insights. Application to gonadotropin hormone release agonist
Elba Romero (1), Nieves Vélez de Mendizábal (1), Josep-María Cendrós (2), Concepción Peraire (2), Rosendo Obach (2), and Iñaki F. Trocóniz (1)
(1), Department of Pharmacy and Pharmaceutical Technology; School of Pharmacy; University of Navarra; Pamplona 31080; Spain.(2), Pharmacokinetics and Metabolism Department, Ipsen Pharma S.A., Sant Feliu de Llobregat, Barcelona, Spain.
Objectives:The gonadotropin hormone release agonist triptorelin (TPT) administered subcutaneously or intramuscularly in sustained release (SR) formulations is being used in the treatment of prostate cancer. So far the relationships between plasma drug concentration (CTPT) and response independent of the type of SR, and between a marker of drug exposure and castration [testosterone (TST) levels in plasma < 0.5 ng/mL] have not been established yet. The aim of this study was (i) To develop a predictive receptor-based pharmacokinetic/pharmacodynamic (PK/PD) model for the TST effects of triptorelin. (ii) To extract relevant clinical PK properties of the SR formulations through a formal mathematical analysis of the model.
Methods: Data (CTPT and TST) from a population of 74 prostate cancer patients and 8 healthy volunteers from four clinical trials (one phase I, two phase II, and one phase III) in which five different triptorelin formulations were tested, were analyzed in the current evaluation. Triptorelin was administered by subcutaneous or intramuscular route. PK/PD model development was done by sequential analysis using nonlinear mixed effects (NONMEM VII). Values below the limit of quantification (representing > 50% of TST observations in some trials) were also considered during the analyses and were handled using the M3 method. The dynamic system analysis was done by phase diagrams to explore qualitative changes in receptor dynamics of total receptors and calculate a concentration threshold (CTHD) required to maintain the patient under the castration level .
Results: The PK/PD model developed reflected the agonist nature of triptorelin, the competitive interaction with the endogenous agonist, and the main characteristics of the receptor system: down-regulation and positive feed-back mechanisms. CTHD was calculated as 0.0351 ng/mL; additionally, the system analysis identified a qualitative change in the behaviour of the receptor dynamics at CTPT of 0.044 ng/mL, and represents the inability of the system to achieve levels of TST lower than 0.061 ng/mL beyond that CTPT value .
Conclusions: This work shows the advantage of using system analysis to extract relevant clinical/biological properties in the case of complex PK/PD models, otherwise difficult to confirm with the only use of standard simulation approaches.
 Beal SL. Ways to fit a PK model with some data below the quantification limit.
 Roberts EB. Making system dynamics useful: a personal memoir. System Dynamics Review. 23:119-136 (2007).