Semi-mechanistic Pharmacodynamic model of complex receptor-hormone dynamics
Victor Mangas Sanjuan (1,2), Elba Romero (3), Iñaki F Troconiz (1)
(1) Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain, (2) Pharmacy and Pharmaceutical Technology Area. School of Pharmacy. University of Valencia, Valencia, Spain, (3) Pharmaceutical Research and Development Laboratory, Department of Pharmacobiology, University of Guadalajara, Guadalajara, Jalisco, México.
Objectives: The objective of this work is to develop a pharmacodynamic model describing hormone time-course after the administration of a receptor agonist at different rates-.
Methods: A simulation exercise was developed in order to characterize the complex and flexible behavior of hormone levels in vivo. Different structural models were proposed incorporating a receptor, hormone and modulator compartments. Several mechanisms were adopted: a down-regulation mechanism, tolerance phenomenon, stimulation of hormone levels through endogenous/exogenous agonist, the rate of change of receptor/hormone levels as an activator of feedback kinetics, a modulator-mediated effect on the receptor/hormone levels. All analyses were performed with Simulx (mlxR package) in R 3.3.1.
Results: Due to the great time-scale between IV (measurements up to 2 days) and SR (measurements up to 300 days) formulations, a standard receptor-agonist model could not characterize the observed outcome. Therefore, the final model includes a modulator cascade (MTT=0.7 days) non-linearly activated by the rate of change of hormone levels, which stimulates hormone loss through an exponential function based on the concentrations of modulator in the last compartment (CMT=5). Deterministic and stochastic simulations were implemented in Simulx.
Conclusion: A semi-mechanistic pharmacodynamic model able to simulate the extent and flexibility of receptor and hormone dynamics was developed. After IV administration, the large amount of exogenous agonist perturbs in a greater extent the hormone synthesis and loss, which could not be characterized with standards models available. The rate of change of hormone and a feedback effect on hormone levels through a delayed modulator synthesis allowed to predict the different hormone dynamics after IV and SR administration.