Population pharmacokinetic-pharmacodynamic modelling of angiotensin receptor blockade in healthy volunteers

Objective: To compare the pharmacokinetic and pharmacodynamic characteristics of angiotensin II receptor antagonists as a therapeutic class. Design: Population pharmacokinetic-pharmacodynamic modelling study. Methods: The data of 14 phase I studies with 10 different drugs were analysed. A common population pharmacokinetic model (two compartments, mixed zero-and first-order absorption, two metabolite compartments) was applied to the 2685 drug and 900 metabolite concentration measurements. A standard nonlinear mixed effect modelling approach was used to estimate the drug-specific parameters and their variabilities. Similarly, a pharmacodynamic model was applied to the 7360 effect measurements, i.e. the decrease of peak blood pressure response to intravenous angiotensin challenge recorded by finger photoplethysmography. The concentration of drug and metabolite in an effect compartment was assumed to translate into receptor blockade [maximum effect (E-max) model with first-order link]. Results: A general pharmacokinetic-pharmacodynamic (PK-PD) model for angiotensin antagonism in healthy individuals was successfully built up for the 10 drugs studied. Representatives of this class share different pharmacokinetic and pharmacodynamic profiles. Their effects on blood pressure are dose-dependent, but the time course of the effect varies between the drugs. Conclusions: The characterisation of PK-PD relationships for these drugs gives the opportunity to optimise therapeutic regimens and to suggest dosage adjustments in specific conditions. Such a model can be used to further refine the use of this class of drugs.