C. Csajka, T. Buclin, K. Fattinger°, H.R. Brunner,J. Biollaz
Divisions of Clinical Pharmacology and Hypertension, University Hospital,Lausanne and °Zürich, Switzerland
The aim of this work was to assess the PK-PD relationships for various A2RA using a common model. The original data of 14 phase I studies testing 10 different A2RA (losartan, candesartan, tasosartan, irbesartan, TAK-536, SC-52458, L-159 282, LRB-081, UP-269-6 and CS-866) and involving 151 healthy volunteers treated by single raising doses were included in the PK-PD analysis. A population PK model was applied to the 2685 drug and 900 metabolite concentration data, to estimate the drug-specific parameters and their variabilities using NONMEM. A common model (2 compartments for drug and 2 for active metabolite, mixed 0- and 1st-order absorption) appeared appropriate to fit to all drug profiles. Similarly, a PD model was applied to the 7360 effect measurements, i.e. peak blood pressure responses to iv angiotensin challenge injections recorded by finger photoplethysmography (Finapres). The concentration of drug and metabolite in an effect compartment was assumed to decrease the peak response to angiotensin. This effect was best described using a sigmoid Emax model with 1st-order link. Thus, a general PK-PD model could be successfully built up for the whole family of drugs studied. The analysis of a pharmaceutical class using a common model provides an interesting basis for kinetic/dynamic comparisons. Simulations based on such a model can be used to evaluate further refinements in the clinical use of the drugs (optimisation of doses and intervals, galenic improvements, dosing adaptation in pathological conditions, prediction of drug interactions).
Reference: PAGE 10 () Abstr 183 [www.page-meeting.org/?abstract=183]
Poster: poster