Iñaki F. Trocóniz 1, Christiane Tillmann 2, Dirk Trommeshauser2, Matthias Klueglich3, Juliet Roberts4, Hans G. Schaefer2
1, Department of Pharmacy; School of Pharmacy; University of Navarra; Pamplona; Spain
Purpose: To develop a pharmacokinetic/pharmacodynamic model capable to describe simultaneously and semi mechanistically the time course of the heart rate response measured at rest (HRrest) and at end of exercise (HRexe) after administration of Cilobradine.
Methods: 96 healthy female and male volunteers, receiving once daily oral doses of Cilobradine at dose levels of 0.25, 0.5, 1, 2 and 5mg or placebo over a period of two weeks, were included in the analysis. Plasma samples and response measurements were taken extensively during the first and the last day of administration, as well as trough values in-between. A total of 1173 plasma concentration values (C), 3312 HRrest and 1467 HRexe measurements were used to build the PK-PD models. All the analyses were performed under the population approach using the FOCE method implemented in NONMEM V.
Results: Absorption process and disposition of Cilobradine in plasma were best described through a first order absorption and a three compartment body model respectively. HRrest and HRexe data were fitted separately with an EMAX model relating drug effects with the predicted effect site concentrations. The estimates of EC50 and ke0 were very similar for the two responses, 4.57 and 5.16 ng/mL and 0.009 and 0.0147 h-1, respectively. The derived t1/2ke0 values predict that distribution equilibrium between plasma and biophase will be achieved after three weeks of continuous treatment, a very unlikely phenomena taking into account the site of action for this type of drugs. Probably such a delay is due to another mechanisms different from drug distribution. A standard indirect response model was used to describe regulation of heart rate. The increase in response after 3 min of exercise was modeled as an increase of θ magnitude in the zero order rate constant of synthesis (ksyn) for a period of 3 min. A slow adaptation process, governed with the kadapt rate constant and including two transit compartments, served to relate drug effects with the inhibition in ksyn. The decrease in kadapt as a function of C was found to be linear.
Conclusions: The model shows an example of how to deal with responses that are experimental and temporally altered during the study period.
Reference: PAGE 14 (2005) Abstr 734 [www.page-meeting.org/?abstract=734]
Poster: poster