Dinesh P. de Alwis, Iñaki F. Troconiz*, Christiane Tillmann and Hans G. Schaefer
Eli Lilly and Company Ltd, Clinical Pharmacology, Windlesham, Surrey, United Kingdom ; *Dept of Pharmacy, School of Pharmacy, University of Navarra, Pamplona, Spain.
Although the PK/PD analysis of blood pressure has been reported on several occasions, the models developed did not take into account the day variations in the response. Recently (Hempel et al., 1998) developed a model using NONMEM where the circadian variations in 24h-ambulatory blood pressure measurements (24h-ABPM) were used, allowing the estimation of pharmacodynamic parameters of moxonidine and their estimates of interindividual variability. In the current study, the PK/PD model previously developed with 24h ABPM for moxonidine was used in another patient population and compared with those obtained from the PK/PD analysis using manual blood pressure data.
The pharmacokinetics of moxonidine were best described by a one compartment model with first order absorption and first order elimination. The model was parameterised in terms of CL/F, V/F, ka.
The final baseline model for blood pressure consisted of two cosine functions allowing interoccasion variability, i.e. intraindividual deviations from day to day. The PK/PD analysis of blood pressure measurements (24h ABPM and manual) was based on 32 patients receiving either moxonidine (0.6 mg, 0.9 mg and 1.2 mg) or placebo. The pharmacodynamics of moxonidine were best described by an inhibitory Emax model with an effect link compartment.
In conclusion, for both types of measurements (manual and 24h ABPM) the typical population estimates for ke0, EC50 and Emax were very similar. The data obtained during the manual blood pressure recordings did not allow for the estimation of interindividual variability in the pharmacodynamic parameters. However, using 24h ABPM data, interindividual variability could be clearly obtained for ke0 and Emax parameters.
Reference:
Hempel G.H. Karlsson M.O, de Alwis D.P, Toublanc N, McNay J and Schaefer H.G (1998). Population pharmacokinetic – pharmacodynamic modelling of moxonidine using 24-hour ambulatory blood pressure measurements. Clinical Pharmacology and Therapeutics, 64 (6), 622-635.
Reference: PAGE 8 (1999) Abstr 147 [www.page-meeting.org/?abstract=147]
Poster: poster