No abstract

A nonlinear mixed-effects modelling approach was used to analyse pharmacokinetic and pharmacodynamic data from two Phase I studies of a platelet activating factor (PAF) antagonist under development for the treatment of seasonal allergic rhinitis. Data for single-dose (8 subjects) and multiple-dose (9 subjects) administration were available for analysis with a program based on an EM algorithm. Pharmacokinetic analyses of plasma drug concentrations were performed using a biexponential model with first-order absorption. PAF response data were modelled with a hyperbolic Emax model. The drug showed nonlinear pharmacokinetics, with the clearance decreasing from 46.0 to 27.1 L h(-1) over a dose range of 160-480 mg. There was an apparent dose dependency within the C50 (concentration producing 50% of the maximum effect) but at higher doses most of the data was above the estimated C50 and when the data was analysed simultaneously a value of 17.57 ng mL(-1) was obtained for C50, with considerable intersubject variability (103%). Consistent results were obtained from the two studies and the population and individual pharmacodynamic parameter estimates from the analyses provided predicted responses that were in good agreement with the observed data. The results were used to simulate a 320-mg twice-daily dosing regimen.

The pharmacokinetics of tenidap can be described by a bi-exponential model with zero order absorption. Based on differences in the log-likelihood, significant covariate-parameter relationships were identified between smoking and CL, and between gender and Vss and CLd. Simulated sparse data analyses indicated that the model would be robust for the analysis of sparse data generated in observational studies.