C. Dubruc, S. Chaufour, P. Rosenzweig, J.P. Thenot and F. Mentré*
Synthélabo Recherche, Chilly-Mazarin (F), *INSERM U436, Pitié Salpêtrière, Paris (F)
The pharmacokinetic profile of mizolastine, a second generation antihistamine agent, was assessed in children aged from 6 to 12 years after a single oral administration of the paediatric solution. Optimal sampling times and the number of subjects with different designs were calculated from a population D-optimal protocol. Eighteen children were included in this study (13 boys and 5 girls) with a mean age of 8.6 years and a mean weight of 30.6 kg. Seven subjects had multiple blood samples at 0.25, 0.50, 0.75, 2.0, 3.0 and 6.0 hours, 3 had one sampling point at 8 hours, 2 at 12 hours, 3 at 24 hours and 3 at 32 hours. The data were fitted with NONMEM using an open two-compartment model with a zero order absorption phase. This model included five parameters : Tabs, V/F, CL/F, ” and $ . A multiplicative model for the random effects was used and the error variance model was additive and heteroscedastic. A first run was performed using the mg/kg dose and estimating interindividual variability for each parameter with the FO method. The interindividual variability estimated for V/F, ” and $ was close to zero. A second run was performed with interindividual variability only on CL/F and Tabs. Using the FOCE method, the population mean values were Tabs = 0.608 h, V/F = 0.274 L/kg, CL/F = 0.0953 L/h/kg, ” = 0.476 h-1 and $ = 0.0735 h-1 with coefficients of variation of 20.5% for CL/F and 38.3% for Tabs. The estimated coefficient of variation of the error was 30%. In this run in mg/kg, no relationships with body weight were found in the POSTHOC estimates. Futhermore, when a run was performed using the total dose (mg) with variability only for CL/F and Tabs, the objective function was larger. These parameters were used to estimate the dose of mizolastine for a clinical study in allergic children.
Reference: PAGE 8 (1999) Abstr 149 [www.page-meeting.org/?abstract=149]
Poster: poster