Population pharmacokinetic analysis and optimization of the experimental design for mizolastine solution in children

Mizolastine is a second generation antihistamine agent approved in Europe f or the treatment of allergic rhinitis and skin conditions for which Sanofi- Synthelabo is developing a pediatric solution. Our objective was to design the population pharmacokinetic (PK) study of mizolastine pediatric solution in children. A bioavailability study of this solution compared to the mark eted tablet H as performed in 18 young volunteers. These PK data were analy zed by nonlinear regression wing a two-compartment open model with zero-ord er absorption. From the estimated parameters, we designed population PK stu dies in two groups of children: 6 to 12 years and 2 to 6 years respectively . To compare several population designs and to derive the optimal ones, we used the determinant of the Fisher information matrix of the population cha racteristics using a first-order expansion of the model. We have evaluated a "reference" population design with IO samples (from 0.25 to 36 hr after d rug intake) per child in 6 children, which could nor be implemented in prac tice for ethical reasons, We then derived optimal population designs with 1 , 2, 3, 4, or 5 samples per child and a total of 60 samples. Finally, the d esigns that were implemented in the population PK study were "compromise" p opulation designs with 60 samples: one defined for 20 children 6 to 12 year s old, and one with 24 children 2 to 6 years. In the older group, the popul ation design involved 8 children with a catheter from which 6 samples at li me 0.25, 0.5, 0.75, 2, 3, and 6hr after drug intake are collected. and 12 c hildren with only one sample at lime 8, IZ, 24, or 36 hr. In the younger gr oup, the population design involved 15 children with a catheter who are div ided in three groups with four samples at different times from 0.25 to 6 hr after drug intake, and IZ children with only one sample at lime 8, 12, 18, or 24 hr. The expected average increase of Variances of these designs comp ared to the reference design were 1.6 and 1.8 for the older and younger gro up, respectively, which was decided to be acceptable. Better population des igns would have invoiced three groups of children with five samples per chi ld but could not be implemented in practice. The data of the PK study in ch ildren 6 to 12 years were available and were analyzed using NONMEM. A total of 53 concentrations were obtained in 18 children. The same two-compartmen t model with zero-order absorption was used. The interindividual variabilit y in children was small. The estimated population parameters in children 6 to 12 years, were 0.28 L/kg for V-c/F, 0. 10 L/hr per kg for CL/F, 0.53 hr( -1) for lambda (1), 0.076 hr(-1) for lambda (2). and 0.49 hr for T-abs. The se values were close to the median values observed in young volunteers when standardized to 70 kg: notably, CL/F in L/hr per kg was similar, so that a dose of 0.15 mg/kg o.d. for mizolastine pediatric solution should give an equivalent area under the curve to a 10 mg o.d. tablet in adults.