Population pharmacokinetic analysis of mizolastine and validation from sparse data on patients using the nonparametric maximum likelihood method.
A population analysis of the kinetics of mizolastine was performed from concentrations on 449 allergic patients, using the nonparametric maximum likelihood method (NPML). A two-compartment open model with zero-order absorption was used to describe the kinetics of mizolastine after oral administration. A heteroscedastic variance model was assumed for the error. To explain the kinetic variability, eight covariates were introduced in the analysis: gender, pharmaceutical dosage form, age, body weight, serum creatinine concentration, creatinine renal clearance, plasma levels of hepatic transaminases ASAT and ALAT. Their relationships to the kinetic parameters were studied by means of the estimated distribution of each kinetic parameter conditional on different levels of each covariate. An important interindividual kinetic variability was found for all parameters. Moreover, several kinetic parameters among which the duration of absorption were found to be influenced by pharmaceutical dosage form and gender. Body weight and creatinine renal clearance were found to have a little influence on the oral clearance and the smallest disposition rate constant. This population analysis was validated on a separate group of 247 other patients. For each observed concentration of this sample, a predictive distribution was computed using the individual covariates. Predicted concentrations and standardized prediction errors were deduced. The mean and variance of the standardized prediction errors were, respectively, 0.21 and 2.79. Moreover, in the validation sample, the predicted cumulative distribution function of each observed concentration was computed. Empirical distribution of these values was not significantly different from a uniform distribution, as expected under the assumption that the population model estimated by NPML is adequate.
Mesnil
F
F
INSERM U 436, Paris, France.
Mentré
F
F
Dubruc
C
C
Thénot
J P
JP
Mallet
A
A
D001562:Benzimidazoles / Q000493:pharmacokinetics*; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D016013:Likelihood Functions; D015233:Models, Statistical; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results
D001562:Benzimidazoles; D006634:Histamine H1 Antagonists; C076170:mizolastine