PURPOSE: The purpose was to develop a population pharmacokinetic model for montelukast after intravenous administration. Clinical trial simulations were conducted using the model developed to identify the lowest intravenous dose in 6- to 14-year-old children that would give montelukast systemic exposures that were comparable to those found to be associated with efficacy in adults. METHODS: Two clinical studies were conducted where montelukast was administered intravenously as a 7-mg dose to adults and as a 3.5-mg dose to children aged 6 to 14 years. Model development included defining the base pharmacostatistical model and investigating the effects of demographic variables [age and total body weight (TBW)] on the structural parameters, using a nonlinear mixed effect modeling approach. RESULTS: A linear three-compartment pharmacokinetic model was found to best describe the disposition of montelukast. Inclusion of TBW as a covariate caused a 35% and 63% decrease in the interindividual variabilities on clearance and central volume of distribution, respectively. Trial simulations suggested that a 5.25-mg intravenous dose of montelukast should be chosen in children aged 6 to 14 years. CONCLUSIONS: The model developed can adequately describe the intravenous pharmacokinetics of montelukast and can be used as a useful tool for dose selection in pediatric subpopulations.
RCT Entities:
PURPOSE: The purpose was to develop a population pharmacokinetic model for montelukast after intravenous administration. Clinical trial simulations were conducted using the model developed to identify the lowest intravenous dose in 6- to 14-year-old children that would give montelukast systemic exposures that were comparable to those found to be associated with efficacy in adults. METHODS: Two clinical studies were conducted where montelukast was administered intravenously as a 7-mg dose to adults and as a 3.5-mg dose to children aged 6 to 14 years. Model development included defining the base pharmacostatistical model and investigating the effects of demographic variables [age and total body weight (TBW)] on the structural parameters, using a nonlinear mixed effect modeling approach. RESULTS: A linear three-compartment pharmacokinetic model was found to best describe the disposition of montelukast. Inclusion of TBW as a covariate caused a 35% and 63% decrease in the interindividual variabilities on clearance and central volume of distribution, respectively. Trial simulations suggested that a 5.25-mg intravenous dose of montelukast should be chosen in children aged 6 to 14 years. CONCLUSIONS: The model developed can adequately describe the intravenous pharmacokinetics of montelukast and can be used as a useful tool for dose selection in pediatric subpopulations.
Authors: B Knorr; H H Nguyen; G L Kearns; C Villaran; M L Boza; T F Reiss; J D Rogers; J Zhang; P Larson; S Spielberg Journal: J Clin Pharmacol Date: 2001-06 Impact factor: 3.126
Authors: B Knorr; P Larson; H H Nguyen; S Holland; T F Reiss; P Chervinsky; K Blake; C H van Nispen; G Noonan; A Freeman; R Haesen; N Michiels; J D Rogers; R D Amin; J Zhao; X Xu; B C Seidenberg; B J Gertz; S Spielberg Journal: J Clin Pharmacol Date: 1999-08 Impact factor: 3.126
Authors: J J Zhao; J D Rogers; S D Holland; P Larson; R D Amin; R Haesen; A Freeman; M Seiberling; M Merz; H Cheng Journal: Biopharm Drug Dispos Date: 1997-12 Impact factor: 1.627