Qian Li1,2, Kai Wang3, Jun Zhou4, Wei Zhao1,2, Hai-Yan Shi2, Yue-E Wu1, Yue Zhou1, Min Kan1, Yi Zheng1, Guo-Xiang Hao1, Xin-Mei Yang2, Yi-Lei Yang2, Le-Qun Su2, Xiao-Ling Wang5, Evelyne Jacqz-Aigrain6,7. 1. Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China. 2. Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, People's Republic of China. 3. Department of Respiratory Disease, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, People's Republic of China. 4. Clinical Training Center, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, People's Republic of China. 5. Clinical Research Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, People's Republic of China. 6. Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, AP-HP, Paris, France. 7. University Paris Diderot, Sorbonne Paris-Cité, Paris, France.
Abstract
BACKGROUND: Montelukast, a potent oral selective leukotriene-receptor antagonist, inhibits the action of cysteinyl-leukotriene in patients with asthma. Although pharmacokinetic studies of montelukast have been reported in Caucasian adults and children, and showed large inter-individual variability on pharmacokinetics, none of these studies has been explored in Chinese children. Given the potential inter-ethnic difference, the purpose of the present study was to evaluate the effects of developmental factors and pharmacogenetics of CYP2C8 and SLCO2B1 on montelukast clearance in Chinese pediatric patients. METHODS: After the administration of montelukast, blood samples were collected from children and plasma concentrations were determined using an adapted micro high-performance liquid chromatography coupled with the fluorescence detection (HPLC-FLD) method. A previously published pharmacokinetic model was validated using the opportunistic pharmacokinetic samples, and individual patient's clearance was calculated using the validated model. Population pharmacokinetic analysis was performed using a nonlinear mixed-effects model approach (NONMEM V 7.2.0) and variants of CYP2C8 and SLCO2B1 were genotyped. RESULTS: Fifty patients (age range: 0.7-10.0 years) with asthma were enrolled in this study. The clearance of montelukast was significantly higher in children with the SLCO2B1 c.935GA and c.935AA genotypes compared with that of children with the SLCO2B1 c.935GG genotype (0.94 ± 0.26 versus 0.77 ± 0.21, p = 0.020). The patient's weight was also found to be significantly corrected with montelukast clearance (p <0.0001). CONCLUSION: The developmental pharmacology of montelukast in Chinese children was evaluated. Weight and SLCO2B1 genotype were found to have independent significant impacts on the clearance of montelukast.
BACKGROUND: Montelukast, a potent oral selective leukotriene-receptor antagonist, inhibits the action of cysteinyl-leukotriene in patients with asthma. Although pharmacokinetic studies of montelukast have been reported in Caucasian adults and children, and showed large inter-individual variability on pharmacokinetics, none of these studies has been explored in Chinese children. Given the potential inter-ethnic difference, the purpose of the present study was to evaluate the effects of developmental factors and pharmacogenetics of CYP2C8 and SLCO2B1 on montelukast clearance in Chinese pediatric patients. METHODS: After the administration of montelukast, blood samples were collected from children and plasma concentrations were determined using an adapted micro high-performance liquid chromatography coupled with the fluorescence detection (HPLC-FLD) method. A previously published pharmacokinetic model was validated using the opportunistic pharmacokinetic samples, and individual patient's clearance was calculated using the validated model. Population pharmacokinetic analysis was performed using a nonlinear mixed-effects model approach (NONMEM V 7.2.0) and variants of CYP2C8 and SLCO2B1 were genotyped. RESULTS: Fifty patients (age range: 0.7-10.0 years) with asthma were enrolled in this study. The clearance of montelukast was significantly higher in children with the SLCO2B1 c.935GA and c.935AA genotypes compared with that of children with the SLCO2B1 c.935GG genotype (0.94 ± 0.26 versus 0.77 ± 0.21, p = 0.020). The patient's weight was also found to be significantly corrected with montelukast clearance (p <0.0001). CONCLUSION: The developmental pharmacology of montelukast in Chinese children was evaluated. Weight and SLCO2B1 genotype were found to have independent significant impacts on the clearance of montelukast.
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