Drug Design, Development and Therapy (Dec 2019)
Developmental Pharmacogenetics of SLCO2B1 on Montelukast Pharmacokinetics in Chinese Children
Abstract
Qian Li,1,2,* Kai Wang,3,* Hai-Yan Shi,2 Yue-E Wu,1 Yue Zhou,1 Min Kan,1 Yi Zheng,1 Guo-Xiang Hao,1 Xin-Mei Yang,2 Yi-Lei Yang,2 Le-Qun Su,2 Xiao-Ling Wang,4 Evelyne Jacqz-Aigrain,5,6 Jun Zhou,7,* Wei Zhao1,2,* 1Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, People’s Republic of China; 2Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, People’s Republic of China; 3Department of Respiratory Disease, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, People’s Republic of China; 4Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of China; 5Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, AP-HP, Paris, France; 6University Paris Diderot, Sorbonne Paris-Cité, Paris, France; 7Clinical Training Center, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun ZhouClinical Training Center, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, 16766 Jing Shi Street, Jinan 250014, People’s Republic of ChinaTel/Fax +86 531 8237 3200Email [email protected] ZhaoDepartment of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, 44 Culture West Road, Jinan 250012, People’s Republic of ChinaTel/Fax +86 531 8838 3308Email [email protected]: 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.Keywords: montelukast, ontogeny, pharmacogenetics, children
