<p>Developmental Pharmacogenetics of SLCO2B1 on Montelukast Pharmacokinetics in Chinese Children</p>

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 interindividual 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 highperformance 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.

Pharmacogenomics and Pediatric Asthmatic Medications

“…Mougey utilized the Asthma Symptoms Utility Index (ASUI) to measure drug responsiveness and found that those with the rs12422149 GG genotype demonstrated greater improvement at three months and six months compared to the those with the AG genotype [74]. Similarly, a study by Li with 50 Chinese children with an average age of 4.4 years old found lower montelukast clearance in the SLCO2B1 rs12422149 GG genotype compared to the GA and AA (0.77 ± 0.21 vs. 0.94 ± 0.26, p = 0.020) [75]. Those with the GG genotype displayed better responsiveness to montelukast due to lower drug clearance leading to increased plasma concentrations.…”

“…Those with the GG genotype displayed better responsiveness to montelukast due to lower drug clearance leading to increased plasma concentrations. Li also examined CYP2C8 variations, however no association was found with montelukast clearance in Chinese children [75]. These results may favor genetic testing to identify SLCO2B1, rs12422149 GG variants, which presumably should see the greatest effect from monteluakast treatment among LTM medications [76].…”

Pharmacogenomics of Leukotriene Modifiers: A Systematic Review and Meta-Analysis

“…It was reasonable to speculate that SLCO2B1 gene affected the pharmacokinetics of montelukast by affecting OATP2B1 protein, and thus the efficacy of montelukast. Several studies have demonstrated that SLCO2B1 (rs12422149) exhibited a substantial effect on the pharmacokinetics of montelukast [ 29 , 36 ]. Mougey et al conducted a retrospective analysis and a clinical trial in 2009 and 2011, which concluded that patients with AG genotype of SLCO2B1 (rs12422149) had lower montelukast plasma concentration [ 34 , 35 ].…”

“…Mougey et al conducted a retrospective analysis and a clinical trial in 2009 and 2011, which concluded that patients with AG genotype of SLCO2B1 (rs12422149) had lower montelukast plasma concentration [34,35]. Li et al found similar results showing that montelukast clearance was higher in patients with AG and AA genotype (Table 5) [36]. However, Tapaninen et al and Kim et al did not find a significant relationship in healthy volunteers [49,50].…”