Developmental Pharmacogenetics of SLCO2B1 on Montelukast Pharmacokinetics in Chinese Children

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.

Keywords:

• montelukast
• ontogeny
• pharmacogenetics
• children

Acknowledgments

The abstract of this paper was presented at the European Society for Developmental Perinatal and Paediatric Pharmacology Congress as a poster presentation with interim findings. The poster’s abstract was published in “Poster Abstracts” in Archives of Disease in Childhood.

Data Sharing Statement

The pharmacogenetic data can be shared by emailing requests to the corresponding author.

Disclosure

WZ reports grants from the National Science and Technology Major Project for Major New Drugs Innovation and Development, the Young Taishan Scholars Program of Shandong Province, and the Qilu Young Scholars Program of Shandong University, during the conduct of the study. The authors report no other conflicts of interest in this work.

Additional information

Funding

This study was supported by National Science and Technology Major Project for Major New Drugs Innovation and Development (2017ZX09304029-001; 2017ZX09304029-002), Young Taishan Scholars Program of Shandong Province and Qilu Young Scholars Program of Shandong University.