Association of CYP2C19 polymorphisms and lansoprazole-associated respiratory adverse effects in children

Abstract

Objective: To determine whether cytochrome P450 (CYP)2C19 haplotype associates with lansoprazole-associated adverse event frequency.

Study design: Respiratory adverse events from a clinical trial of lansoprazole in children with asthma were analyzed for associations with extensive or poor metabolizer (PM) phenotype based on CYP2C19 haplotypes. Carriers of CYP2C19*2, *3, *8, or *9 alleles were PMs; carriers of 2 wild-type alleles were extensive metabolizers (EMs). Plasma concentrations of lansoprazole were determined in PM and EM phenotypes.

Results: The frequency of upper respiratory infection among PMs (n = 45) was higher than that among EMs (n = 91), which in turn was higher than that in placebo subjects (n = 135; P = .0039). The frequency of sore throat (ST) was similarly distributed among EMs and PMs (P = .0015). The OR (95% CI) for upper respiratory infections in PMs was 2.46 (1.02-5.96) (P = .046); for EMs, the OR (95% CI) was 1.55 (0.86-2.79). The OR (95% CI) for ST in EMs and PMs was 2.94 (1.23-7.05, P = .016) vs 1.97 (1.09-3.55, P = .024), respectively. Mean ± SD plasma concentrations of lansoprazole were higher in PMs than in EMs: 207 ± 179 ng/mL vs 132 ± 141 ng/mL (P = .04).

Conclusions: Lansoprazole-associated upper respiratory infections and ST in children are related in part to CYP2C19 haplotype. Our data suggest that lansoprazole-associated adverse events in children may be mitigated by adjusting the conventional dose in PMs. Additional studies are required to replicate our findings.

Trial registration: ClinicalTrials.gov NCT00604851.

Keywords: CYP; Cytochrome P450; EM; Extensive metabolizer; PM; PPI; Poor metabolizer; Proton pump inhibitor; SNP; ST; Single nucleotide polymorphism; Sore throat; URI; Upper respiratory tract infection; WT; Wild type.

Figure 1

Comparison of adverse event frequencies by metabolizer phenotype. Metabolizer phenotype classification was based on CYP2C19 haplotype. *P < .01 χ² test for trend. L-EM, lansoprazole extensive metabolizer; L-PM, lansoprazole poor metabolizer.

Figure 2

OR (95% CI) for associating URI, ST, and any adverse event (AE) with lansoprazole metabolizer phenotype. L, lower limit of 95% CI; U, upper limit of 95% CI.