Evaluation of CYP2C8 and CYP2C9 Polymorphisms in Neonates with Patent Ductus Arteriosus Treated with Ibuprofen or Indomethacin: A Retrospective Cohort Study

TL;DR

This study examines how genetic variations in CYP2C8 and CYP2C9 affect treatment response to ibuprofen or indomethacin in neonates with PDA.

Contribution

The study provides new data from the Middle East on the role of CYP2C8 and CYP2C9 polymorphisms in neonatal PDA treatment outcomes.

Findings

No significant association was found between CYP2C8 or CYP2C9 polymorphisms and treatment response in neonates with PDA.

Multiple surfactant doses independently predicted poor treatment response.

Extremely low birth weight showed a borderline association with treatment response.

Abstract

The pharmacologic management of patent ductus arteriosus (PDA) presents a challenge to clinicians due to the interindividual variability in drug response to available medications. There is evidence that CYP2C9 is associated with the response to PDA treatment; however, no data from the Middle East is available. This study aimed to investigate the association between CYP2C8 and CYP2C9 genetic polymorphisms and response to ibuprofen or indomethacin in neonates with PDA. We conducted a retrospective cohort study of neonates with a gestational age < 32 weeks and birthweight < 1500 g with PDA between 2019 and 2023. Eligible neonates were those diagnosed with PDA and treated with at least one course of ibuprofen or indomethacin. Genotyping was performed to identify four single-nucleotide polymorphisms (SNPs), namely CYP2C8*3 rs10509681, CYP2C9*2 rs1799853, CYP2C9 rs2153628, and CYP2C9*3 rs1057910. Allele frequencies were compared between responders and non-responders, and non-genetic predictors were assessed using logistic regression. A total of 146 infants were identified. Of these, 86 were enrolled. Genetic analysis showed that the heterozygote genotype (TC) for the CYP2C8 gene was the most common (45%), while wild-type alleles were predominant for CYP2C9 variants. No significant differences in allele frequencies were found between responders and non-responders to the treatment (p > 0.05). In a secondary analysis, the need for multiple surfactant doses independently predicted poor response (aOR 0.244, 95% CI 0.086–0.693, p = 0.008), while extremely low birth weight showed a borderline association (aOR 0.281, 95% CI 0.062–1.268, p = 0.099). Carriers of CYP2C8*3 rs10509681, CYP2C9*2 rs1799853, CYP2C9 rs2153628, and CYP2C9*3 rs1057910 were not associated with variations in response to NSAIDs.

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