Effects of PDE4 gene polymorphisms on efficacy and adverse drug events of ritodrine therapy in preterm labor patients: a prospective observational study

Eur J Clin Pharmacol. 2019 Oct;75(10):1379-1386. doi: 10.1007/s00228-019-02719-9. Epub 2019 Jul 19.

Abstract

Purpose: Phosphodiesterase (PDE) terminates the signaling pathway of myometrial relaxation by degradating cAMP to the inactive 5'-AMP. The PDE4 family is one of the most predominant PDE families that display high affinity to cAMP. The objective of this study was to evaluate the effects of PDE4 gene polymorphisms on tocolytic effects and adverse drug events (ADEs) of ritodrine therapy in patients with preterm labor.

Methods: A total of 170 preterm labor patients were included in this study. To elucidate the effects of genetic polymorphisms on the inter-individual variability of ritodrine efficacy and ADEs, 8 single nucleotide polymorphisms (SNPs) were genotyped: PDE4D (rs1544791, rs983280, rs1504982, rs10940648, rs829259) and PDE4B2 (rs598961, rs2180335, and rs17128809). Additionally, rs1042719 of the ADRB2 gene was included for multivariate analysis. The primary endpoint of this prospective study was the time to delivery (hr). The secondary endpoint was ritodrine-induced ADEs.

Results: The mutant-type homozygote carriers of PDE4B2 rs598961 polymorphism showed shorter median time to delivery than those with other genotypes (adjusted hazard ratio 1.6, 95% confidence interval 1.0 to 2.4, P = 0.035). On the other hand, patients with wild-type homozygotes of PDE4B2 rs17128809 showed 2.6~2.9 times higher ADEs compared to those with other genotypes. Among demographic characteristics, gestational age at start of drug therapy and modified Bishop score were significant factors for time to delivery, whereas height, weight, and BSA were significant factors for ritodrine-induced ADEs after adjusting other factors.

Conclusions: This pharmacogenomic study suggested that PDE4 genetic polymorphisms impact individual susceptibility to β2-adrenergic receptor targeted therapy in patients with preterm labor.

Keywords: Adverse drug events; Phosphodiesterase 4B2 gene; Phosphodiesterase 4D gene; Preterm labor; Ritodrine; Single nucleotide polymorphism; Time to delivery.

Publication types

  • Observational Study

MeSH terms

  • Adrenergic beta-2 Receptor Agonists / adverse effects
  • Adrenergic beta-2 Receptor Agonists / therapeutic use*
  • Adult
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / genetics*
  • Female
  • Humans
  • Obstetric Labor, Premature / drug therapy*
  • Obstetric Labor, Premature / genetics
  • Polymorphism, Single Nucleotide
  • Pregnancy
  • Receptors, Adrenergic, beta-2 / genetics
  • Ritodrine / adverse effects
  • Ritodrine / therapeutic use*
  • Tocolytic Agents / adverse effects
  • Tocolytic Agents / therapeutic use*
  • Treatment Outcome

Substances

  • ADRB2 protein, human
  • Adrenergic beta-2 Receptor Agonists
  • Receptors, Adrenergic, beta-2
  • Tocolytic Agents
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4B protein, human
  • PDE4D protein, human
  • Ritodrine