CYP3A4 genotype is associated with sildenafil concentrations in patients with heart failure with preserved ejection fraction

Pharmacogenomics J. 2018 Apr;18(2):232-237. doi: 10.1038/tpj.2017.8. Epub 2017 Apr 25.

Abstract

Despite its established inter-individual variability, sildenafil has been the subject of only a few pharmacogenetic investigations, with limited data regarding the genetic modulators of its pharmacokinetics. We conducted a pharmacogenetic sub-study of patients randomized to sildenafil (n=85) in the RELAX trial, which investigated the impact of high-dose sildenafil in patients with heart failure with preserved left ventricular ejection fraction (HFpEF). In the overall population, the CYP3A4 inferred phenotype appeared associated with the dose-adjusted peak concentrations of sildenafil at week 12 and week 24 (adjusted P=0.045 for repeated measures analysis), although this P-value did not meet our corrected significance threshold of 0.0167. In the more homogeneous Caucasian subgroup, this association was significant (adjusted P=0.0165 for repeated measures). Hence, CYP3A4 inferred phenotype is associated with peak sildenafil dose-adjusted concentrations in patients with HFpEF receiving high doses of sildenafil. The clinical impact of this association requires further investigation.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Cytochrome P-450 CYP3A / genetics*
  • Exercise Tolerance / drug effects
  • Exercise Tolerance / genetics
  • Female
  • Genotype*
  • Heart Failure / blood
  • Heart Failure / drug therapy
  • Heart Failure / genetics*
  • Humans
  • Male
  • Middle Aged
  • Sildenafil Citrate / blood
  • Sildenafil Citrate / pharmacology
  • Sildenafil Citrate / therapeutic use*
  • Stroke Volume / drug effects
  • Stroke Volume / genetics*
  • Vasodilator Agents / blood
  • Vasodilator Agents / pharmacology
  • Vasodilator Agents / therapeutic use*

Substances

  • Vasodilator Agents
  • Sildenafil Citrate
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human