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

S. De Denus, J. L. Rouleau, D. L. Mann, G. S. Huggins, Naveen Luke Pereira, S. H. Shah, T. P. Cappola, R. Fouodjio, I. Mongrain, M. P. Dubé

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)232-237
Number of pages6
JournalPharmacogenomics Journal
Volume18
Issue number2
DOIs
StatePublished - Apr 1 2018

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Cytochrome P-450 CYP3A
Heart Failure
Genotype
Stroke Volume
Phenotype
Pharmacogenetics
Sildenafil Citrate
Pharmacokinetics
Population

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

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CYP3A4 genotype is associated with sildenafil concentrations in patients with heart failure with preserved ejection fraction. / De Denus, S.; Rouleau, J. L.; Mann, D. L.; Huggins, G. S.; Pereira, Naveen Luke; Shah, S. H.; Cappola, T. P.; Fouodjio, R.; Mongrain, I.; Dubé, M. P.

In: Pharmacogenomics Journal, Vol. 18, No. 2, 01.04.2018, p. 232-237.

Research output: Contribution to journalArticle

De Denus, S, Rouleau, JL, Mann, DL, Huggins, GS, Pereira, NL, Shah, SH, Cappola, TP, Fouodjio, R, Mongrain, I & Dubé, MP 2018, 'CYP3A4 genotype is associated with sildenafil concentrations in patients with heart failure with preserved ejection fraction', Pharmacogenomics Journal, vol. 18, no. 2, pp. 232-237. https://doi.org/10.1038/tpj.2017.8
De Denus, S. ; Rouleau, J. L. ; Mann, D. L. ; Huggins, G. S. ; Pereira, Naveen Luke ; Shah, S. H. ; Cappola, T. P. ; Fouodjio, R. ; Mongrain, I. ; Dubé, M. P. / CYP3A4 genotype is associated with sildenafil concentrations in patients with heart failure with preserved ejection fraction. In: Pharmacogenomics Journal. 2018 ; Vol. 18, No. 2. pp. 232-237.
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