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

• Published in: The pharmacogenomics journal Vol. 18; no. 2; pp. 232 - 237
• Main Authors: de Denus, S, Rouleau, J L, Mann, D L, Huggins, G S, Pereira, N L, Shah, S H, Cappola, T P, Fouodjio, R, Mongrain, I, Dubé, M-P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2018; Nature Publishing Group
• Subjects: 692/53/2423; 692/699/75; Aged; Biomedical and Life Sciences; Biomedicine; Cytochrome P-450; Cytochrome P-450 CYP3A - genetics; Development and progression; Drug metabolism; Drug therapy; Ejection fraction; Exercise Tolerance - drug effects; Exercise Tolerance - genetics; Female; Gene Expression; Genetic aspects; Genotype; Genotypes; Health aspects; Heart diseases; Heart failure; Heart Failure - blood; Heart Failure - drug therapy; Heart Failure - genetics; Human Genetics; Humans; Male; Middle Aged; Oncology; original-article; Patient outcomes; Pharmacokinetics; Pharmacotherapy; Phenotypes; Psychopharmacology; Sildenafil; 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; Ventricle
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/tpj.2017.8

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.