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

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

S de Denus  1   2   3 , J L Rouleau  1   4 , D L Mann  5 , G S Huggins  6 , N L Pereira  7 , S H Shah  8 , T P Cappola  9 , R Fouodjio  2 , I Mongrain  2 , M-P Dubé  1   2   4
Affiliations
Randomized Controlled Trial

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

S de Denus et al. Pharmacogenomics J. 2018 Apr.

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.

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Conflict of interest statement

Conflict of Interest

Simon de Denus has received research grants or been a coinvestigator on grants supported by AstraZeneca, Novartis, Roche and Pfizer. He has received speaker fees from Pfizer and consulting fees from Servier and Novartis. Jean Lucien Rouleau is a consultant for Novartis. Marie-Pierre Dubé has been a coinvestigator on grants supported by AstraZeneca and Pfizer, has received honoraria and research contracts from Roche and is a member of the executive committee of the Dal-GenE trial sponsored by DalCor. A patent was submitted on pharmacogenomic determinants of responses to cardiovascular drugs and Dr Dubé is listed as inventor.

Figures

Figure 1
Figure 1. Concentration:dose ratios of sildenafil according to CYP3A4 inferred phenotype in (A) all patients and (B) Caucasians
After adjusting for age, body mass index and three principal components for genetic ancestry, CYP3A4 inferred phenotype was significantly associated with the sildenafil concentration:dose ratio in Caucasians (P = 0.0165 for repeated measures analysis). EM, extensive metabolisers; IM, intermediate metabolizers.
Figure 2
Figure 2. Concentration:dose ratios of sildenafil according to CYP2C9 inferred phenotype in (A) all patients and (B) Caucasians
EM, extensive metabolisers; IM, intermediate metabolizers. Data presented as mean ± standard deviation.
Figure 3
Figure 3. Concentration:dose ratios of sildenafil according to CYP3A5 inferred phenotype in (A) all patients and (B) Caucasians
EM, extensive metabolisers; IM, intermediate metabolizers; PM, poor metabolizers. Data presented as mean ± standard deviation.
Figure 4
Figure 4. Concentration:dose ratios of sildenafil according to CYP3A4 and CYP3A5 inferred phenotype in Caucasians
Increasing levels of predicted metabolizing capacity showed a trend with decreasing levels of dose-adjusted sildenafil concentrations (F test P = 0.0238). EM, extensive metabolisers; IM, intermediate metabolizers; PM, poor metabolizers. Data presented as mean ± standard deviation.
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References

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