CYP3A5 genetic variability influences sildenafil and metabolite in pulmonary hypertension.

CYP3A5

The CYP3A5*3 allele reduces the activity of the enzyme encoded by CYP3A5 and alters sildenafil metabolism; it is associated with higher sildenafil exposure and better clinical outcomes.

Interindividual variability in sildenafil response among patients with pulmonary hypertension may depend on CYP3A5 polymorphisms, the CYP3A5*3 allele reducing enzyme activity and altering sildenafil metabolism. This cross-sectional study of 92 patients measured plasma concentrations of sildenafil and N-desmethyl sildenafil by HPLC at trough and one hour after administration (C1h), and genotyped CYP3A5 by real-time PCR with TaqMan probes. Thirteen patients (14.13%) were CYP3A5*1/*1 and 79 (85.87%) carried the CYP3A5*3 allele; the latter had a significantly higher C1h sildenafil concentration-to-dose ratio (3.61 ± 2.69 vs 2.66 ± 1.20 ng/mL/mg; p = 0.043), whereas the other parameters, higher for sildenafil and lower for N-desmethyl sildenafil in CYP3A5*3 carriers, did not reach significance. CYP3A5*3 carriers showed greater improvement in 6-minute walk distance (33.74 ± 43.46 m vs -5.58 ± 44.52 m; p = 0.005), WHO functional class (32.00% vs 15.39%; p = 0.042) and EmPHasis-10 scores (-4.15 ± 6.46 vs 1.08 ± 3.80; p = 0.009). The authors conclude that the CYP3A5*3 allele is associated with higher sildenafil exposure and better clinical outcomes, and that CYP3A5 genotyping may facilitate personalised assessment of sildenafil efficacy and clinical outcomes.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The two levels of evidence are unequal: pharmacokinetically, a single parameter reaches significance (C1h concentration-to-dose ratio, p = 0.043), the others moving in the direction expected from reduced enzyme activity without reaching it, whereas all three clinical endpoints are significant (p = 0.005, 0.042 and 0.009) but rest on a CYP3A5*1/*1 group of only 13 patients, against 79 CYP3A5*3 carriers. The study is described as cross-sectional although the clinical results are expressed as improvement: the abstract specifies neither the interval over which it is measured nor any adjustment for dose, concomitant treatment or disease severity, so an effect of genotype is hard to tell apart from confounding. The biological direction is coherent (reduced enzyme activity, higher exposure), but no dose scheme or threshold follows from it: this is a hypothesis to test prospectively before genotyping CYP3A5 to guide sildenafil treatment.

Analysis by Dr Thibaut Benquey