Effect of CYP3A5 genotype on ketoconazole induced QT prolongation

Background/Aim Ketoconazole (Keto) is used extensively as a test inhibitor of cytochrome P450 3A-mediated metabolism in clinical drug interaction studies with drugs that might prolong the QT interval. Prior studies in healthy volunteers suggested that Keto itself, (400mg per day by mouth) contributes to QTc prolongation but inter-individual variability was substantial. We tested the hypothesis that inter-individual difference in prolongation of QTc by Keto are associated with CYP3A5 genotype. Methods 15 healthy volunteers (12 males, 29± 9 yrs) participated in a three phase randomized, crossover study. The subjects were treated with either 200mg QD or 400mg QD of Keto for 6 days. QT interval was measured before, and after treatment using a digitizing pad in three consecutive beats in leads II and V5. The measured QT was corrected based on a linear multiple regression model with log-transformed data (QT and RR). CYP3A5 genotype was done by allele specific real time PCR. Results (see Table 1 and Table 2). Conclusions 200mg of ketoconazole induced prolongation in QTc (delta QTc= 17.2 msec, p<0.0032) as did the 400mg dosage regimen (delta QTc= 16.8 msec, p<0.0065). Subjects who carried two CYP3A5*3 alleles had greater QTc than those with at least one*1 allele (p<0.0001). The extent of QTc prolongation with Keto was independent of CYP3A5 genotype. Clinical Pharmacology & Therapeutics (2005) 77, P5–P5; doi: 10.1016/j.clpt.2004.11.021 Table 1. Effect of Keto on QTc prolongation QTc msec (Mean ± SE) Phase 1 (baseline) 382.2 ± 4.2 Phase 2 399.4 ± 4.8 Phase 3 399.0 ± 4.4 Table 2. Effect of CYP3A5 genotype on Keto induced QTc prolongation CYP3A5 genotype Baseline QTc msec (mean ± SE) QTc msec (mean ± SE) at the end of Keto therapy *1/*1 (n = 3) 369.2 ± 5.3 386.1 ± 5.4 *1/*3 (n = 4) 366.4 ± 5.1 383.4 ± 5.0 *3/*3 (n = 8) 394.2 ± 4.1 411.2 ± 3.7