Effects of CYP3A5 polymorphism and renal impairment on the drug interaction between venetoclax and fluconazole in acute myeloid leukaemia patients.

Abstract

The aim of this study was to investigate the effects of renal function and CYP3A5 polymorphism on the drug interaction between venetoclax and fluconazole in thirty acute myeloid leukaemia patients.The area under the plasma concentration-time curve (AUC) and trough concentration (C₀) of venetoclax and the fluconazole C₀ were obtained from plasma samples on day 7 later after initiation of venetoclax 200 mg/day combined with fluconazole.The fluconazole C₀ values in patients with moderate and severe renal impairment were significantly higher than those in patients with normal or mild impairment (median values 7037, 6234, and 4813 ng/mL, respectively, P = 0.026).In patients with CYP3A5*3/*3 genotype, the AUC_0-24 and C₀ of venetoclax were not associated with fluconazole C₀; however, in patients with a CYP3A5*1 allele, a significant positive correlation was observed between venetoclax C₀ and fluconazole C₀ (r = 0.782, P = 0.004).The metabolism of venetoclax by CYP3A4 is inhibited even at low fluconazole C₀. In patients with a CYP3A5*1 allele, CYP3A5 is inhibited when high fluconazole C₀ is induced by renal impairment.The dose of fluconazole for prophylaxis may be 100 mg in patients with severe renal impairment receiving venetoclax therapy.