Voriconazole and Atazanavir: A CYP2C19-Dependent Manageable Drug–Drug Interaction

Abstract

Voriconazole exposure was variable but Ctrough levels were above 1000 ng/ml in all patients; one CYP2C19 intermediate metabolizer required lower doses of voriconazole (50 mg twice daily) to obtain satisfactory drug concentrations. Atazanavir and ritonavir plasma levels were moderately reduced (area under the curve: -23 and -26%, respectively); raltegravir exposure seemed increased by voriconazole administration (area under the curve: 2.5-fold higher) in a single subject. Coadministration of atazanavir and voriconazole may be feasible in selected HIV-positive patients; therapeutic drug monitoring and CYP2C19 genotyping may optimize exposure of both drugs.

PharmGKB summary

“…Nine studies report an association between intermediate metabolizers and voriconazole metabolism and concentrations [14, 18, 19, 34, 39, 43], though several did not conduct statistical analyses [35, 44, 45]. However, almost every study found that IMs had decreased voriconazole metabolism and increased concentrations as compared to NMs.…”

“…As with PMs, very little evidence exists for an effect of IM genotypes on clinical outcome. One case report noted an individual with the *1/*2 genotype who required a dose reduction due to high trough concentrations [45], and another case report noted an individual with the *1/*2 genotype who had elevated concentrations accompanied by hallucinations and abnormal liver function tests. The latter patient’s adverse effects resolved after stopping voriconazole treatment, and reintroduction at a lower dose was uncomplicated [46].…”

PharmGKB summary

“…Many commonly prescribed drugs are metabolized, inhibited, or induced by the main ATV metabolizing enzymes CYP3A4/5 so there is a high potential for drug-drug interactions, especially in older patients where polypharmacy is common, and in patients co-infected with hepatitis C, tuberculosis, or other opportunistic bacterial or fungal infections, a common complication in individuals with HIV [48]. A case series in four HIV positive patients reported that ATV and ritonavir C min and AUC were only moderately reduced in patients administered voriconazole, a triazole antifungal agent [49]. A recent study in healthy volunteers reported that co-administration of ATV/r with voriconazole also lead to reductions of ATV C min of between 20–30% regardless of the metabolizer phenotype of the primary metabolizing enzyme of voriconazole, CYP2C19 .…”