Atazanavir/Ritonavir + Voriconazole = Precautionary

Effect on Concentration

Atazanavir/Ritonavir
Increase
Applies within class?
No
Voriconazole
Increase
Applies within class?
No

Pharmacologic Effects

Atazanavir/Ritonavir
Effect
N/A
Applies within class?
No
Voriconazole
Effect
N/A
Applies within class?
No

Interaction History

N/A

Last Updated 09-Jul-2018

Summary

Sources

Voriconazole and atazanavir: a CYP2C19-dependent manageable drug-drug interaction. ^

Study Design

In an open-label, nonrandomized study, concomitant use of atazanavir/ritonavir (ATV/r) with voriconazole was evaluated in 32 healthy subjects; CYP2C19 poor metabolizers (PMs; n= 8) and CYP2C19 extensive metabolizers (EMs; n= 24). PMs received voriconazole 100 mg twice daily (BID) on Day 1, followed by voriconazole 50 mg twice daily (BID) on Days 2-3.1,2 After 7-day washout, subjects received ATV/r 300/100 mg once daily (QD) on Days 11-30 with voriconazole 100 mg BID on Day 21, followed by voriconazole 50 mg BID on Days 22-30. EMs received voriconazole 400 mg BID on Day 1, followed by voriconazole 200 mg BID on Days 2-3.1,2 After 7-day washout, subjects received ATV/r 300/100 mg QD on Day 11-30 with voriconazole 400 mg BID on Day 21, followed by voriconazole 200 mg BID on Days 22-30. On Days 3, 20, and 30, serial samples of voriconazole, ATV, ritonavir were collected.2

Study Results

Coadministration of ATV/r and voriconazole decreased ATV and voriconazole plasma concentrations in EMs; decreased ATV concentrations and increased voriconazole concentrations in PMs. Metabolizer status N ATV/r (dose/freq) Voriconazole (dose/freq) Cmax vori AUC vori Cmin vori EM 20 300/100 daily 200 mg BID 0.87 (0.8,0.96) 0.88 (0.82,0.95) 0.8 (0.72,0.90) PM 8 50 mg BID 0.81 (0.66,1.00) 0.8 (0.65,0.97) 0.69 (0.54,0.87) Metabolizer status N ATV/r (dose/freq) Voriconazole (dose/freq) Cmax atv AUC atv Cmin atv EM 20 300/100 daily 200 mg BID 0.9 (0.78,1.04) 0.67 (0.58,0.78) 0.61 (0.51,0.72) PM 8 50 mg BID 4.38 (3.55,5.39) 5.61 (4.51,6.99) 7.65 (5.71,10.2)

Study Conclusions

The investigators concluded that the impact of ATV/r on voriconazole is highly dependent on CYP2C19 genotype; in EMs, coadministration of ATV/r decreased voriconazole AUC by 33% while in PMs ATV/r markedely increased voriconazole. The latest prescribing information for ATV (Reyataz®) published in March 2015 and HIV/AIDS treatment guidelines state that voriconazole and ATV/r should not be used concomitantly unless potential benefits outweigh risks; if used concomitantly, patients should be monitored for voriconazole-associated adverse effects and loss of voriconazole or atazanavir efficacy. Consider monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly. Additionally, some experts recommend the use of CYP2C19 genotyping to optimize the exposure of both drugs. Concomitant use of voriconazole with ATV alone, without low-dose (100 mg BID) ritonavir, may increase concentrations of both drugs; consider monitoring for toxicities associated with ATV and/or voriconazole.

References

Calcagno A, Baietto L, Pagani N. Voriconazole and atazanavir: a cyp2c19-dependent manageable drug-drug interaction. Pharmacogenomics. 2014; 10: 1281-1286.