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Impact of Atazanavir/Ritonavir on Antifungal Depends on CYP2C19 Genotype
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13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona
Mark Mascolini
Atazanavir/ritonavir lowered exposure of the antifungal voriconazole in people with good drug metabolism via the CYP2C19 enzyme, but the protease inhibitors (PIs) sharply increased voriconazole exposure in people with poor metabolism via CYP2C19, according to results of a study in healthy volunteers [1].
Bristol-Myers Squibb investigators and Dutch collaborators believe their findings "support the current recommendation that coadministration of voriconazole [2] and atazanavir/ritonavir is not recommended unless an assessment of the benefit/risk justifies the use of voriconazole." The results also underline the potential importance of genetics to pharmacokinetics and drug-drug interactions.
Metabolism of voriconazole relies mainly on the CYP2C19 enzyme, and to lesser degrees on CYP3A4 and CYP2C9. Concentrations of the antifungal are 2- to 4-fold higher in CYP2C19 poor metabolizers (PMs) than in CYP2C19 extensive metabolizers (EMs). Taken at a dose of 100 mg twice daily, ritonavir lowers steady-state voriconazole area under the concentration-time curve (AUC) 39% in EMs [3], probably because ritonavir induces CYP2C19.
The researchers planned this study to assess the impact of atazanavir/ritonavir at the standard 300/100-mg once-daily dose on pharmacokinetics of voriconazole in CYP2C19 EMs and PMs. This open-label nonrandomized study involved 24 healthy volunteers with at least one functional CYP2C19 allele (EMs) and 8 with no functional CYP2C19 alleles (PMs).
Study participants took voriconazole alone on days 1 to 3 and then no drug for 7 days. They took standard-dose atazanavir/ritonavir alone on days 11 to 20, then the PIs plus voriconazole on days 21 to 30. EMs took 200 mg of voriconazole twice daily and 400 mg twice daily on days 1 and 21. PMs took 50 mg of voriconazole twice daily and 100 mg twice daily on days 1 and 21. The researchers collected serial samples on days 3, 20, and 30 to measure levels of voriconazole, atazanavir, and ritonavir.
Twenty of 24 EMs and 7 of 8 PMs completed the study. Three EMs dropped out because of rash and 1 withdrew consent. One PM withdrew consent but contributed complete pharmacokinetic data.
Among EMs, codosing of voriconazole and atazanavir/ritonavir lowered voriconazole AUC by 33% (90% confidence interval [CI] 22% to 42%) and minimum concentrations (Cmin) by 39% (90% CI 28% to 49%). Coadministration cut atazanavir AUC by 12% (90% CI 5% to 18%) and Cmin by 20% (90% CI 10% to 28%).
Among PMs, giving the drugs together boosted voriconazole maximum concentration (Cmax), AUC, and Cmin 4.4-, 5.6-, and 7.7-fold. Codosing lowered atazanavir AUC by 20%, Cmax by 19%, and Cmin by 31%. Ritonavir AUC and Cmax did not change substantially with voriconazole codosing in either study group.
Most adverse events were mild or moderate. In EMs hyperbilirubinemia affected 63% of study participants when they were taking the PIs, and headache affected 50% and blurred vision 33% during voriconazole dosing. In PMs high bilirubin was the most frequent adverse event, affecting 13%.
The investigators concluded that the impact of atazanavir/ritonavir on voriconazole concentrations "is highly dependent on CYP2C19 genotype."
References
1. Zhu L, Uy J,. Bruggemann R, et al. CYP2C19 genotype-dependent pharmacokinetic drug interaction between voriconazole and ritonavir boosted atazanavir in healthy subjects. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona. Abstract O_08.
2. PubMed Health. Voriconazole. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000305/
3. Liu P, Foster G, Gandelman K, et al. Steady-state pharmacokinetic and safety profiles of voriconazole and ritonavir in healthy male subjects. Antimicrob Agents Chemother. 2007;51:3617-3626. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2043278/?tool=pubmed
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