Immune outcomes of lung transplant recipients with different cytochrome P450 3A5 phenotypes after discontinuation of voriconazole antifungal prophylaxis.

Abstract

Tacrolimus forms the backbone of immunosuppression regimens in lung transplant recipients (LTRs). It is extensively metabolized by cytochrome P450 (CYP) 3A5 enzymes, of which polymorphisms can significantly affect tacrolimus dose requirements. It is unknown how coadministration of tacrolimus with voriconazole, a potent CYP3A5 inhibitor, affects rejection rates or empiric dose adjustments needed after voriconazole discontinuation. This retrospective cohort study compares LTRs with poor (PR) versus intermediate/extensive (IE) CYP3A5 metabolizer phenotypes. The primary endpoint is cumulative immune outcomes within three months of voriconazole discontinuation; secondary endpoints include change in tacrolimus dose-to-concentration ratios after voriconazole discontinuation. Thirty-four patients underwent full analysis: 13 IE and 21 PR metabolizers. A higher proportion of IE metabolizers were African American (46.2%vs. 9.5%, p=.03). There was no significant difference in composite immune outcomes, though there was a proportionally higher frequency of new donor-specific antibody development in PR metabolizers (14.3%vs 7.7%, p=.56). Both groups required approximately 2.5 to 3-fold tacrolimus dose increases post-voriconazole discontinuation to re-attain therapeutic levels. This novel investigation sheds light on how CYP3A5 phenotype could be used to guide tacrolimus dosing, with the goal of preventing both toxicity and organ rejection.