Sex and ethnicity may chiefly influence the interaction of fluconazole with calcineurin inhibitors

Background. Calcineurin inhibitors (CNI) and azole antifungal agents have b een reported to interact in a disparate manner, The azole dose and route an d the level of involvement of the liver and intestines have been implicated , although data are limited, A significant interaction may result in CNI to xicity, and withdrawal of the azole may result in subtherapeutic CNI concen trations. Fluconazole, available in both intravenous and oral formulations, is commonly used in transplant recipients and is ideal for determining the presence of a disparate effect on CNI concentrations. We retrospectively i nvestigated the interaction of CNIs with fluconazole, evaluating CNI blood troughs corrected for daily CNI dose, the factors influencing the interacti on, and the effect on clinical outcomes in renal and simultaneous pancreas kidney transplant recipients. Methods. Twenty-eight patients received a CNI and fluconazole during the ca lendar year 1999, but only 19 patients had documented CNI blood troughs and outpatient follow-up, There were 25 episodes of use in the 19 included pat ients. CNI blood troughs were evaluated for changes induced by fluconazole, given by both routes, and clinical outcomes were tracked. Results. Data demonstrated both intravenous and oral fluconazole alter CNI blood concentrations. Two metabolic patterns were observed, and we termed t hese convergent and divergent. Divergent metabolizers did not have signific ant interaction (n=5), and convergent metabolizers did have a significant i nteraction (n=15), One patient had a divergent episode after a previous con vergent episode. The main contributors to the lack of interaction appeared to be female sex and African American ethnicity. Additionally, tacrolimus l evels were significantly more affected than cyclosporine, during and after fluconazole administration. No patient experienced nephrotoxicity or cellul ar rejection related to antifungal therapy. Conclusions. Oral and intravenous fluconazole appear to increase oral CNI t rough concentrations to a similar extent even after adjusting for daily cal cineurin dose. These interactions appear to be chiefly influenced by sex an d ethnicity. Further prospective study is necessary to clarify this issue.