Effect of Posaconazole on Cyclosporine Blood Levels and Dose Adjustment in Allogeneic Blood and Marrow Transplant Recipients

Abstract

eThe posaconazole prescribing information recommends an upfront cyclosporine dose reduction upon initiation of posaconazole prophylaxis. We examined this recommendation in the early phase of allogeneic transplantation, where cyclosporine levels potentially becoming subtherapeutic following upfront dose reduction would be deleterious to transplant outcome. Our data show that while posaconazole leads to an increase in cyclosporine levels, subsequent cyclosporine dose reduction can be safely guided by therapeutic drug monitoring and is not required upfront. Therefore, the current recommendation may be modified. Posaconazole is a novel triazole with broad-spectrum antifungal activity and a favorable toxicity profile (4, 7) that is currently approved for primary antifungal prophylaxis in allogeneic blood and marrow transplantation (allo-BMT) recipients with graft-versus-host disease (GVHD) (18). Posaconazole prophylaxis in allo-BMT recipients is normally administered in combination with immunosuppressive drugs for GVHD prophylaxis and/or treatment, most commonly cyclosporine (CsA). On the basis of its CYP3A4-inhibitory activity, posaconazole increases the exposure to CsA, warranting a recommendation for close monitoring of blood CsA levels and subsequent CsA dose adjustment, as required. It is noteworthy that the posaconazole prescribing information also includes a recommendation for upfront reduction of the dose of CsA upon initiation of combined treatment (17), which emerged from a very small study of cardiac transplantation (16) and has never been analyzed in allo-BMT recipients. In these patients, the potential occurrence of subtherapeutic blood CsA levels, even transiently, has a strong negative impact on GVHD and on the outcome of allo- BMT (5,6,11,12,14,19). The clinical need for such an upfront CsA dose reduction in patients starting posaconazole in this clinical setting ought to be studied.We have recently reported on the clinical efficacy and safety of primary antifungal prophylaxis with posaconazole during the early phase of allo-BMT (15). Here we present an analysis of the impact of posaconazole prophylaxis on CsA management in this clinical setting. Since potential subtherapeutic blood CsA levels pose the highest risk during the early posttransplant period, for this study we prospectively decided not to reduce the dose of CsA at the start of combined treatment with posaconazole. Instead, blood CsA levels were monitored at least three times weekly and the dose was adjusted as required to maintain trough CsA levels within the therapeutic range (125 to 300 ng/ml) or if CsA-related toxicity occurred. Other than this, all patients received posaconazole in keeping with the recommendations for administration in the product prescribing information. A total of 41 recipients of a first allo-BMT were included in this study (Table 1), with institutional approval by the clinical research ethics committee (CEIC Bellvitge; EPA 008/08). Patients were on steady-state CsA twice daily as a 2-h intravenous infusion for GVHD...

Comparison of itraconazole, voriconazole, and posaconazole as oral antifungal prophylaxis in pediatric patients following allogeneic hematopoietic stem cell transplantation

“…Another pharmacokinetic analysis showed that a CsA dose reduction of up to 50 % was necessary with concomitant posaconazole treatment [36]. …”

Dose adjustment of immunosuppressants during co-administration of posaconazole: a systematic review

“…In the presence of p o s a c o n a z o l e , p l a s m a c o n c e n t r a t i o n s o f t h e s e immunosuppressants are substantially increased [15,16,17] and this increase is associated with adverse events [15,18]. The increase in exposure of immunosuppressants in the presence of posaconazole requires adjustment of the dose of the immunosuppressant to sustain the therapeutic levels of the drug and reduce adverse events associated with increased immunosuppressant concentrations [13,20,21]. The prescribing information for posaconazole recommends reducing the dose of cyclosporine by approximately 75% and the dose of tacrolimus approximately one-third of the original dose upon initiation of posaconazole treatment [19].…”

Cyclosporine use in Hematopoietic Stem Cell Transplantation: Pharmacokinetic Approach

“…administration. Temporal pattern of CsA level changes due to institution or discontinuation of co-medicating azole has been observed to be within days to few weeks [115][116][117]. Another common antifungal in this setting, micafungin, showed no interacting effect [118].…”

“…It seems that voriconazole is the strongest metabolic inhibitor of CsA among common azole antifungals used in HSCT although specifically designed studies for head to head comparison in this setting are lacking. Itraconazole and posaconazole also increase CsA exposure regarding trough, peak and AUC values but maybe to a lower extent than voriconazole [18,21,115]. It has been stated that drug interaction for voriconazole or itraconazole and CsA is more detectable than fluconazole even by iv.…”

“…CsA dose reduction even down to 50% and applying lower values for iv. to oral dose transition have been proposed accordingly [21,115]. It seems that voriconazole is the strongest metabolic inhibitor of CsA among common azole antifungals used in HSCT although specifically designed studies for head to head comparison in this setting are lacking.…”