Life-Threatening Complications Suspected Due to Clinical Pharmacokinetic Interaction Between Cyclosporine A and Triazole Antifungal Agents in Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) Recipients.

It is well documented that the co-medication with the triazole antifungal agents is associated with a flattening of the CSA blood concentration profile via the cytochrome P450 3A4 dependent metabolic pathway in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Then it raises the question if the therapeutic monitoring of CsA trough levels is sufficient enough to reflect the drug exposure and to assess the transplant-related complications such as transplant rejection and drug toxicity.

To evaluate the tolerability, toxicity and clinical outcome of the co-administration of CSA and triazole antifungal agents in allo-HSCT recipients.

A retrospective review of the medical records of 104 consecutive patients undergoing allo-HSCT for hematologic malignancies at our transplant center over past 5 years was conducted. The causality of administration of CSA in combination with triazole in 12 cases with life-threatening complications experiencing supratherapeutic trough levels of CSA were identified and analyzed.

In all these 12 patients, the CSA trough levels remained highly than therapeutic range even after gradual tapering of CSA dosage. Shortly after the engraftment, 6 patients (50 %) developed acute graft-versus-host disease (aGVHD) and non-infectious pulmonary complication, and 2 patient (16.66 %) acute graft rejection. Which indicates the trough plasma concentration might be inadequately reflect CSA absorption profile. Whereas, 4 (33.33 %) patients were evaluated with neurological complications, 1 (8.33%) patient cardiovascular complication accompanied by acute renal failure and liver dysfunction, that might be ascribed to CSA-related adverse effects. 10 (83.33 %) out of the 12 patients eventually died, 2 (16.66 %) patient are still alive after graft rejecting. The major causes of death were GVHD related pulmonary injury with fungi infection

Although preemptive CSA dosage reduction and the close monitoring of its whole blood trough levels may minimize the drug-toxicity when co-administration with triazole antifungal agents, the different clinical spectrum and different disease evolution post transplant in this group warn that in the set of hematopoietic cell transplantation with CSA as immunosuppression agent the individual variables influence the drug-exposure and drug-toxicity. Thereof, as clinicians we should not be mislead by trough plasma concentrations as a routine therapeutic drug monitoring in terms of CSA exposure related efficacy or toxicity, especially when CSA in combination with triazole.

No relevant conflicts of interest to declare.