Effect of posaconazole introduction on immunosuppressive therapy in allogeneic hematopoietic stem cell allotransplantation recipients developing graft versus host disease

Dr. Julia TONINIa,  Marion DÉCISIERa, Dr. Anne THIÉBAUT-BERTRANDa, Dr. Claude-Eric BULABOISa, Pr. Jean-Yves CAHNa, Pr. Françoise STANKE-LABESQUEa

a CHU de Grenoble

Background:  Recipients of allogeneic hematopoietic stem cell allotransplantation (AHSCT) developing graft-versus-host disease (GVHD) received posaconazole (PCZ) for prophylaxis of invasive fungal infections. Because of P450 cytochrome inhibition, PCZ is responsible for drug interactions, especially with narrow therapeutic range drugs such as immunosuppressive (IS) agents. Nevertheless, drug interactions between PCZ and the different IS therapies used in AHSCT patients developing GVHD and frequently presenting digestive disorders remain to be better documented. This study aimed at determining the effect of PCZ introduction on residual plasmatic concentrations (Cmin) and administered dosage of IS in those patients.

Methods: The data concerning PCZ and IS treatments were retrospectively analyzed in 32 adult patients presenting a GVHD post AHSCT and receiving PCZ for prophylaxis treatment (200 mg tid). Blood measurements were performed for PCZ and IS Cmin using validated LC-MS/MS methods. IS Cmin were monitored before and at 7, 14, 21 and 30 days after PCZ administration. 

Results: Among the 32 patients (age: 48.3±11.8 years, BMI: 22.5±3.6 kg.m-2), 5 received twice PCZ prophylaxy. PCZ Cmin did not differ in patients treated with cyclosporine (n=24) or everolimus (n=9) (Cmin=1.2±0.7 vs 1.5±0.9 mg/L respectively, p>0.05). After PCZ introduction, everolimus Cmin increased to 227.5% at D21 without any dosage reduction despite half of the patients presenting Cmin higher than therapeutic range. Cyclosporine Cmin slightly increased and dosage reduced (amplitude of 20% for both at D30) without reaching statistical significance. Diarrhea was responsible for a 50% reduction in Cmin PCZ but had no incidence on IS concentrations of cyclosporine (230±101 vs 202±89 mg/L in absence or presence of diarrhea) or everolimus (6.39±3.93 vs 5.86±2.57 ng/mL in absence or presence of diarrhea).

Conclusion: The introduction of PCZ susceptible of increasing IS Cmin in ASHCT patients developing GVHD was well managed for cyclosporine treated patients whereas everolimus Cmin were above therapeutic range for half of the patients with no dosage modifications associated. Everolimus dosage adaptation should therefore be performed in those patients. When diarrhea occurred, patients presented a drastic decrease of PCZ plasmatic concentrations, but not of IS, in favor of a specific mechanism of absorption for PCZ.

Keywords : therapeutic dose monitoring, posaconazole, immunosupressive agents, allogeneic hematopoietic stem cell allotransplantation , graft-versus-host disease