Micafungin Does Not Influence the Concentration of Tacrolimus in Patients after Allogeneic Hematopoietic Stem Cell Transplantation.

Purpose: Tacrolimus (Tac) is commonly used for stem cell transplant (SCT) recipients as an agent for prophylaxis of graft-versus-host disease (GVHD) and because of its narrow therapeutic index a close drug monitoring is needed. Micafungin (MCFG) is widely used as a strong antifungal agent in empirical therapy for patients with febrile neutropenia. Both Tac and MCFG are substrates of CYP3A4 in vitro. Therefore, there is a risk of drug interaction by the coadministration of these 2 agents.

Methods: Five consecutive Japanese patients (3 males and 2 females) with hematological malignancies who received allogeneic SCT in our hospital between August 2005 and December 2006 were enrolled in this study. We estimated the drug interaction of Tac and MCFG by evaluating the pharmacokinetics in 5 cases of allogeneic SCT. The patients initially received 24 hour continuous intravenous administration of Tac at 0.01 mg/kg. The dose was then adjusted to a concentration between 10–12 ng/ml by monitoring of the concentration 3 times a week. MCFG was started at 150 mg/body/day as an empirical therapy in order to manage the neutropenic fever suggesting fungal infection. MCFG was administered as a one hour infusion. For the determination of both Tac and MCFG concentration, serial blood samples were drawn from the patients at 1, 4, 8 and 24 hours after the initiation of therapy. Tac concentrations were determined by the microparticle enzyme immunoassay method using an IMx Tacrolimus II analyzer (Abbott Diagnostics, Abbott Park, IL). The concentration of MCFG in blood was analyzed by high performance liquid chromatography (HPLC). HPLC was performed using a Phenomenex Luna 3μ C18 column (4.6 mm x 150 mm) as an analytical column.

Results: Five patients were included in this study; 3 were male and 2 were female. The age of patients ranged from 37 to 71 years, with a median age of 53 years. The donor source was unrelated bone marrow (BM) in 1 patient, peripheral blood stem cells (PBSC) from a related donor in 1 patient, and cord blood (CB) in 3 patients. The mean value of the concentration/dose (CD) ratio of Tac in all patients administered concomitant MCFG was 704.7 ± 61.8 ((ng/mL)/(mg/(kg x day)) and the value without MCFG was 710.3 ± 390.4 ((ng/mL)/(mg/(kg x day)). The proportion of the CD ratio in patients treated with Tac and MCFG to the CD ratio in patients treated with Tac alone was 0.886, 0.960, 1.08 and 1.04 for 1, 4, 8 and 24 hours, respectively. For both Tac and MCFG, the 90% confidence intervals for the primary PK parameters (i.e., the CD ratio at each time point) ranged from 80% to 125%. The concentrations of MCFG at 1, 4, 8 and 24 hours after the start of infusion were 27.3, 20.0, 16.7 and 9.4, respectively. Pharmacokinetic parameters of MCFG was following; AUC (area under the curve) 368 ± 172 mg x hr/L, Vd (distribution volume in elimination phase) 0.223 ± 0.106 L/kg, clearance 0.0088 ± 0.003 L/(hr x kg) and elimination half life 18.3 ± 1.7 hr.

Conclusion: We concluded that there was no drug interaction between Tac and concomitantly administered MCFG in SCT recipients.