Hepatic Drug Interaction Between Tacrolimus and Lansoprazole in a Bone Marrow Transplant Patient Receiving Voriconazole and Harboring CYP2C19 and CYP3A5 Heterozygous Mutations

Background: A drug interaction between oral tacrolimus (TAG) and lansoprazole (LAN) has been reported in patients with CYP2C19 hetero/homozygous mutations and the CYP3A5 *3/*3 genotype. A PubMed search (implemented March 16, 2011) using search terms drug interaction, tacrolimus, and lansoprazole failed to identify drug interactions in CYP3A5 extensive metabolizers and parenterally administered TAC. Objective: The purpose of this study was to report a case of drug interaction between intravenously administered TAG and LAN in a patient being treated with voriconazole (VCZ) and harboring CYP2C19 and CYP3A5 heterozygous mutations. Case Summary: An 18-year-old Japanese man weighing 53 kg with an anaplastic large cell lymphoma received continuous IV administration of TAG as post-transplantation prophylaxis against graft-versus-host disease (GVHD) after an allogeneic bone marrow transplantation (BMT). He began receiving IV LAN 60 mg/d and VCZ 400 mg/d initiated the day before BMT. His blood TAG concentrations were within the range of 9-16 ng/mL from post-BMT day 5 to 26. The engraftment of the donor's hematopoietic cells was observed on day 17. The LAN dose was reduced to 15 mg/d PO on day 26, and the blood TAG concentration subsequently decreased to 6.6 ng/mL, with GVHD-related symptoms emerging on day 28. Consequently, the plasma VCZ concentration also decreased from 5.0 ng/mL to 2.5 ng/mL after reducing the LAN dose. VCZ was switched to liposomal amphotericin B on day 48. Thereafter, the blood TAG concentration decreased to 4.4 ng/mL on day 51. Ultimately, the patient died on day 77 because of the recurrence and progression of lymphoma. Other drugs taken were acyclovir, ursodeoxycholic acid, cefepime, meropenem, vancomycin, lenograstim, and dopamine hydrochloride. The genotyping analyses using the pre-BMT and post-engraftment (day 33) samples indicated that both were CYP2C19 *1/*2, CYP3A5 *1/*3 and CYP2C9 *1/*1. The calculated Drug Interaction Probability Score between TAG and LAN was 6, indicating a probable interaction. TAG and VCZ concentrations were measured by an affinity column-mediated immunometric assay and HPLC, respectively. Mutant alleles were examined using the multiplex extension of unlabeled oligonucleotide primers with fluorescently labeled dideoxynucleoside triphosphates. Conclusions: In a BMT patient with CYP2C19 and CYP3A5 heterozygous mutations, blood TAG concentration decreased after reducing the LAN dose, which appeared to be caused by a reduction in plasma VCZ concentration. (an Ther. 2011;33:1077-1080) (C) 2011 Elsevier HS Journals, Inc. All rights reserved.