Hepatic Drug Interaction Between Tacrolimus and Lansoprazole in a Bone Marrow Transplant Patient Receiving Voriconazole and Harboring CYP2C19 and CYP3A5 Heterozygous Mutations Hepatic drug interaction between tacrolimus and lansoprazole in a bone marrow transplant patient receiving voriconazole and harboring CYP2C19 and CYP3A5 heterozygous mutations

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Background: A drug interaction between oral tacrolimus (TAC) and lansoprazole (LAN) has been reported in patients with CYP2C19 homozygous mutations and the CYP3A5 *3/*3 genotype. A Pubmed search (date of implementation, March 16, 2011) using search terms drug interaction, tacrolimus, and lansoprazole, failed to identify the drug interactions in CYP3A5 extensive metabolizers , and parenterally administrated TAC.Objective: To report a case of drug interaction between intravenous TAC 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 intravenous administration of TAC as post-transplantation prophylaxis against graft-versus-host disease (GVHD) after an allogeneic bone marrow transplantation (BMT). He began receiving intravenous LAN 60 mg/day and VCZ 400 mg/day initiated the day before BMT. His blood TAC 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/day orally on day 26, and the blood TAC 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 TAC 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 and CYP3A5*1/*3. The calculated Horn drug interaction probability scales between TAC and LAN is 6, indicating a probable interaction. TAC and VCZ concentrations were measured by an affinity column-mediated immunometric assay and high performance liquid chromatography, respectively. Mutant alleles were examined using the multiplex extension of unlabeled oligonucleotide primers with fluorescently labeled dideoxynucleotide triphosphates.Conclusions: Blood TAC concentration decreased after reducing the LAN dose, which was likely caused by a reduction in plasma VCZ concentration, in a BMT patient with CYP2C19 and CYP3A5 heterozygous mutations.



    CLINICAL THERAPEUTICS 33(8), 1077-1080, 2011-08-01


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