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Clinical Therapeutics/Volume 33, Number 8, 2011

Case Report

Hepatic Drug Interaction Between Tacrolimus and Lansoprazole ina Bone Marrow Transplant Patient Receiving Voriconazole andHarboring CYP2C19 and CYP3A5 Heterozygous Mutations

Takuya Iwamoto, PhD1; Fumihiko Monma, MD, PhD2; Atsushi Fujieda, MD, PhD2;Kaname Nakatani, MD, PhD3; Naoyuki Katayama, MD, PhD2; andMasahiro Okuda, PhD1

1Department of Pharmacy, Mie University Hospital, Faculty of Medicine, Mie University, Tsu, Mie, Japan;2Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan; and3Department of Molecular and Laboratory Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan

ABSTRACTBackground: A drug interaction between oral tacroli-

mus (TAC) and lansoprazole (LAN) has been reported inpatients with CYP2C19 hetero/homozygous mutationsand the CYP3A5 *3/*3 genotype. A PubMed search (im-plemented March 16, 2011) using search terms drug in-teraction, tacrolimus, and lansoprazole failed to identifydrug interactions in CYP3A5 extensive metabolizers andparenterally administered TAC.

Objective: The purpose of this study was to report aase of drug interaction between intravenously admin-stered TAC and LAN in a patient being treated withoriconazole (VCZ) and harboring CYP2C19 andYP3A5 heterozygous mutations.Case Summary: An 18-year-old Japanese man weigh-

ng 53 kg with an anaplastic large cell lymphoma receivedontinuous IV administration of TAC as post-transplan-ation prophylaxis against graft-versus-host diseaseGVHD) after an allogeneic bone marrow transplanta-ion (BMT). He began receiving IV LAN 60 mg/d andCZ 400 mg/d initiated the day before BMT. His bloodAC concentrations were within the range of 9–16g/mL from post-BMT day 5 to 26. The engraftment ofhe donor’s hematopoietic cells was observed on day 17.he LAN dose was reduced to 15 mg/d PO on day 26,nd the blood TAC concentration subsequently de-reased to 6.6 ng/mL, with GVHD-related symptomsmerging on day 28. Consequently, the plasma VCZ con-entration also decreased from 5.0 ng/mL to 2.5 ng/mLfter reducing the LAN dose. VCZ was switched to lipo-omal amphotericin B on day 48. Thereafter, the blood

AC concentration decreased to 4.4 ng/mL on day 51.

August 2011

Ultimately, the patient died on day 77 because of therecurrence and progression of lymphoma. Other drugstaken were acyclovir, ursodeoxycholic acid, cefepime,meropenem, vancomycin, lenograstim, and dopaminehydrochloride. The genotyping analyses using the pre-BMT and post-engraftment (day 33) samples indicatedthat both were CYP2C19 *1/*2, CYP3A5 *1/*3 andCYP2C9 *1/*1. The calculated Drug Interaction Proba-bility Score between TAC and LAN was 6, indicating aprobable interaction. TAC and VCZ concentrations weremeasured by an affinity column-mediated immunometricassay and HPLC, respectively. Mutant alleles were exam-ined using the multiplex extension of unlabeled oligonu-cleotide primers with fluorescently labeled dideoxy-nucleoside triphosphates.

Conclusions: In a BMT patient with CYP2C19 andCYP3A5 heterozygous mutations, blood TAC concen-tration decreased after reducing the LAN dose, whichappeared to be caused by a reduction in plasma VCZconcentration. (Clin Ther. 2011;33:1077–1080) © 2011Elsevier HS Journals, Inc. All rights reserved.

Key words: CYP2C19 polymorphism, drug interac-tion, lansoprazole, tacrolimus, voriconazole.

INTRODUCTIONA drug interaction between oral tacrolimus (TAC) andlansoprazole (LAN) has been reported in patients with

Accepted for publication July 7, 2011.doi:10.1016/j.clinthera.2011.07.0060149-2918/$ - see front matter

© 2011 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics

CYP2C19 hetero/homozygous mutations and theCYP3A5 *3/*3 genotype.1–3 However, a PubMedsearch (implemented March 16, 2011) using the searchterms drug interaction, tacrolimus, and lansoprazolefailed to identify drug interactions in CYP3A5 exten-sive metabolizers and parenterally administrated TAC.

CASE SUMMARYAn 18-year-old Japanese man weighing 53 kg with ananaplastic large cell lymphoma received continuous IVTAC after an allogeneic bone marrow transplantation(BMT). Blood TAC concentrations were measuredroutinely by an affinity column-mediated immunomet-

Figure. Blood concentrations of tacrolimus (TAC) (ozole (VCZ) (solid triangles, right axis), and smarrow transplantation (BMT) in this case rprazole (LAN) in a BMT patient receiving Vmutations. L-AMB � liposomal amphotericin

ric assay. IV LAN 60 mg/d and voriconazole (VCZ)

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400 mg/d were started the day before BMT. The pa-tient’s blood TAC concentrations were within 9–16ng/mL from post-BMT day 5 to 26. The engraftment ofthe donor’s hematopoietic cells was observed on day17. The LAN dose was reduced to 15 mg/d PO onday 26, and the blood TAC concentration subse-quently decreased to 6.6 ng/mL, with graft-versus-host disease (GVHD)–related symptoms emerging onday 28 (Figure). On the same day, the TAC dose wasincreased from 0.78 mg/d to 1.08 mg/d because of highfever and skin GVHD stage 3. On day 29, hydrocorti-sone was initiated at 200 mg/d to treat GVHD. On day30, the TAC dose was increased to 1.20 mg/d because

ircles, left axis), plasma concentrations of voricona-oms of graft-versus-host disease (GVHD) after boneof hepatic drug interaction between TAC and lanso-nd harboring CYP2C19 and CYP3A5 heterozygous

pen cympteportCZ aB.

of a low blood TAC concentration (8.8 ng/mL), diar-

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T. Iwamoto et al.

rhea, and residual skin GVHD stage 2. The plasmaVCZ concentration was confirmed to have decreasedfrom 5.0 �g/mL to 2.5 �g/mL after LAN dose reduc-tion using stored samples by HPLC. When the bloodTAC concentration increased to 10.8 ng/mL on day 32,GVHD symptoms abated nearly completely. On day35, the blood TAC concentration decreased to 8.8 ng/mL, and consequently, the TAC dose was increased to1.36 mg/d. VCZ was switched to liposomal amphoter-icin B on day 48; thereafter, the TAC concentrationdecreased to 4.4 ng/mL on day 51.

Because of the recurrence of lymphoma, TAC wasnot increased to provide a graft-versus-leukemia effect.On day 77, the patient died due to disease progression.Other drugs taken were acyclovir, ursodeoxycholicacid, cefepime, meropenem, vancomycin, lenograstim,and dopamine hydrochloride. The patient did not eatgrapefruit or drink grapefruit juice while receiving theTAC infusion. Genotyping analyses using the pre-BMT (stored) and post-engraftment (day 33, fresh)samples indicated both harbored CYP2C19 *1/*2,CYP3A5 *1/*3 and CYP2C9 *1/*1. This case studywas reviewed and approved by the ethics committee of

Table. Drug Interaction Probability Scale8 results foreport of hepatic drug interaction in a bone mboring CYP2C19 and CYP3A5 heterozygous m

Q1 Are there previous credible reports of this intQ2 Is the observed interaction consistent with thQ3 Is the observed interaction consistent with thQ4 Is the event consistent with the known or rea

or offset)?Q5 Did the interaction remit upon dechallenge o

drug? (If no dechallenge, use “unknown” andQ6 Did the interaction reappear when the precip

continued use of object drug?Q7 Are there reasonable alternative causes for thQ8 Was the object drug detected in the blood o

proposed interaction?Q9 Was the drug interaction confirmed by any o

object drug (other than drug concentrationsQ10 Was the interaction greater when the precipi

precipitant drug dose was decreased?Total Score

Scoring: yes � �1; no � –1; unknown or not applicable �Drug interaction scale: �8 � highly probable; 5–8 � proba

August 2011

Mie University, and written informed consent was ob-tained from the patient.

DISCUSSIONA drug interaction between orally administered TAC andLAN was reported in liver transplant recipients withCYP2C19 *2/*3 and CYP3A5 *3/*3 genotypes.1 An-other study revealed that the dose-adjusted AUC0–12 of

AC was highest in the CYP2C19 homozygous muta-ions with the CYP3A5 *3/*3 genotype among variousombinations of CYP2C19 and CYP3A5 genotypes.2

However, drug interactions in CYP3A5 extensive me-tabolizers and parenterally administrated TAC have notbeen reported.

The increased severity of GVHD was judged to berelated to reduced blood TAC concentrations duringthe management of this patient. Hepatic TAC metab-olism due to CYP3A4/5 was thought to have increasedafter the LAN dose reduction, resulting in a lowerblood TAC concentration because there were nochanges in other medications, including TAC dose, orliver and kidney function, before and after LAN dosereduction.

rolimus (TAC) and lansoprazole (LAN) in this casew transplant patient receiving voriconazole and har-ions.

on in humans? �1wn interactive properties of precipitant drug? �1wn interactive properties of object drug? �1le time course of the interaction (onset and/ �1

precipitant drug with no change in the objectquestion 6.)

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drug was readministered in the presence of 0

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Clinical Therapeutics

VCZ is well distributed to organs, and the reportedKi value of VCZ for the inhibition of CYP3A is 1.04�g/mL.4 Because the plasma protein binding rate ofVCZ is reportedly �58%,5 the free fraction of VCZafter LAN dose reduction was estimated to be 1.05�g/mL (based on a total concentration of 2.5 �g/mL),which is nearly equal to the Ki value for CYP3A. Inddition, the blood TAC concentration decreased afterithdrawal of VCZ in our case. The drug interactionetween TAC and VCZ was also reported in the liverransplant patients and allogeneic hematopoietic stemell transplantation recipients.6,7 These facts suggesthat the decline in plasma VCZ concentration dis-inctly influenced the decreased blood concentration ofAC after the LAN dose reduction.The direct interaction between TAC and LAN was

lso considered in this case. The Drug Interactionrobability Scale score between TAC and LAN is 6,

ndicating a probable interaction (Table).8 Althoughthis case was not a genotypical CYP3A5 poor metabo-lizer, inhibition of CYP3A5 by VCZ likely decreasedthe patient’s capacity to metabolize TAC, recapitulat-ing a CYP3A5 poor-metabolizer phenotype, thus caus-ing an interaction between TAC and LAN. This notionis supported by the recent report indicating that he-patic CYP3A5 *3/*3 carriers showed 1.6-fold higherTAC concentration/dose ratio than CYP3A5 *1 carri-ers when LAN was concomitantly administered.9

CONCLUSIONSIn a BMT patient with CYP2C19 and CYP3A5heterozygous mutations, blood TAC concentration de-creased after reduction of the LAN dose, which ap-peared to be caused by a reduction in plasma VCZconcentration. Further studies using a larger samplesize are required to verify the VCZ-mediated drug in-teraction between TAC and LAN.

ACKNOWLEDGMENTSThe authors thank the medical staff of the Hematologyand Oncology ward at Mie University Hospital fortheir assistance in this study. There was no industry(drug or assay) involvement in the design, conduct,

funding, analysis, or publication of the results. The

u.ac.jp

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authors have indicated that they have no conflicts ofinterest regarding the content of this article.

Dr. Iwamoto was responsible for the literaturesearch, figure creation, data collection, data interpre-tation, and writing of the manuscript. Drs. Monma,Fujieda, and Katayama were responsible for the eval-uation of GVHD symptoms, data collection, and datainterpretation. Dr. Nakatani analyzed mutant allelesof CYP3A5, 2C19 and 2C9, and was responsible forthe data interpretation. Dr. Okuda was responsible fordata interpretation and review of the manuscript.

REFERENCES1. Hosohata K, Masuda S, Ogura Y, et al. Interaction between

tacrolimus and lansoprazole, but not rabeprazole in living-donor liver transplant patients with defects of CYP2C19 andCYP3A5. Drug Metab Pharmacokinet. 2008;23:134–138.

2. MiuraM, InoueK,KagayaH,etal. Influenceof rabeprazoleandlansoprazole on the pharmacokinetics of tacrolimus in relationto CYP2C19, CYP3A5 and MDR1 polymorphisms in renaltransplant recipients. Biopharm Drug Dispos. 2007;28:167–175.

3. Takahashi K, Motohashi H, Yonezawa A, et al. Lansoprazole-tacrolimus interaction in Japanese transplant recipient withCYP2C19polymorphism.AnnPharmacother.2004;38:791–794.

4. Jeong S, Nguyen PD, Desta Z. Comprehensive in vitro analysis ofvoriconazole inhibition of eight cytochrome P450 (CYP) enzymes:major effect on CYPs 2B6, 2C9, 2C19, and 3A. Antimicrob AgentsChemother.2009;53:541–551.

5. Leveque D, Nivoix Y Jehl F, Herbrecht R. Clinical pharmacoki-netics of voriconazole. Int J Antimicrob Agents. 2006;27:274–284.

6. Venkataramanan R, Zang S, Gayowski T, Singh N. Voricona-zole inhibition of the metabolism of tacrolimus in a livertransplant recipient and in human liver microsomes. Antimi-crob Agents Chemother. 2002;46:3091–3093.

7. Mori T, Aisa Y, Kato J, et al. Drug interaction betweenvoriconazole and calcineurin inhibitors in allogeneic hemato-poietic stem cell transplant recipients. Bone Marrow Trans-plant. 2009;44:371–374.

8. Horn JR, Hansten PD, Chan LN. Proposal for a new tool toevaluate drug interaction cases. Ann Pharmacother. 2007;41:674–680.

9. Hosohata K, Masuda S, Katsura T, et al. Impact of intestinalCYP2C19 genotypes on the interaction between tacrolimusand omeprazole, but not lansoprazole, in adult living-donor

liver transplant patients. Drug Metab Dispos. 2009;37:821–826.

Address correspondence to: Dr. Masahiro Okuda, Department of Phar-macy, Mie University Hospital, Faculty of Medicine, Mie University, 2-174Edobashi, Tsu, Mie 514-8507, Japan. E-mail: okudam@clin.medic.mie-

Volume 33 Number 8