CASE REPORTS

Adverse Reactions During Imatinib and Lansoprazole Treatment in Gastrointestinal Stromal Tumors
Giovanni Severino, Caterina Chillotti, Roberto De Lisa, Maria Del Zompo, and Raffaella Ardau

OBJECTIVE: To report the case of a patient affected by gastrointestinal stromal tumors (GIST) who developed cutaneous adverse drug reactions during treatment with imatinib and lansoprazole. CASE SUMMARY:

After 2 months of treatment with imatinib 400 mg/day, a 60-year-old white female affected by GIST developed bilateral palpebral edema with hyperemic conjunctivae and labial edema when lansoprazole 15 mg/day was introduced to treat dyspeptic symptomatology. Treatment was discontinued, and on reintroduction of both drugs, the patient developed Stevens Johnson syndrome. Two months later, generalized cutaneous reactions appeared immediately following reintroduction of low-dose imatinib with corticosteroid plus lansoprazole treatment. After discontinuation of all drugs, with the exception of the corticosteroid, the progression of cutaneous lesions stopped. The use of imatinib is commonly associated with a high dose-dependent rate of rash and edema. Several cases of StevensJohnson syndrome have also been described, although not in patients affected by GIST. Severe skin reactions have been reported for lansoprazole including erythema multiforme, StevensJohnson syndrome, and toxic epidermal necrolysis. Applying Naranjos algorithm, the adverse events were considered possible due to imatinib and probable due to lansoprazole.

DISCUSSION:

CONCLUSIONS: On the basis of the data reported, we conclude that the adverse reactions described may be attributed to either drug alone. However, combined use of drugs may increase the risk of onset of these adverse reactions due to a potential drug interaction involving CYP3A4. KEY WORDS: gastrointestinal stromal tumors, imatinib, lansoprazole.

Ann Pharmacother 2005;39:xxxx. Published Online, 16 Nov 2004, www.theannals.com, DOI 10.1345/aph.1E127

matinib is a therapeutic option for gastrointestinal stromal I tumors (GIST). A significant relationship has been revealed between the dose used and the occurrence of rash
1

tient who developed serious cutaneous adverse reactions during treatment with imatinib and lansoprazole. Case Report
A 60-year-old white female, free from concurrent medical conditions and use of medication, had been diagnosed with GIST 11 years previously and treated surgically. The patient subsequently presented an unresectable recurrence of the tumor in May 2003; treatment with imatinib 400 mg/day was started without any adverse effects. Two months later, lansoprazole 15 mg/day was introduced to treat dyspeptic symptomatology. Ten days later, the patient exhibited bilateral palpebral edema with hyperemic conjunctivae and labial edema, and both drugs were immediately withdrawn. Five days after discontinuing therapy, she was restarted on imatinib and lansoprazole at doses used in the previous regimen. Twenty-four hours later, bilateral palpebral edema with hyperemic conjunctivae and labial edema reappeared; oxatomide 30 mg/day, a piperazine derivative with antihistaminic property, was prescribed for 3 days. In spite of the addition of the latter, the patients symptoms worsened, and she developed mucocutaneous lesions that led to her admission to the hospital with a diagnosis of StevensJohnson syndrome. All drugs

and edema, the most common adverse reactions of this drug.2 Lansoprazole is a proton-pump inhibitor used for the treatment of acid-related disorders. During lansoprazole therapy, the most common dermatologic reactions include skin rash, urticaria, and pruritus.3 In addition, serious dermatologic reactions, such as StevensJohnson syndrome, toxic epidermal necrolysis, and erythematous or bullous rashes including erythema multiforme, have been reported with both drugs.2,4 We describe the case of a pa-

Author information provided at the end of the text. This work was partly supported by Regional Funds for Drug Surveillance granted by the local Assessorato Regionale alla Sanit, Regione Autonoma della Sardegna.

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G Severino et al.

were immediately discontinued, and the patient was treated with methylprednisolone and desloratadine. She was discharged from the hospital after 5 days, and methylprednisolone and desloratadine treatment was discontinued 30 days later. Two months later, imatinib 300 mg/day, prednisone 25 mg/day, and desloratadine 5 mg/day were reintroduced. One day prior to the reintroduction of imatinib, the patient failed to inform physicians that she had taken a dose of lansoprazole. Twenty-four hours after the reintroduction of medication, there was a recurrence of palpebral and labial edema with generalized body rash. All drugs were withdrawn, with the exception of corticosteroid and antihistaminic therapy. The progression of cutaneous lesions stopped, and the patient displayed a good clinical response to escalating doses of the steroid.

Discussion The protein tyrosine kinases constitute a large and diverse family of homologous proteins acting as important regulators of intracellular signal transduction pathways. The deregulation of protein kinase activity has been shown to play a central role in the pathogenesis of human cancer.1 In particular, mutations in the cellular proto-oncogene KIT that lead to constitutive activation of the KIT tyrosine kinase (CD117) have been described in most human GIST. KIT is thought to promote tumor growth or prevent apoptosis in this disease. Imatinib is an orally bioavailable, small-molecule inhibitor of some tyrosine kinases involved in cell signaling including KIT, platelet-derived growth-factor receptor, and BCR-ABL fusion protein. Treatment with imatinib is promising in patients with GIST. GIST arise from mesenchymal stem cells within the gastrointestinal tract and are generally malignant. The median survival of patients with unresectable or metastatic soft-tissue sarcomas, including GIST, has been estimated at 53 weeks, and conventional chemotherapy is ineffective with regard to survival.5 In 2 important trials, imatinib was shown to be active against GIST and well tolerated. In both studies, edema and rash were described as common adverse effects unrelated to dose.6,7 In patients treated with imatinib, Ph1-positive leukemia, rash, and edema were the most common adverse reactions observed and were strongly dose related. In particular, the prevalence rate for rash was about 60% for a dose of 400 mg/day and reached 93% among patients with doses of 600 800 mg/day. Edema occurred in 60% of patients with doses of 400 mg/day and 86% of those receiving 600 800 mg/day.8 More recently, StevensJohnson syndrome has been described after one week of treatment with imatinib 600 mg/day in a 42-year-old man in the blast crisis phase of chronic myeloid leukemia in which allogenic peripheral blood stem-cell transplantation had failed.9 The pathophysiology of this cutaneous reaction is still unclear and, although drug-induced StevensJohnson syndrome has been thought to occur through an immunologic mechanism, a possible dose relationship has been proposed for imatinib. Some authors have suggested the possibility of managing significant cutaneous reactions to imatinib, including StevensJohnson syndrome, by using concomitant shortterm steroid therapy or reintroducing the drug with gradual dose escalation.10 Once-weekly dosing has been proposed
s

in a case study for a patient on maintenance therapy for acute lymphoblastic leukemia with recurrent cutaneous reactions due to imatinib.11 Treatment with imatinib 400 mg/day alone for 2 months was well tolerated by our patient and did not cause any adverse effects. Common imatinib cutaneous adverse reactions, such as facial reactions, started just 10 days after introduction of lansoprazole during imatinib 400 mg/day treatment. Severe, generalized cutaneous reactions appeared immediately, even when a low dose of imatinib (300 mg/day) with corticosteroid therapy was reintroduced concurrently with lansoprazole. Lansoprazole is largely metabolized by CYP3A4 and CYP2C19 and is a weak noncompetitive inhibitor of CYP3A4. The peak plasma concentrations of lansoprazole are often <1 M. Yet, the inhibition constant (Ki) for lansoprazole inhibition of CYP3A4A is 165 M. In fact, the [I]/Ki ratio is <0.005. Even if this estimate were errant by an entire order of magnitude (such that the [I]/Ki ratio were as high as 0.05), the characterization of its inhibition of CYP3A4A substrates would be unlikely by current Food and Drug Administration/Pharmaceutical Research and Manufacturers of America/European Federation for Pharmaceutical Sciences standards. In contrast, ketoconazoles Ki for CYP3A inhibition is <0.1 M.12 Imatinib is extensively metabolized by CYP3A4; coadministration of a single dose of substances such as ketoconazole that inhibit CYP3A4 increases the mean AUC of imatinib by 40% in healthy subjects.13 When lansoprazole is administered concomitantly, it should elicit a slight increase in the bioavailability of imatinib.12 However, CYP3A4 is the most abundant isoform of cytochrome P450, and interindividual variations in expression levels of CYP3A4 have been observed in the adult human liver. These variations may affect efficacy and toxicity of currently used drugs. The variable expression of CYP3A4 is at least partially due to multiple factors including induction by drugs, endogenous compounds, environmental chemicals, and genetic factors.14 Although at present it is somewhat premature to conclude that an interaction at the level of CYP3A4 exists between these 2 drugs, we advise particular caution when administering imatinib with CYP3A4 inhibitors such as lansoprazole. We applied Naranjos algorithm to each of the drugs used in our patient.15 The score generated suggests that the adverse effects were possible due to imatinib and probable due to lansoprazole. Nevertheless, as the patient was not rechallenged with either drug alone, we cannot exclude that the reactions observed may have been caused by single administration of either drug. Conclusions Based on the case presented here, we assume that either imatinib or lansoprazole given alone may be considered a possible cause of the adverse reactions or that use of the 2 drugs together may increase the risk of onset of these adverse reactions due to a drug interaction. The possibility of a potential metabolic interaction at the level of CYP3A4
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ADRs with Imatinib and Lansoprazole

between imatinib and lansoprazole is interesting and may find confirmation in future studies. On the basis of observations made in this case report, particular caution is advised when administering imatinib with lansoprazole.
We thank Angela Cau MD, General Practitioner, for the first ADR report.

abilities to metabolize testosterone and chlorpyrifos. J Pharmacol Exp Ther 2001;299:825-31. 15. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.

EXTRACTO

Giovanni Severino MD, Clinical Pharmacologist, Section of Clinical Pharmacology, Department of Neurosciences, B.B. Brodie, University of Cagliari, Cagliari, Italy Caterina Chillotti MD, Clinical Pharmacologist, Section of Clinical Pharmacology, Department of Neurosciences, B.B. Brodie, University of Cagliari and Local Health Unit 8 Roberto De Lisa MD, Resident Specialist, Section of Clinical Pharmacology, Department of Neurosciences, B.B. Brodie, University of Cagliari Maria Del Zompo MD, Full Professor; Director, Section of Clinical Pharmacology, Department of Neurosciences, B.B. Brodie, University of Cagliari and ASL 8 Raffaella Ardau MD, Clinical Pharmacologist, Section of Clinical Pharmacology, Department of Neurosciences, B.B. Brodie, University of Cagliari and ASL 8 Reprints: Dr. Ardau, Section of Clinical Pharmacology, Department of Neurosciences, B.B. Brodie, University of Cagliari and ASL 8, P.O. San Giovanni di Dio, Via Ospedale 46, 09124 Cagliari, Italy, fax 39 070 653584, mosca@unica.it

References
1. Buchdunger E, OReilly T, Wood J. Pharmacology of imatinib (STI571). Eur J Cancer 2002;38(suppl 5):S28-36. DOI 10.1016/S0959-8049(02)80600-1 2. Brouard M, Saurat JH. Cutaneous reactions to STI571. N Engl J Med 2001;345:618-9. 3. Package insert. Prevacid (lansoprazole). www.fda.gov/medwatch/ SAFETY/2003/03AUG_PI/Prevacid_PI.pdf (accessed 2004 Feb 11). 4. Bong JL, Lucke TW, Douglas WS. Lichenoid drug eruption with proton pump inhibitors. BMJ 2000;320:283. 5. van Oosterom AT, Judson I, Verweij J, Stroobants S, Donato di Paola E, Dimitrijevic S, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a Phase I study. Lancet 2001;358: 1421-3. DOI 10.1016/S0140-6736(01)06535-7 6. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472-80. 7. Verweij J, van Oosterom A, Blay JY, Judson I, Rodenhuis S, van der Graaf W, et al. Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group Phase II study. Eur J Cancer 2003;39:2006-11. DOI 10.1016/S0959-8049(02)00836-5 8. Valeyrie L, Bastuji-Garin S, Revuz J, Bachot N, Wechsler J, Berthaud P, et al. Adverse cutaneous reactions to imatinib (STI571) in Philadelphia chromosomepositive leukemias: a prospective study of 54 patients. J Am Acad Dermatol 2003;48:201-6. DOI 10.1067/mjd.2003.44 9. Hsiao LT, Chung HM, Lin JT, Chiou TJ, Liu JH, Fan FS, et al. Stevens Johnson syndrome after treatment with STI571: a case report. Br J Haematol 2002;117:620-2. DOI 10.1046/j.1365-2141.2002.03499.x 10. Rule SA, OBrien SG, Crossman LC. Managing cutaneous reactions to imatinib therapy. Blood 2002;100:3434-5. 11. Tanvetyanon T, Nand S. Overcoming recurrent cutaneous reactions from imatinib using once-weekly dosing. Ann Pharmacother 2003;37:181820. DOI 10.1345/aph.1D184 12. Ko JW, Sukhova N, Thacker D, Chen P, Flockhart DA. Evaluation of omeprazole and lansoprazole as inhibitors of cytochrome P450 isoforms. Drug Metab Dispos 1997;25:853-62. 13. Electronic Medicines Compendium (2003): http://emc.medicines.org.uk (accessed 2004 Feb 11). 14. Dai D, Tang J, Rose R, Hodgson E, Bienstock RJ, Mohrenweiser HW, et al. Identification of variants of CYP3A4 and characterization of their

OBJETIVO: Informar el caso de una paciente con tumors estromales gastrointestinales (TEGI) que desarroll reacciones adversas cutneas relacionadas al tratamiento con imatinib y lansoprazol. RESUMEN DE CASO: Despus de dos meses de recibir tratamiento con el imatinib, una mujer blanca de 60 aos con tumors estromales gastrointestinales desarroll edema palpebral bilateral con conjuntiva hipermica y edema labial al iniciar el lansoprazol para tartar sntomas de dispepsia. El tratamiento fue suspendido y al reiniciar ambos medicamentos, la paciente desarroll el syndrome de StevensJohnson. Dos meses ms tarde, present reacciones cutneas generalizadas inmediatamente despus de reiniciar el imatinib en dosis bajas junto a la terapia de corticosteroids ms lansoprazol. Al suspender todos los medicamenots, con excepcin del corticosteroide, se detuvo el progreso de las lesiones cutneas. DISCUSIN: el uso del imatinib est comnmente asociado a una incidencia alta de erupcin y edema relacionadas a la dosis. Tambin se han descrito varios casos del syndrome de StevensJohnson, aunque no en pacientes afectados por TEGI. Se han informado reacciones cutneas severas causadas por el lansoprazol, incluido la eritema multiforme, el syndrome de StevensJohnson y la necrlisis epidrmica txica. Al implementer el algoritmo de Naranjo, se consider la posibilidad de una reaccin adversa relacionada al uso de medicamentos causada por el imatinib y con alguna probabilidad al lansoprazol. CONCLUSIONES: Segn informacin reportada, concluimos que las reacciones adversas relacionadas aluso de medicamenots que se describen podran atribuirse a cualquiera de los dos frmacos. Sin embargo, el uso de dos frmacos juntos podra aumentar el riesgo del inicio de estas reacciones adversas debido al potencial de interaccin de medicamentos mediante el CYP3A4.

Rafaela Mena Berrios

RSUM

Dcrire le cas dune patiente avec une tumeur stromale gastrointestinale qui a prsent des effets indsirables cutans suite la prise de limatinib et du lansoprazole. RSUM DU CAS: Une patiente de 60 ans a prsent de loedme bilatral priorbital avec conjonctivite aprs 2 mois de traitement sous imatinib et de loedme labial lorsque le lansoprazole a t introduit pour une dyspepsie. Le traitement a t discontinu et suite la rintroduction des 2 mdicaments, la patiente a dvelopp un syndrome de Stevens Johnson. Deux mois plus tard, une ruption cutane gnralise est apparue immdiatement suite la reprise dune faible dose dimatinib, dune corticothrapie, et du lansoprazole. Les lsions cutanes sont disparues suite larrt de tous ces mdicaments except la corticothrapie. DISCUSSION: Limatinib est frquemment associ la prsence druptions cutanes et doedmes priorbitaux. Plusieurs cas de StevensJohnson ont t dcrits, cependant ces patients ne prsentaient par de tumeur stromale gastro-intestinale. Des ractions cutanes svres ont galement t rapportes avec le lansoprazole incluant un rythme multiforme, un syndrome de StevensJohnson, et une ncrose pidermique toxique. En utilisant lchelle de Naranjo, une association possible entre lapparition des ruptions cutanes et limatinib et le lansoprazole a t tablie. CONCLUSIONS: Les auteurs concluent que les ruptions cutanes pouvaient tre associes la prise de limatinib et du lansoprazole. Ces effets pourraient tre expliqus par une interaction au niveau des CYP3A4 entre limatinib et le lansoprazole.
OBJECTIF:

Louise Mallet

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