Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease

doi:10.1016/S0016-5085(00)70140-5

Gastroenterology

Volume 118, Issue 4, April 2000, Pages 705-713

https://doi.org/10.1016/S0016-5085(00)70140-5 Get rights and content

Abstract

Background & Aims: The effects of 6-mercaptopurine (6-MP) are mediated via its intracellular conversion to 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) nucleotide metabolites, the latter genetically controlled by thiopurine methyltransferase (TPMT). We sought to determine optimal therapeutic 6-MP metabolite levels and their correlation with medication-induced toxicity and TPMT genotype. Methods: Therapeutic response was determined in 92 pediatric patients with inflammatory bowel disease coincidentally with hematologic, pancreatic, and hepatic laboratory parameters, and compared with erythrocyte metabolite levels and TPMT genotype. Results: Clinical response was highly correlated with 6-TG levels (P < 0.0001) but not with any other variable, including 6-MMP levels, drug dose, gender, and concurrent medications. The frequency of therapeutic response increased at 6-TG levels > 235 pmol/8 × 10⁸ erythrocytes (P < 0.001). Hepatotoxicity correlated with elevated 6-MMP levels (>5700 pmol/8 × 10⁸ erythrocytes; P < 0.05). Although leukopenia was associated with higher 6-TG levels (P < 0.03), it was observed in only 8% of responders. Patients heterozygous for TPMT (8/92) had higher 6-TG levels (P < 0.0001), and all responded to therapy. Conclusions: 6-MP metabolite levels and TPMT genotyping may assist clinicians in optimizing therapeutic response to 6-MP and identifying individuals at increased risk for drug-induced toxicity.

GASTROENTEROLOGY 2000;118:705-713

Section snippets

Patient population

Patients less than 19 years of age followed up by the clinical investigators (M.C.D. and E.G.S.) at Ste-Justine Hospital IBD Center were eligible for inclusion if they had undergone 6-MP or AZA treatment for at least 4 months. Diagnoses of CD, ulcerative colitis (UC), or indeterminate colitis were established by standard clinical, radiological, histological, and endoscopic criteria.²⁸ Patients with leukopenia or increased serum hepatic or pancreatic enzyme activities before initiation of

Metabolite levels and therapeutic response

The study population was divided into patients with a satisfactory clinical response and those who failed therapy. In the single-sampled patient group, 27 of 46 (59%) responded and 19 of 46 (41%) failed. In the multisampled patients, 20 of 46 (43%) had a response sustained at each clinical evaluation point, 11 (24%) never achieved a clinical response, and 15 (33%) responded inconsistently over time. Among all 173 metabolite measurements, 103 (60%) corresponded to patients with a clinical

Discussion

This study demonstrates that erythrocyte 6-TG concentration, not drug dose, is significantly and independently associated with therapeutic response to 6-MP in children with IBD. Our data corroborate our previous pilot study in IBD,²⁶ as well as reports in acute lymphoblastic leukemia, suggesting that 6-TG levels above particular cutoff points are related to disease-free survival, independent of other factors known to affect prognosis, including standardized dosing regimens.22, 24, 25 Our

Acknowledgements

The authors thank Hughes Sinnett and Sylvain Latour for technical support.

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The aim of this study was to assess how 6-thioguanine nucleotide (6-TGN) levels and use of oral methotrexate relate to the pharmacokinetics of biologics.
This was a prospective cohort study including patients with inflammatory bowel diseases on maintenance doses of infliximab, vedolizumab, or ustekinumab on monotherapy or combination with a thiopurine or oral methotrexate. We collected 6-TGN concentrations, biomarker levels, and clinical and endoscopic disease activity. The primary outcomes were infliximab, vedolizumab, and ustekinumab concentrations as well as anti-drug antibodies (ADAs).
A total of 369 patients were recruited (113 infliximab, 133 vedolizumab, and 123 ustekinumab). Patients with 6-TGN levels ≥146 pmol per 8 × 10⁸ red blood cells (RBCs), and those receiving combination therapy with thiopurine or oral methotrexate had significantly higher infliximab concentrations when compared with monotherapy (median levels of 17.4 μg/mL on thiopurine with 6-TGN ≥146 pmol per 8 × 10⁸ RBCs, 17.1 on methotrexate, and 3.9 on infliximab monotherapy; P = .001 for both comparisons). However, there was no association between the use of immunomodulators and 6-TGN concentrations with vedolizumab (median levels of 8.8 on thiopurine with 6-TGN ≥152 pmol per 8 × 10⁸ RBCs, 6.8 on methotrexate, and 10.5 on vedolizumab monotherapy; P > .05 for both comparisons) or ustekinumab median concentrations (median levels of 5.0 on thiopurine with 6-TGN ≥154 pmol per 8 × 10⁸ RBCs, 5.2 on methotrexate and 7.0 on ustekinumab monotherapy; P > .05 for both comparisons). Fourteen (12%) patients had anti-infliximab antibodies, while 1 patient had ADAs in each of the other drug cohorts.
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^☆: Address requests for reprints to: Ernest G. Seidman, M.D., Division of Gastroenterology and Nutrition, Sainte-Justine Hospital, 5734, 3175 Cote-St-Catherine Road, Montreal, Quebec, Canada H3T 1C5. e-mail: [email protected]; fax: (514) 345-4999.

^☆☆: Drs. Sinnett, Théorêt, and Seidman share equal senior authorship.

^★: Supported by the Charles Bruneau Foundation (to D.S. and Y.T.), Fonds de la Recherche en Santé du Québec (Scholarships to D.S. and E.G.S.), and Fonds pour la Formation de Chercheurs et l'Aide à la Recherche (Studentship to S.L.).

^★★: Dr. Targan is a Founder of Prometheus Labs; Ste-Justine Hospital and Drs. Sinnett, Théorêt, and Seidman have a royalty agreement for the use of the described tests for the management of IBD with Prometheus Labs.

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Alimentary TractPharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease☆,☆☆,★,★★

Abstract

Section snippets

Patient population

Metabolite levels and therapeutic response

Discussion

Acknowledgements

Lancet

Gastroenterology

Gastroenterology

Gastroenterology

Lancet

J Pediatr

Lancet

A controlled double blind study of azathioprine in the management of Crohn's disease

Gut

Treatment of Crohn's disease with 6-mercaptopurine: a long-term, randomized, double blind study

N Engl J Med

Azathioprine and 6-mercaptopurine in Crohn's disease. A meta-analysis

Ann Intern Med

Randomized controlled trial of azathioprine withdrawal in ulcerative colitis

Br Med J

6-Mercaptopurine (6-MP) and prednisone therapy for newly diagnosed pediatric Crohn's disease (CD): a prospective multicenter, placebo-controlled clinical trial (abstr)

Gastroenterology

6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity

Ann Intern Med

Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience

Gut

Toxicities and infections associated with chronic 6-mercaptopurine (6-MP) use in Crohn's disease (CD): do we need to discontinue treatment?

Gastroenterology

Immunosuppressive therapy in pediatric inflammatory bowel disease: results of a survey of the North American Society for Pediatric Gastroenterology and Nutrition. Subcommittee on immunosuppressive use of the Pediatric IBD Collaborative Research Forum

Am J Gastroenterol

The clinical pharmacology of 6-mercaptopurine

Eur J Clin Pharmacol

Variable bioavailability of oral mercaptopurine. Is maintenance chemotherapy in acute lymphoblastic leukemia being optimally delivered?

N Engl J Med

Azathioprine pharmacokinetics after intravenous, oral, delayed release oral and rectal foam administration

Gut

Intraindividual variation in 6-mercaptopurine pharmacokinetics during oral maintenance therapy of children with acute lymphoblastic leukemia

Eur J Clin Pharmacol

Clinical implications of thiopurine methyltransferase-optimization of drug dosage and potential drug interactions

Ther Drug Monitoring

The comparative metabolism of imuran and 6-mercaptopurine in man

Proc Am Assoc Cancer Res

Mercaptopurine Pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity

Am J Hum Genet

Childhood leukemia: a relationship between intracellular 6-MP metabolites and neutropenia

Br J Clin Pharmacol

Variable 6-mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia

J Clin Oncol

Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism

Clin Pharmacol Ther

Mercaptopurine metabolism and risk of relapse in childhood lymphoblastic leukemia

Lancet

Alimentary Tract
Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease☆,☆☆,★,★★