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Methods of optimizing drug therapeutic efficacy for treatment of immune-mediated gastrointestinal disorders

a technology drug therapeutic efficacy, which is applied in the field of optimizing drug therapeutic efficacy for immune-mediated gastrointestinal disorders, can solve the problems of increased risk of intestinal cancer for patients with ibd, potentially fatal hematopoietic toxicity, and patients with less active tpmt being more susceptible to toxic side effects of 6-mp therapy

Inactive Publication Date: 2001-07-05
HOPITAL SAINTE JUSTINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010] Further provided by the invention is a method of optimizing therapeutic efficacy and reducing toxicity associated with 6-mercaptopurine drug treatment of an immune-mediated gastrointestinal disorder. The method includes the steps of administering a 6-mercaptopurine drug to a subject having an immune-mediated gastrointestinal disorder; determining a level of 6-thioguanine in the subject having the immune-mediated gastrointestinal disorder; and determining a level of 6-methyl-mercaptopurine in the subject having the immune-mediated gastrointestinal disorder, where a level of 6-thioguanine less than a predetermined minimal therapeutic level indicates a need to increase the amount of 6-mercaptopurine drug subsequently administered to the subject, thereby increasing therapeutic efficacy; where a level of 6-thioguanine greater than a predetermined toxic level of 6-thioguanine indicates a need to decrease the amount of 6-mercaptopurine drug subsequently administered to the subject, thereby reducing toxicity associated with 6-mercaptopurine treatment of the immune-mediated gastrointestinal disorder; and where a level of 6-methyl-mercaptopurine greater than a predetermined toxic level of 6-methyl-mercaptopurine indicates a need to decrease the amount of 6-mercaptopurine drug subsequently administered to the subject, thereby reducing toxicity associated with 6-mercaptopurine treatment of the immune-mediated gastrointestinal disorder.

Problems solved by technology

In addition, patients with IBD are at increased risk for the development of intestinal cancer.
Patients who less efficiently methylate these thiopurines have more extensive conversion to 6-TGN, which can lead to potentially fatal hematopoietic toxicity.
Therefore, patients who have less active TPMT can be more susceptible to toxic side effects of 6-MP therapy.
Although drugs such as 6-MP and AZA have been used for treating IBD, non-responsiveness and drug toxicity unfortunately complicate treatment in some patients.
Therefore, many physicians are reluctant to treat patients with AZA because of its potential side effects, especially infection and neoplasia.
Where the elevated 6-mercaptopurine metabolite is 6-thioguanine, the toxicity associated with 6-mercaptopurine treatment can be, for example, hematologic toxicity.
Therefore, patients with high TPMT activity can be more susceptible to toxic effects of 6-MP drug therapy.
In addition, CD is associated with an increased risk of intestinal cancer.
In addition, ulcerative colitis and especially long-standing, extensive disease is associated with an increased risk of colon carcinoma.
However, it was unknown what concentrations of 6-MP metabolites correlated with optimized therapeutic efficacy or with toxicity (Cuffari et al., supra, 1996a).
Although 6-MP drugs such as 6-MP and azathioprine can be used for effective treatment of an immune-mediated GI disorder, including IBDs such as Crohn's disease or ulcerative colitis, administration of such drugs can be associated with toxic side effects.
Where the elevated 6-MP metabolite is 6-MMP, the toxicity associated with 6-MP drug treatment can be, for example, hepatic toxicity.

Method used

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  • Methods of optimizing drug therapeutic efficacy for treatment of immune-mediated gastrointestinal disorders
  • Methods of optimizing drug therapeutic efficacy for treatment of immune-mediated gastrointestinal disorders
  • Methods of optimizing drug therapeutic efficacy for treatment of immune-mediated gastrointestinal disorders

Examples

Experimental program
Comparison scheme
Effect test

example ii

6-Mercaptopurine Metabolite Levels Correlate with Optimal 6-MP Therapy in IBD Patients

[0077] This example describes prospective examination of the correlation of 6-MP metabolite levels with therapeutic response to 6-MP drug therapy and 6-MP drug related toxicity in IBD patients treated with 6-MP.

[0078] To obtain additional statistical data on IBD patients treated with a 6-MP drug, additional patients and samples were analyzed and combined with the data obtained in Example I. Blood was sampled at least once in 93 IBD patients followed at Sainte-Justine Hospital IBD Center, Montreal, Canada, who were administered 6-MP drug therapy for at least 4 months. The 93 patients were pediatric patients, with 80 diagnosed as having CD, 8 diagnosed as having UC, and 5 diagnosed as having indeterminate colitis (CD or UC). All but 7 patients were given AZA. The dosages were converted to 6-MP equivalents using a factor of 2.07 as described in Example I. For some patients, two or more samples were ob...

example iii

Gender and Age Differences in Metabolism of a 6-MP Drug

[0083] This example describes gender and age differences observed in pediatric patients treated with 6-MP drug therapy.

[0084] Pediatric IBD patients undergoing 6-MP drug therapy were assessed for levels of 6-MP metabolites. These patients were wild type for TPMT. Patients were assessed based on gender and age as it relates to puberty. Puberty is established at 12 years of age in girls and 14 years of age in boys.

[0085] As shown in Table 3, the 6-MMP values are much lower in boys after puberty (greater than 14 years). Since the total amount of thiometabolites is lower, this indicates that either lower doses of 6-MP are used or that there is a difference in the bioavailability of 6-MP after puberty in males.

3TABLE 3 6-MP Metabolite Levels in Pediatric IBD Patients 6-TG level 6-MMP level Number (pmol per (pmol per Ratio Observed 8 .times. 10.sup.8 RBC) 8 .times. 10.sup.8 RBC) 6-MMP / 6-TG Girls 39 182.2 3447.0 18.52 (0-12 y) Girls 11...

example iv

Thiopurine Methyltransferase (TPMT) Genotyping and Responsiveness to 6-MP Drug Therapy

[0087] This example describes TPMT genotyping of IBD patients treated with 6-MP drug therapy.

[0088] The genotype of TPMT was determined in IBD patients that were responders and non responders. Genotyping of TPMT was measured essentially as described previously (Baccichet et al., Leuk. Res. 21:817-823 (1997); Zietkiewicz et al., Gene 205:161-171 (1997)). The data shown in Table 4 indicate that patients heterozygous for the TPMT mutation had significantly higher 6-TG levels compared to those patients without the mutation. All heterozygote patients were responders to 6-MP.

4TABLE 4 TPMT Genotyping of IBD Patients Heterozygote Normal Responder 100% 55% Non responder 0% 45% mean 6-TG 589* 247 p value *less than 0.0001

[0089] TPMT genotyping revealed that 8 of 93 (9%) of patients were heterozygotes. No homozygous TPMT deficient patients were detected. All 8 heterozygotes responded to 6-MP and had 6-TG leve...

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Abstract

The present invention provides a method of optimizing therapeutic efficacy and reducing toxicity associated with 6-mercaptopurine drug treatment of an immune-mediated gastrointestinal disorder such as inflammatory bowel disease. The method of the invention includes the step of determining the level of one or more 6-mercaptopurine metabolites in the patient having an immune-mediated gastrointestinal disorder.

Description

[0001] This application claims the benefit of priority of provisional application Ser. No. 60 / 101,714, filed Sep. 24, 1998, which is incorporated herein by reference.[0002] The present invention relates generally to autoimmunity and immune-mediated gastrointestinal disorders such as inflammatory bowel disease and more specifically to methods for optimizing treatment of immune-mediated gastrointestinal disorders.BACKGROUND INFORMATION[0003] Immune-mediated gastrointestinal disorders encompass a wide range of debilitating gastrointestinal diseases of various etiologies. One such immune-mediated gastrointestinal disorder, inflammatory bowel disease (IBD), is the collective term used to describe two gastrointestinal disorders of unknown etiology: Crohn's disease (CD) and ulcerative colitis (UC). The course and prognosis of IBD, which occurs world-wide and is reported to afflict as many as two million people, varies widely. Onset of IBD is predominantly in young adulthood with diarrhea, ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/52A61K31/522A61P1/04G01N33/00
CPCA61K31/52A61K31/522G01N33/564G01N33/94G01N2800/06G01N2800/065G01N2800/24G01N2800/245Y10T436/142222Y10T436/147777Y10T436/141111A61P1/00A61P1/04A61P37/00
Inventor SEIDMAN, ERNEST G.THEORET, YVES
Owner HOPITAL SAINTE JUSTINE
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