Pharmacoeconomic analysis of thiopurine methyltransferase polymorphism screening by polymerase chain reaction for treatment with azathioprine in Korea

K.-T. Oh, A. H. Anis1 and S.-C. Bae

Department of Internal Medicine, Division of Rheumatology, Hanyang University College of Medicine and the Hospital for Rheumatic Diseases, Hanyang University Medical Center, Seoul, Republic of Korea and 1Department of Health Care and Epidemiology, University of British Columbia, Vancouver, Canada.

Correspondence to: S.-C. Bae, The Hospital for Rheumatic Diseases, Hanyang University Medical Center, Seoul 133–792, Republic of Korea. E-mail: scbae@hanyang.ac.kr


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objectives. To evaluate the value of genotype-based dosing by polymerase chain reaction (PCR)-based polymorphism screening in terms of cost-effectiveness for treatment with azathioprine in Korea.

Methods. Decision analysis was employed to compare a genotype-based dosing strategy with the conventional weight-based dosing strategy using a hypothetical cohort composed of rheumatoid arthritis and systemic lupus erythematosus patients. The time horizon was set up as 1 yr. Direct medical costs were used. Data used were obtained from previous reports, except for PCR and admission costs, which were from real cases. Cost-effectiveness analysis was conducted from a societal perspective. Outcomes were measured as a total expected cost and an incremental cost-effective ratio.

Results. In the base case model, total expected cost and the probability of not dropping out owing to serious adverse events of the conventional weight-based dosing and the genotype-based dosing strategy were 1339x103 Korean won ($US 1117) and 1109x103 Korean won ($US 926), and 97.06 and 99.90%, respectively.

Conclusions. Our model suggests that a genotype-based dosing strategy through PCR-based thiopurine methyltransferase (TPMT) polymorphism screening is less costly and more effective than the conventional weight-based dosing strategy in Korea, as it was associated with a marked reduction in the number of serious adverse events.

KEY WORDS: Thiopurine methyltransferase, Polymorphism, Screening, Polymerase chain reaction, Azathioprine, Pharmacoeconomic analysis, Korea.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Azathioprine has been used as a second-line agent in treating rheumatological diseases, often as an alternative to methotrexate in rheumatoid arthritis (RA) or to cyclophosphamide in systemic lupus erythematosus (SLE). In spite of its moderate clinical efficacy and relatively low cost, the use of azathioprine has been limited owing to large inter-individual differences in outcomes, which result from either haematological toxicity or insufficient effect [1]. Moreover, it is well known that these features are largely associated with individually variant thiopurine methyltransferase (TPMT) activities [2, 3].

TPMT is a cytoplasmic enzyme that catalyses the S-methylation of thiopurine drugs, such as 6-mercaptopurine, 6-thioguanine and azathioprine. TPMT enzymatic activity usually shows a trimodal distribution of high, intermediate and very low activity among the population [4, 5], but inter-ethnic and inter-racial differences have been found to affect the distribution of TPMT activity [6]. It has been reported that the major factors responsible for the observed divergence in TPMT activity are the major polymorphisms of the TPMT genotypes, i.e. wild, heterozygous mutant and homozygous mutant type [5].

Many reports have suggested that the efficacy or toxicity profiles of azathioprine therapy could be substantially improved in a significant proportion of cases if an individual's TPMT enzymatic activity were taken into account [7]. Currently, interest in screening for TPMT activity prior to thiopurine drug therapy is increasing.

A biochemical assay for TPMT enzymatic activity in red blood cells (RBCs) has been used in some laboratories. However, its use is limited in some clinical applications because of possible interference by recent episodes of blood transfusion, some medications or alcohol [8, 9], and few available laboratories, as well as possible inconsistencies in the results between laboratories [10].

On the other hand, polymerase chain reaction (PCR) genotyping for the TPMT polymorphism produces a rapid result, is not expensive and is not subject to interference by exogenous factors. Furthermore, PCR genotyping has been found to be well correlated with blood TPMT enzymatic activity with over a 95% concordance rate, and to have a high sensitivity and specificity [11, 12]. All of these qualities imply the practicality of PCR genotyping as a screening method. To date there has been only one report regarding the cost-effectiveness of screening for variant TPMT activity for treatment with azathioprine, which showed that the introduction of PCR testing might represent good value in certain Canadian health-care settings [13]. However, the cost-effectiveness of screening in the Korean context is unknown.

Here, we undertook to compare the economic benefit of two azathioprine treatment strategies—conventional weight-based dosing and PCR genotype-based dosing—for two common rheumatological diseases, RA and SLE, and to provide a pharmacoeconomic analytical model for genotype screening for treatment with azathioprine.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Goal of study
This study was designed to verify whether the genotype-based dosing of azathioprine could result in better outcomes, but primarily from the point of view of cost-effectiveness rather than efficacy-based outcomes.

Therefore, the goal of our study was to evaluate genotype-based dosing of azathioprine in terms of cost-effectiveness compared with conventional weight-based dosing in patients with RA or SLE.

Study design
A decision analytical model was used to compare conventional weight-based dosing and genotype-based dosing strategies. This study was performed on a hypothetical cohort composed of adult patients (50 kg body weight) with moderate to severe RA or SLE, who required azathioprine treatment because of the unsuitability of methotrexate or cyclophosphamide. We then progressed the hypothetical cohort according to the basic scenario; the time horizon was set at 1 yr.

In terms of the development of a decision tree, previously reported values were used to determine the decision probabilities of each branch leading from each chance node. The reported prevalence rate of TPMT activity was used as a pre-test prior probability and the decision tree method was used to calculate the conditional probability by combining the prevalence rate of TPMT activity to the sensitivity and specificity of PCR genotyping for type *2, *3A, *3B and *3C. Expected costs were calculated by combining the probabilities and costs of each branch.

Decision tree analysis was conducted from a societal perspective and initially performed on the base case, followed by sensitivity analysis with the range of values. We searched for data of prevalence rates of TPMT activities, sensitivity and specificity of PCR genotyping, and a possible incidence rate of severe adverse reactions from intermediate activity from previous reports. From these data, we selected values that were most frequently cited and feasible as representative ones for a base case analysis, but did sensitivity analyses using disregarded values (Fig. 1).



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FIG. 1. Decision tree of basic case.

 
Outcome measures
Outcomes were measured as a total expected cost incorporating the incidence of severe adverse events and an incremental cost-effectiveness ratio. We presumed that if a patient developed severe bone marrow toxicity, azathioprine treatment was discontinued and follow-up discontinued. The incremental cost-effectiveness ratio was calculated as the ratio of the individual total expected 1-yr follow-up cost to the probability of not dropping out owing to serious adverse events.

Basic scenario
Because this study was based on a hypothetical cohort, it required a fundamental scenario to progress the cohort, including drug dosage, laboratory test schedule and the establishment of a condition in which patients would be dropped out of the cohort. The basic assumptions were as follows.

  1. Thoe drug dosage and follow-up schedule of azathioprine were based on the guidelines in PDR® (Physician's Desk Reference) and on suggestions in previous reports. In a genotype-based dosing strategy, target doses were established based on suggestions made in an earlier study [2].
  2. In conventional weight-based dosing, azathioprine was started at 1 mg/kg daily. Dose increment began at 8 weeks, and thereafter was incremented in 0.5 mg/kg steps at 4-week intervals; the target dose was 2.5 mg/kg. Laboratory follow-up testing was carried out every 2 weeks until the dose had stabilized. After the dose had stabilized, laboratory follow-up testing was done every 6 weeks.
  3. In genotype-based dosing, the drug dosage and laboratory testing follow-up schedule was planned according to genotype.
    1. In the wild type, because a high TPMT activity would be expected, azathioprine was started at a daily dose of 1 mg/kg. Dose increment began at 4 weeks, and thereafter with 0.5 mg/kg steps at 4-week intervals. The target daily dose was 2.5 mg/kg. A laboratory test was performed every 4 weeks until the daily dose had stabilized. Laboratory follow-up testing was then performed every 6 weeks.
    2. In the heterozygous mutant type, because TPMT activity would be reduced, azathioprine was started at 0.5 mg/kg per day. Dose increment began at 4 weeks, and thereafter in 0.5 mg/kg steps at 4-week intervals. The target dose was 1 mg/kg per day. Laboratory testing was performed every 4 weeks until dosage had stabilized. Laboratory follow-up testing was then performed every 6 weeks.
    3. In the homozygous mutant type, azathioprine was started at 0.25 mg/kg per day and the dosage was not incremented. Laboratory testing was done initially at 4 weeks, and every 6 weeks thereafter.

  4. We made the assumption that, when the azathioprine dosage exceeded the optimum dose in heterozygotes, severe or mild bone marrow toxicity would occur, and in homozygotes, severe bone marrow toxicity would occur, but not in the wild type. We defined severe bone marrow toxicity as a condition of severe leucopenia (white blood count <2.0 x109/l) or secondary infection or a fatal condition [14]. A patient with severe bone marrow toxicity was excluded from the cohort after 3 weeks of treatment. However, in other patients with mild bone marrow toxicity, azathioprine was withdrawn until the bone marrow recovered and then re-administered at a reduced dose. The ranges of the proportion of severe bone marrow toxicity were taken into account in sensitivity analysis.
  5. Adverse reactions that were not life-threatening, such as hepatotoxicity or gastrointestinal upset, were not considered, because these kinds of adverse reactions can be caused by idiosyncratic and unpredictable reactions quite independently of TPMT activity.

Costs
In this study, only direct medical costs were considered, which included costs to the patients themselves and the health-care scheme. The costs of azathioprine, which included prescribing, compounding and laboratory test fees (only complete blood count and blood chemistry for liver enzymes were included) during the follow-up period of 1 yr, were used in the calculation of total cost, in accordance with the 2002 Korean insurance system. PCR costs for TPMT genotyping and hospital admission costs owing to severe bone marrow toxicity as a result of azathioprine treatment were estimated from four real cases at Hanyang University Hospital, Seoul, Republic of Korea. The admission cost included the total cost of blood and platelet transfusions, the use of granulocyte colony-stimulation factor, antibiotics and the isolation room fee during the hospital stay. Costs were calculated in Korean won and the $US exchange rate used was $US 1 to 1193 Korean won.

Base case analysis (Fig. 1)
The decision tree was folded back to obtain total expected costs by incorporating the incidence of severe adverse events from intermediate activity, and cost-effectiveness ratio. In the base case, the prevalence rates of high, intermediate and low TPMT activity among the general population were 88.7, 11 and 0.3%, respectively [5], and the sensitivity and specificity of PCR genotyping were 96.3 and 100%, respectively [12]. The PCR cost of genotyping for types *2, *3A, *3B and *3C was calculated as 60 x103 Korean won ($US 50), and the possible incidence rate of severe adverse reactions from intermediate activity was 24% [14]. The hospital admission cost was 2996 x103 Korean won/case ($US 2501), which represented an average of four real cases between 1500 x103 Korean won ($US 1257) and 6152 x103 Korean won ($US 5157) at our hospital.

Sensitivity analysis
After performing base case analysis, sensitivity analyses were performed with the range of prevalence rates of TPMT activities, admission costs, PCR cost and the incidence rates of severe adverse reactions resulting from intermediate activity. We accepted 3.2% as a low prevalence rate, which was suggested as a prevalence rate of decreased TPMT activity in the Korean population [15]; 1500 x103 Korean won ($US 1252) as a low admission cost, based on the cases at our hospital; and a 9% incidence rate as a low rate of severe adverse reactions from intermediate TPMT activity. Since the PCR test for TPMT genotyping is not commercially established in Korea, we performed a sensitivity analysis with a wide range of values for PCR cost.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Base case analysis
Considerable differences were found between the total expected costs and the probability of not dropping out owing to serious adverse events of the two strategies. The total expected costs of the conventional weight-based dosing and the genotype-based dosing strategies were 1339 x103 Korean won ($US 1117) and 1109 x103 Korean won ($US 926), respectively. The risk of incidence of severe adverse reactions in the conventional weight-based dosing strategy was more than 29 times higher than in the genotype-based dosing strategy, i.e. 2.94 vs 0.10%, and the probabilities of not dropping out in the conventional weight-based dosing and the genotype-based dosing strategies were 97.06 and 99.90%, respectively (Table 1). The genotype-based dosing strategy was superior to the conventional weight-based dosing as it was found to be less costly and more effective (Fig. 2).


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TABLE 1. Outcomes in base case analysis

 


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FIG. 2. The cost-effectiveness plane in base case and sensitivity analyses.

I. Base case analysis.

II. Sensitivity analysis with 3.2% prevalence rate of decreased TPMT activity.

III. Sensitivity analysis with 1500 x103 won ($US 1252) hospital admission cost.

IV. Sensitivity analysis with 120 x103 won ($US 100) PCR cost.

V. Sensitivity analysis with 9% incidence rate of severe adverse events from intermediate TPMT activity.

VI. Sensitivity analysis with 3.2% prevalence rate, 1500 x103 won ($US 1252) admission cost, 120 x103 won ($US 100) PCR cost, and 9% incidence rate of severe adverse events from intermediate TPMT activity. *Genotype-based dosing strategy. **Conventional weight-based dosing strategy.

 
Sensitivity analysis
In the case where there was a 3.2% prevalence rate of decreased TPMT activity, even though the difference in the total cost and the incidence rate of severe adverse reactions between the two strategies was decreased, the genotype-based dosing strategy was still superior to the conventional weight-based dosing strategy.

In terms of the 1500 x103 Korean won ($US 1252) admission cost, even though the difference in the total cost was decreased, the genotype-based dosing strategy was still superior to the conventional weight-based dosing strategy.

In the case where there was a 9% incidence rate of severe adverse reactions resulting from intermediate TPMT activity, the genotype-based dosing strategy was still superior to the conventional weight-based dosing strategy.

When the cost of PCR testing was doubled, 120 x103 Korean won ($US 100) as a high PCR cost, even though the difference in the total cost was decreased, the genotype based-dosing strategy was still superior to that of the conventional weight-based dosing strategy. In fact, in our model, at least a 330 x103 Korean won ($US 278) PCR cost was required to reach the equivalence point in the two strategies, but considering the current Korean insurance system, this seems unreasonably high for a genotyping test.

Finally, even though we considered all of the above situations simultaneously, including a 3.2% prevalence rate of decreased TPMT activity, a 1500 x103 Korean won ($US 1252) admission cost, a 120 x103 Korean won ($US 100) PCR cost, and a 9% incidence rate of severe adverse reactions from intermediate activity, the superiority of the genotype-based dosing strategy in terms of cost-effectiveness was not changed.

As can be seen from the sensitivity analysis, our model was insensitive to variable values. These findings seem to be due to the reduced incidence rate of severe adverse reactions, resulting in fewer hospitalizations, and a lowered cost by reducing the frequency of follow-up and laboratory testing in the genotype-based dosing strategy (Table 2, Fig. 2).


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TABLE 2. Outcomes in sensitivity analysis

 

    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We found that a genotype-based dosing strategy for treatment with azathioprine, after PCR screening for the TPMT polymorphism, is a more cost-effective strategy than the conventional weight-based dosing strategy, resulting from the lower total cost and higher effectiveness in avoiding the severe adverse events associated with azathioprine therapy.

It has been reported that severe drug adverse events, which occur from supposedly correctly applied drug therapy, have a high cost and cause many deaths [16]. A significant proportion of these adverse events are probably due to inter-individual genetic differences in response to medication. Therefore, it has been suggested that identifying patients at risk of unwanted events prior to therapy by characterizing an individual's genetic make-up would improve the efficacy and toxicity profiles of drug therapy, and provide substantial medical and financial benefits [17, 18].

Pharmacogenetics involves the scientific study of pharmacological response and its modification by hereditary influence [19]. TPMT polymorphism is a good candidate for pharmacogenetic screening, because its role in high incidence rates of severe adverse reactions associated with decreased TPMT activity is well known [20].

It is well known that the distribution of TPMT enzymatic activity varies between races [6]. For example, the prevalence rate of diminished activity has been reported as 11% in Caucasians [5], 27% in black Americans [21], 3.4% in Chinese [22, 23] and 3.2% in the Korean population [15]. Furthermore, the distribution of TPMT activity has been found to show various patterns, i.e. trimodal [5], bimodal [23] or unimodal [15, 24]. For example, TPMT activity among the Caucasian population showed a trimodal distribution: 89% high, 11% intermediate and 0.3% of very low TPMT activity [5]; but the Chinese population showed a bimodal distribution: 96.6% high and 3.4% intermediate. Therefore, it is likely that the incidence rate of severe adverse reactions in different racial groups differs.

The functional gene for human TPMT is located on chromosome band 6p22.3 and includes 10 exons. TPMT is inherited as a single autosomal dominant trait, and it shows a codominant genetic polymorphism [25]. To date, types *2, *3A, *3B, *3C, *3D, *4, *5, *6, *7 and *8 have been identified as alleles responsible for low levels of TPMT enzymatic activity [26]. In this study, we amplified types *2, *3A, *3B and *3C by PCR, because these types are known to be the major mutation types and to act as non-functioning mutants, whereas types *3D, *4, *5, *6, *7, *8 and *9 have been described as possible private mutations, and are very rarely found [26]. In addition to TPMT mutation at exons, there is another mutation type known as the variable number tandem repeat (VNTR). This is located within the TPMT promoter, and its length varies from three to nine repeats, *V3, *V4, *V5, *V6, *V7, *V8 and *V9.

The TPMT genotype is classified into three types: a wild type that has wild/wild alleles, a heterozygous type that has wild/mutant alleles, and a homozygous mutant type that has mutant/mutant alleles [5]. It has been suggested that wild type usually shows high TPMT activity, that the heterozygous mutant type shows intermediate activity, and that the homozygous mutant type shows very low TPMT activity. Consequently, it has been suggested that doses should be adjusted according to genotypes, i.e. no dose adjustment in the wild type, a 50% dose reduction in the heterozygous mutant, and an 8–15-fold dose reduction in the homozygous mutant [2, 27, 28]. Based on this suggestion, we designed target doses for each genotype, namely 2.5, 1 and 0.25 mg/kg for the wild type, heterozygous mutant and homozygous mutant, respectively.

Azathioprine, one of the thiopurine drugs, has been used for its cytotoxic effects in leukaemia, and immunomodulatory or immunosuppressive effects after organ transplantation and in autoimmune diseases. In the rheumatology field, azathioprine has been used as an alternative to methotrexate in RA and to cyclophosphamide in SLE. Because azathioprine may be a good alternative to methotrexate in patients intolerant to this drug, a reduction in azathioprine's toxicity profile could make it an attractive alternative to methotrexate. Besides its use in RA, azathioprine is also commonly used in SLE, as a less effective but less toxic alternative to cyclophosphamide, as a maintenance regimen after cyclophosphamide pulse therapy in the treatment of nephritis, or as a steroid-sparing agent for non-renal manifestation in patients unsuitable for cyclophosphamide treatment.

But, despite its relatively low price and moderately good efficacy, azathioprine use has been limited because of its severe dose-related adverse effects, such as severe bone marrow toxicity, leading to a high discontinuation rate ranging from 10% [29] to 37% [30], and even high mortality rate.

Recently, there has been an effort to overcome the above limitation in clinical application of azathioprine. Among the methods used to avoid adverse reactions, the weight-based stepwise incremental dosing method with frequent laboratory testing has been recommended. However, this method is said to be inefficient at completely avoiding toxicity, because high levels of 6-thioguanine nucleotides can occur many days before the bone marrow reserve is exhausted and the peripheral blood cell count begins to fall abruptly [31]. Considering the high predictability of decreased TPMT enzymatic activity and its clinically harmful consequences, many authors have stressed that the screening of TPMT activity in thiopurine drug candidates before administration could significantly lower the incidence of serious adverse events and, furthermore, that it would be cost-effective [7, 12, 17, 30, 32].

Two methods are available for assessing an individual's TPMT activity. One involves a biochemical assay of TPMT activity in RBC [33]. This method allows the fast screening of a large population, and it is currently used in a small number of medical centres. However, this method has many limitations. First, recent blood transfusion, medication, alcohol or food may interfere with the results. Second, azathioprine itself can induce TPMT activity in erythrocytes, making direct assessment of the enzyme activity difficult [8, 34, 35]. Third, only a few research centres in the world (it is not available in Korea) can assay TPMT activity, thus limiting the widespread application of this assay as a screening test. Fourth, inter-laboratory results do not always agree, even for the same samples, probably due to impurities in commercially available thioguanine and differences in assay conditions among laboratories [10, 12, 36].

On the other hand, PCR genotyping for TPMT polymorphism has been shown to be rapid, sensitive and specific compared with the biochemical assay method [7, 12]. Furthermore, it is not affected by exogenous factors and, as mentioned above, the concordance rate with blood TPMT activity may exceed 95%. All of these considerations imply that it is possible to detect subjects with decreased TPMT activity by PCR genotyping in more than 95% of cases and indicates the feasibility of genotyping as a low-cost routine screening method.

One study performed a cost analysis of TPMT polymorphism screening by PCR genotyping, based on actual cases of bone marrow toxicity caused by azathioprine administration [37]. The study showed that screening by PCR genotyping provides a cost-benefit. However, this study had some limitations concerning the possible circumstances of azathioprine administration. First, no consideration was made of the sensitivity and specificity of PCR genotype-based dosing: that is, the authors assumed that the sensitivity of PCR genotyping was 100%. However, the sensitivity of PCR genotyping for types *2, *3A, *3B and *3C and the concordance rates between genotyping by PCR and phenotype have been reported to vary. These findings suggest the possible existence of mutant alleles other than types *2, *3A, *3B and *3C, possible technical errors in PCR genotyping, and the modulating effects of VNTR polymorphisms on TPMT activity. Therefore, it seems inappropriate to assume a PCR sensitivity of 100%. Second, no consideration was made of the possible differences in the prevalence rates of mutation among the different races. Third, only the simple costs incurred over a 6-month period were taken into account, and no consideration of outcome in terms of pharmacoeconomic analysis was made.

Therefore, we performed an economic analysis using two strategies, a genotype-based dosing strategy by PCR and a conventional weight-based dosing strategy, by using a hypothetical cohort in which major events follow previously reported rules. To progress the hypothetical cohort, a reasonable scenario is required. Therefore, we adopted consistent rules for drug dosage, laboratory testing, cost generation and for the calculation of probability of events in a decision tree, and then progressed the cohort by following these rules. Finally, economic analysis was carried on each strategy.

We initially analysed the base case, and followed this with sensitivity analysis to verify the validity of base case analysis. As mentioned earlier, the prevalence rates of decreased TPMT activity have been reported to be racially dependent. There is no uniform consensus on the prevalence rates of decreased TPMT activity in Koreans or Asians, but many authors quote 11% as the prevalence rate of decreased TPMT activity in Caucasians. Therefore, we adopted an 11% prevalence rate of decreased TPMT activity in the base case and 3.2% as a low prevalence rate of decreased TPMT activity in the sensitivity analysis, which was reported as the prevalence rate in Koreans. In fact, although we performed a sensitivity analysis with a prevalence rate of 0.3%, which is the lowest reported prevalence rate [38], the advantage of genotype-based dosing was not reversed (data not shown).

At present, the exact fraction of patients who would experience bone marrow toxicity from azathioprine is not known, and no accurate data exist as to how many patients who develop bone marrow toxicity discontinue azathioprine. A small cohort study involving 67 patients demonstrated a 37% discontinuation rate of azathioprine treatment as a whole [30]. In this study, the proportion of patients with the heterozygous mutant type was 9%, and 83% of the patients among the heterozygous mutant type group discontinued azathioprine treatment owing to bone marrow toxicity. It was reported that the discontinuation rate of azathioprine treatment owing to haematological toxicity was 9% in the Cochrane Systematic Review data base [39]. However, in a 27-yr study of 739 patients with inflammatory bowel diseases using a fixed azathioprine dose of 2 mg/kg per day [14], 5% of the patients developed bone marrow toxicity, and 24.3% of the patients among the toxicity group showed severe bone marrow toxicity that resulted in death or severe infection. Based on these data, we presumed that 24.3% of the patients with decreased TPMT activity revealed severe bone marrow toxicity and the others revealed mild bone marrow toxicity. In the present study, we assumed that patients who experienced severe bone marrow toxicity were admitted and that azathioprine was discontinued. The rest of the patients with mild bone marrow toxicity restarted low-dose azathioprine treatment after recovery of bone marrow.

Our model has some limitations. First, only direct medical costs were calculated. However, because indirect cost would be substantially greater for adverse events, we do not believe that this would affect our conclusions. Second, we fixed the sensitivity/specificity of the PCR test in our model, and did not undertake a sensitivity analysis. However, because possible inter-laboratory differences in the sensitivity/specificity of the PCR test could partly result from differences in inter-laboratory technical conditions, it was not feasible to consider all laboratory situations. Therefore, we assumed a well-established laboratory. Third, because our analysis was performed with several basic assumptions, there will be a gap between our accepted scenario and practice. Therefore, we set up a basic scenario based on PDR guidelines and previously reported data by using a critical literature review, and performed sensitivity analysis to compensate for the limitations.

The present study, which used a decision analytical model with a hypothetical cohort, suggests that a genotype-based dosing strategy for treatment with azathioprine, after PCR screening for the TPMT polymorphism, is more cost-effective than the conventional weight-based dosing strategy. Moreover, this strategy can potentially reduce the known serious adverse reactions of the weight-based strategy. In addition, because we set up this model using evidence-based presumptions, we suggest that our hypothetical cohort-based pharmacoeconomic analysis trial could be used as a model for other ethnic and racial groups.


    Acknowledgments
 
This work was supported by a grant of the Korea Health 21 R&D project, Ministry of Health and Welfare, Republic of Korea (01-PJ3-PG6-01GN11-0002).

Conflicts of interest

The authors have declared no conflicts of interest.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Schutz E, Gummert J, Mohr F, Oellerich M. Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient. Lancet 1993;341:436.[ISI][Medline]
  2. Krynetski EY, Tai HL, Yates CR et al. Genetic polymorphism of thiopurine methyltransferase: clinical importance and molecular mechanisms. Pharmacogenetics 1996;6:279–90.[ISI][Medline]
  3. Weinshilboum R. Methyltransferase pharmacogenetics. Pharmacol Ther 1989;43:77–90.[CrossRef][ISI][Medline]
  4. Krynetski EY, Evans WE. Pharmacogenetics as a molecular basis for individualized drug therapy: the thiopurine S-methyltransferase paradigm. Pharm Res 1999;16:342–9.[CrossRef][ISI][Medline]
  5. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980;32:651–2.[ISI][Medline]
  6. Klemetsdal B, Tollefsen E, Loennechen T et al. Interethnic differences in thiopurine methyltransferase activity. Clin Pharmacol Ther 1992;51:24–31.
  7. Steimer W, Potter JM. Pharmacogenetic screening and therapeutic drugs. Clin Chim Acta 2002;315:137–55.[CrossRef][ISI][Medline]
  8. Lennard L. Clinical implications of thiopurine methyltransferase—optimization of drug dosage and potential drug interactions. Ther Drug Monit 1998;20:527–31.[CrossRef][ISI][Medline]
  9. Tai HL, Krynetski EY, Yates CR et al. Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am J Hum Genet 1996;58:694–702.[ISI][Medline]
  10. Kroplin T, Fischer C, Iven H. Inhibition of thiopurine S-methyltransferase activity by impurities in commercially available substrates: a factor for differing results of TPMT measurements.Eur J Clin Pharmacol1999;55:285–91.[CrossRef][ISI][Medline]
  11. Otterness D, Szumlanski C, Lennard L et al. Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin Pharmacol Ther 1997;62:60–73.[ISI][Medline]
  12. Yates CR, Krynetski EY, Loennechen T et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 1997;126:608–14.[Abstract/Free Full Text]
  13. Marra CA, Esdaile JM, Anis AH. Practical pharmacogenetics: the cost-effectiveness of screening for thiopurine S-methyltransferase polymorphisms in patients with rheumatological conditions treated with azathioprine. J Rheumatol 2002;29:2507–12.[ISI][Medline]
  14. Connell WR, Kamm MA, Ritchie JK, Lennard-Jones JE. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut 1993;34:1081–5.[Abstract]
  15. Park-Hah JO, Klemetsdal B, Lysaa R, Choi KH, Aarbakke J. Thiopurine methyltransferase activity in a Korean population sample of children. Clin Pharmacol Ther 1996;60:68–74.[ISI][Medline]
  16. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. J Am Med Assoc 1998;279:1200–5.[Abstract/Free Full Text]
  17. Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn's disease. A meta-analysis. Ann Intern Med 1995;123:132–42.[Abstract/Free Full Text]
  18. Lennard L, Van Loon JA, Lilleyman JS, Weinshilboum RM. Thiopurine pharmacogenetics in leukemia: correlation of erythrocyte thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations. Clin Pharmacol Ther 1987;41:18–25.[ISI][Medline]
  19. Kalow W. Pharmacogenetics. Heredity and the response to drugs. Philadelphia: Saunders, 1962.
  20. Weinshilboum RM. Methylation pharmacogenetics: thiopurine methyltransferase as a model system. Xenobiotica 1992;22:1055–71.[ISI][Medline]
  21. Jones CD, Smart C, Titus A, Blyden G, Dorvil M, Nwadike N. Thiopurine methyltransferase activity in a sample population of black subjects in Florida. Clin Pharmacol Ther 1993;53:348–53.[ISI][Medline]
  22. Lee EJ, Kalow W. Thiopurine methyltransferase activity in a Chinese population. Clin Pharmacol Ther 1993;54:28–33.[ISI][Medline]
  23. Kham SK, Tan PL, Tay AH, Heng CK, Yeoh AE, Quah TC. Thiopurine methyltransferase polymorphisms in a multiracial Asian population and children with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2002;24:353–9.[CrossRef][ISI][Medline]
  24. Jang IJ, Shin SG, Lee KH et al. Erythrocyte thiopurine methyltransferase activity in a Korean population. Br J Clin Pharmacol 1996;42:638–41.[ISI][Medline]
  25. Collie-Duguid ES, Pritchard SC, Powrie RH et al. The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics 1999;9:37–42.[ISI][Medline]
  26. Krynetski EY, Evans WE. Genetic polymorphism of thiopurine S-methyltransferase: molecular mechanism and clinical importance. Pharmacology 2000;61:136–46.[CrossRef][ISI][Medline]
  27. Suarez-Almazor ME, Soskolne CL, Saunders LD, Russell AS. Use of second line drugs for the treatment of rheumatoid arthritis in Edmonton, Alberta. Patterns of prescription and longterm effectiveness. J Rheumatol 1995;22:836–43.[ISI][Medline]
  28. Evans WE, Horner M, Chu YQ, Kalwinsky D, Roberts WM. Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr 1991;119:985–9.[ISI][Medline]
  29. Present DH, Korelitz BI, Wisch N, Glass JL, Sacher DB, Pasternack BS. Treatment of Crohn's disease with 6-mercaptopurine: a long-term randomized double blind study. N Engl J Med 1980;302:981–7.[Abstract]
  30. Black AJ, McLeod HL, Capell HA et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med 1998;129:716–8.[Abstract/Free Full Text]
  31. Dutz JP, Ho VC. Immunosuppressive agents in dermatology. An update. Dermatol Clin 1998;16:235–51.[CrossRef][ISI][Medline]
  32. McLeod HL, Miller DR, Evans WE. Azathioprine induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient (letter). Lancet 1993;341:1151.[ISI][Medline]
  33. Weinshilboum RM, Raymond FA, Pazmino PA. Human erythrocyte thiopurine methyltransferase: radiochemical microassay and biochemical properties. Clin Chim Acta 1978;85:323–33.[CrossRef][ISI][Medline]
  34. Andersen JB, Szumlanski C, Weinshilboum RM, Schmiegelow K. Pharmacokinetics, dose adjustments, and 6-mercaptopurine/methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency. Acta Paediatr 1998;87:108–11.[CrossRef][ISI][Medline]
  35. McLeod HL, Relling MV, Liu Q, Pui CH, Evans WE. Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia. Blood 1995;85:1897–902.[Abstract/Free Full Text]
  36. Spire-Vayron de la Moureyre C, Debuysere H, Mastain B et al. Genotypic and phenotypic analysis of the polymorphic thiopurine S-methyltransferase gene (TPMT) in a European population. Br J Pharmacol 1998;125:879–87.[Abstract]
  37. Tavadia S, Mydlarski PR, Reis MD et al. Screening for azathioprine toxicity: a pharmacoeconomic analysis based on a target case. J Am Acad Dermatol 2000;42:628–32.[ISI][Medline]
  38. Kubota T, Chiba K. Frequencies of thiopurine S-methyltransferase mutant alleles (TPMT*2, *3A, *3B and *3C) in 151 healthy Japanese subjects and the inheritance of TPMT*3C in the family of a propositus. Br J Clin Pharmacol 2001;51:475–7.[CrossRef][ISI][Medline]
  39. Suarez-Almazor ME, Spooner C, Belseck E. Azathioprine for treating rheumatoid arthritis. Cochrane Database Syst Rev 2000;(4):CD001461.[Medline]
Submitted 15 March 2003; Accepted 7 July 2003





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