Mercaptopurine

Oral
Acute lymphoblastic leukaemia

Patients taking xanthine oxidase inhibitors: Reduce to 25% of the usual dose.

Pharmacogenomics:

Mercaptopurine is a prodrug that must be activated to form its major active metabolites, thioguanine nucleotides (TGNs). It is catabolised by thiopurine S-methyltransferase (TPMT) into inactive methylmercaptopurine base, which leaves less parent drug available to form active TGNs. TPMT variant alleles are associated with low enzyme activity and pronounced thiopurine pharmacologic effects. Moreover, nudix hydrolase 15 (nucleotide diphosphatase [NUDT15]) catalyses the conversion of cytotoxic thioguanine triphosphate (TGTP) metabolites to form the less toxic thioguanine monophosphate. Defects in NUDT15-mediated TGTP degradation results in more TGTP available for DNA incorporation, thereby allowing for DNA damage and apoptosis. TPMT genotyping or phenotyping, and NUDT15 genotyping may be considered prior to initiating mercaptopurine treatment.

The prevalence of TPMT alleles considerably vary among different populations. Inherited TPMT deficiency was observed as the primary genetic cause of thiopurine intolerance in Europeans and Africans. The most common low-activity allele in Caucasians is TPMT*3A with approx 5% frequency but is less prevalent in individuals who originate from India and Pakistan. In East Asian, African-American, and some African populations, TPMT*3C is the most common variant with approx 2% frequency, however, TPMT*8 may be more common in Africans than previously observed (approx 2%). In general, TPMT*2 occurs much less commonly while TPMT*3B occurs rarely.

The prevalence of non-functional alleles in the NUDT15 gene is common in Asians and Hispanic populations. NUDT15 poor metabolisers were observed approx 1 in every 50 patients of East Asian descent. In addition, NUDT15 deficiency is also more prevalent in individuals of Hispanic ethnicity especially those with high levels of Native American genetic ancestry.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline recommendations as of October 2018:

TPMT phenotypes:

TPMT normal metabolisers
Carriers of 2 normal function alleles (e.g. *1/*1) have lower levels of TGN metabolites and have normal risk of thiopurine-related leucopenia, neutropenia and myelosuppression.
Initiate therapy with the normal starting dose (e.g. 75 mg/m² daily or 1.5 mg/kg daily), then adjust doses including other combination agents without emphasis on mercaptopurine. After each dose adjustment, allow at least 2 weeks to reach steady-state concentrations.

TPMT intermediate metabolisers and possible intermediate metabolisers
TPMT intermediate metabolisers are carriers of 1 normal function allele and 1 no function allele (e.g. *1/*2, *1/*3A, *1/*3B, *1/*3C, *1/*4) while TPMT possible intermediate metabolisers are carriers of 1 uncertain/unknown function allele and 1 no function allele (e.g. *2/*8, *3A/*7). These phenotypes and genotypes have moderate to high levels of TGN metabolites resulting in increased risk of thiopurine-related leucopenia neutropenia and myelosuppression.
Initiate therapy with lowered doses at 30-80% of normal dose if the normal starting dose is ≥75 mg/m² daily or ≥1.5 mg/kg daily (e.g. Initiate at 22.5-60 mg/m² daily or 0.45-1.2 mg/kg daily), then adjust doses according to degree of myelosuppression and disease-specific guidelines. After each dose adjustment, allow 2-4 weeks to reach steady-state concentrations. If myelosuppression occurs, emphasise on reducing mercaptopurine dose over other agents depending on other combination therapy. If the normal starting dose is already <75 mg/m² daily or <1.5 mg/kg daily, dose reduction may not be recommended.

TPMT poor metabolisers
Carriers of 2 no function alleles (e.g. *2/*3A, *2/*3C, *3A/*3A, *3A/*3C, *3A/*4, *3C/*4) have extremely high concentrations of TGN metabolites resulting in possible fatal toxicity without dose reduction and greatly increased risk of thiopurine-related leucopenia, neutropenia and myelosuppression.
Initiate therapy with drastically reduced doses and frequency for malignant conditions. Reduce the daily dose by 10-fold and given 3 times weekly instead of daily (e.g. 10 mg/m²/day given just 3 times weekly), then adjust doses according to degree of myelosuppression and disease-specific guidelines. After each dose adjustment, allow 4-6 weeks to reach steady-state concentrations. If myelosuppression occurs, emphasise on reducing mercaptopurine dose over other agents. Consider alternative non-thiopurine immunosuppressant treatment for non-malignant conditions.

NUDT15 phenotypes:

NUDT15 normal metabolisers
Carriers of 2 normal function alleles (e.g. *1/*1) have normal risk of thiopurine-related leucopenia, neutropenia and myelosuppression.
Initiate therapy with the normal starting dose (e.g. 75 mg/m² daily or 1.5 mg/kg daily), then adjust doses including other combination agents without emphasis on mercaptopurine. After each dose adjustment, allow at least 2 weeks to reach steady-state concentrations.

NUDT15 intermediate metabolisers, and possible intermediate metabolisers
NUDT15 intermediate metabolisers are carriers of 1 normal function allele and 1 no function allele (e.g. *1/*2, *1/*3) while NUDT15 possible intermediate metabolisers are carriers of 1 uncertain function and 1 no function allele (e.g. *2/*5, *3/*6). These phenotypes and genotypes have increased risk of thiopurine-related leucopenia, neutropenia and myelosuppression.
Initiate therapy with lowered doses at 30-80% of normal dose if the normal starting dose is ≥75 mg/m² daily or ≥1.5 mg/kg daily (e.g. Initiate at 22.5-60 mg/m² daily or 0.45-1.2 mg/kg daily), then adjust doses according to degree of myelosuppression and disease-specific guidelines. After each dose adjustment, allow 2-4 weeks to reach steady-state concentrations. If myelosuppression occurs, emphasise on reducing mercaptopurine dose over other agents depending on other combination therapy. If the normal starting dose is already <75 mg/m² daily or <1.5 mg/kg daily, dose reduction may not be recommended.

NUDT15 poor metabolisers
Carriers of 2 no functional alleles (e.g. *2/*2, *2/*3, *3/*3) have greatly increased risk of thiopurine-related leucopenia, neutropenia and myelosuppression.
Initiate therapy at 10 mg/m² daily, then adjust doses according to myelosuppression and disease-specific guidelines. After each dose adjustment, allow 4-6 weeks to reach steady state concentrations. If myelosuppression occurs, emphasise on reducing mercaptopurine dose over other agents. Consider alternative non-thiopurine immunosuppressant treatment for non-malignant conditions.

Dose reduction may be needed.

Dose reduction may be needed.

Should be taken on an empty stomach. Best taken on an empty stomach 1 hr before or 2 hr after meals. Ensure adequate fluid intake.

Pregnancy and lactation.

Patients with TPMT and NUDT15 deficiency (e.g. TPMT and NUDT15 intermediate, possible intermediate, and poor metabolisers); previous varicella zoster virus infection, autoimmune conditions (e.g. inflammatory bowel disease). Renal and hepatic impairment. Children.

Significant: Rarely, malignancies (e.g. lymphoproliferative disorders, skin cancers, sarcomas, uterine cervical cancer in situ), infections (e.g. severe or atypical infection and viral reactivation), photosensitivity, chromosomal aberrations, tumour lysis syndrome (leading to hyperuricaemia, hyperuricosuria, uric acid nephropathy).
Nervous: Malaise.
GI: Nausea, vomiting, stomatitis, diarrhoea, anorexia.
Dermatologic: Rash.
Potentially Fatal: Myelosuppression (manifested as leucopenia, thrombocytopenia, anaemia), hepatotoxicity (i.e. hepatic necrosis).

PO: D

Avoid excessive exposure to sun and UV light.

Consider TPMT genotypic or phenotypic tests, and NUDT15 genotypic tests to identify deficiency prior to treatment initiation. Regularly monitor haematological count (e.g. haemoglobin, platelet, WBC w/ differential) and LFTs (e.g. serum transaminase, alkaline phosphatase and bilirubin levels). Closely monitor haematologic function when changing between formulations. Obtain FBC daily during remission induction.

Symptoms: Nausea, vomiting, diarrhoea, anorexia, myelosuppression, hepatic dysfunction, gastroenteritis. Management: General supportive treatment w/ appropriate blood transfusion, if necessary.

Decreases pharmacological effect of anticoagulants (e.g. warfarin, acenocoumarol). May diminish immune response to vaccines. Increased adverse effects w/ xanthine oxidase inhibitors (e.g. allopurinol, oxipurinol, thiopurinol, febuxostat). Increased myelosuppression w/ aminosalicylate derivatives (e.g. mesalazine, olsalazine, sulfasalazine), co-trimoxazole, ribavirin, and other myelosuppressive agents. Increased risk of Epstein-Barr virus-associated lymphoproliferative disorders w/ multiple immunosuppressive agents.

Decreased bioavailability w/ food, milk or dairy products.

Description:
Mechanism of Action: Mercaptopurine, a purine nucleoside analogue, is a pro-drug metabolised to thioguanine nucleotide (TGN). TGN inhibits de novo synthesis and interconversions of purine and is incorporated into the DNA and RNA, thereby inhibiting nucleic acid synthesis and causing cell death.
Pharmacokinetics:
Absorption: Variably and incompletely absorbed from the GI tract. Food intake may decrease bioavailability. Bioavailability: 5-37%. Time to peak plasma concentration: W/in 2 hr.
Distribution: Crosses the blood-brain barrier. Plasma protein binding: Approx 19%.
Metabolism: Extensively and rapidly metabolised in the liver via thiol methylation by thiopurine S-methyltransferase (TPMT) to methyl-mercaptopurine (inactive) and via oxidation by xanthine oxidase to 6-thiouric acid (inactive).
Excretion: Via urine (46%, as unchanged drug and as metabolites). Elimination half-life: 47 min (tab); approx 2 hr (susp).

Source: National Center for Biotechnology Information. PubChem Database. Mercaptopurine, CID=667490, https://pubchem.ncbi.nlm.nih.gov/compound/Mercaptopurine (accessed on Jan. 22, 2020)

Store between 15-25°C.
Wear gloves during receiving, unpacking, and placing in storage.

Cytotoxic Chemotherapy / Immunosuppressants

L01BB02 - mercaptopurine ; Belongs to the class of antimetabolites, purine analogues. Used in the treatment of cancer.

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Mercaptopurine Tablets USP 50 mg (West Ward Pharmaceuticals Corp.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 24/07/2017.

Purixan 20 mg/mL Oral Suspension (Nova Laboratories Ltd). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 24/07/2017.