Usage
- Thioguanine is primarily used to treat acute leukemias, particularly acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). It is also used in the treatment of chronic myeloid leukemia (CML). It is an antineoplastic antimetabolite, specifically a purine analog.
- Pharmacological Classification: Antineoplastic antimetabolite.
- Mechanism of Action: Thioguanine integrates into DNA and RNA, disrupting nucleic acid synthesis and inhibiting cell proliferation. It also undergoes methylation, forming metabolites that inhibit purine synthesis.
Alternate Names
- 6-TG
- 2-Amino-6-mercaptopurine
- 6-Thioguanine
- Brand Name: Tabloid, Lanvis
How It Works
- Pharmacodynamics: Thioguanine is an antineoplastic antimetabolite that disrupts DNA and RNA synthesis, thereby suppressing cell proliferation. Its cytotoxic effects primarily target rapidly dividing cells, such as those in the bone marrow, leading to myelosuppression.
- Pharmacokinetics: Thioguanine is administered orally and its absorption is variable and incomplete. It is metabolized in the liver by methylation and xanthine oxidase, with inactive metabolites excreted primarily in the urine. The drug can also be deactivated by guanine deaminase.
- Mode of Action: Thioguanine incorporates into DNA and RNA, disrupting nucleic acid function and cell replication. Its metabolites inhibit purine synthesis, further hindering cell growth. Thioguanine’s cytotoxic action is cell cycle-specific, mainly affecting the S phase.
- Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Thioguanine doesn’t directly bind to receptors or modulate neurotransmitters. Its primary action involves inhibiting enzymes essential for nucleotide synthesis, thereby interfering with DNA replication.
- Elimination Pathways: Thioguanine’s metabolites are eliminated mostly through renal excretion, with a minor portion eliminated in the feces.
Dosage
Standard Dosage
Adults:
- Initial dose: 2 mg/kg/day orally. If no response or toxicity is observed after 4 weeks, this dose can be cautiously increased up to 3mg/kg/day.
- The daily dose is usually calculated to the nearest multiple of 20mg.
- The total daily dose may be given at one time.
Children:
- Initial dose: 2 mg/kg/day orally. If no response or toxicity is observed after 4 weeks, this dose can be cautiously increased up to 3mg/kg/day.
- Pediatric patients are more sensitive to thioguanine’s effects; monitor closely for liver toxicity.
- Adjust doses based on body surface area and clinical response.
Special Cases:
- Elderly Patients: Consider reducing the initial dosage due to potential age-related decline in hepatic, renal, or cardiac function.
- Patients with Renal Impairment: Dosage reduction may be necessary for patients with impaired renal function.
- Patients with Hepatic Dysfunction: Reduce the dosage for patients with liver impairment to minimize the risk of hepatotoxicity.
- Patients with Comorbid Conditions: Patients with comorbid conditions like diabetes or cardiovascular diseases should be monitored closely.
Clinical Use Cases
Thioguanine’s clinical use is primarily focused on the treatment of leukemias. Its use in settings like intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations is not indicated.
Dosage Adjustments:
- Dose modifications are necessary for hepatic or renal dysfunction.
- For patients with known TPMT or NUDT15 enzyme deficiencies, thioguanine dosage requires careful adjustment due to increased myelosuppression risks.
- Patients homozygous for TPMT or NUDT15 deficiency typically require 10% or less of the standard dose.
Side Effects
Common Side Effects:
- Nausea
- Vomiting
- Loss of appetite
- Sores in the mouth and throat
- Hair loss
- Itching or skin rash
- Darkened skin color
Rare but Serious Side Effects:
- Liver toxicity (veno-occlusive disease)
- Myelosuppression (anemia, leukopenia, thrombocytopenia)
- Jaundice
- Unusual bleeding or bruising
- Signs of infection (fever, chills, weakness)
- Severe allergic reactions
Long-Term Effects:
- Secondary malignancies
- Infertility
Adverse Drug Reactions (ADR):
- Myelosuppression, hepatotoxicity, severe allergic reactions, and secondary malignancies.
Contraindications
- Hypersensitivity to thioguanine or any component of the formulation
- Prior resistance to thioguanine or mercaptopurine
Drug Interactions
- Immunosuppressants: increased risk of infection
- Allopurinol: potential for increased myelosuppression
- Busulfan: potential for hepatotoxicity
- TPMT inhibitors (e.g., sulfasalazine, mesalazine, olsalazine): increased risk of thioguanine toxicity
- Live vaccines: increased risk of infection
Pregnancy and Breastfeeding
- Pregnancy Safety Category: D (positive evidence of human fetal risk)
- Fetal Risks: Teratogenic, embryotoxic, mutagenic
- Breastfeeding: Not recommended due to potential for serious adverse reactions in the infant.
Drug Profile Summary
- Mechanism of Action: Purine analog antimetabolite that integrates into DNA and RNA, disrupting nucleic acid synthesis and cell proliferation.
- Side Effects: Nausea, vomiting, myelosuppression, hepatotoxicity, infection risk.
- Contraindications: Hypersensitivity, prior drug resistance.
- Drug Interactions: Immunosuppressants, allopurinol, busulfan, TPMT inhibitors, live vaccines.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy; avoid breastfeeding.
- Dosage: 2 mg/kg/day initially, up to 3 mg/kg/day; adjust for renal/hepatic impairment and genetic factors.
- Monitoring Parameters: Complete blood count, liver function tests, TPMT/NUDT15 genotype.
Popular Combinations:
Thioguanine is frequently used in combination chemotherapy regimens for acute leukemias, often including cytarabine, prednisone, vincristine and cyclophosphamide.
Precautions
- Monitor complete blood counts and liver function tests regularly.
- Test for TPMT and NUDT15 enzyme activity before starting therapy.
- Avoid live vaccines during and after treatment.
- Provide patients with information on managing side effects and recognizing signs of toxicity.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Thioguanine?
A: The initial dose for adults and children is usually 2 mg/kg/day orally. The dose can be cautiously increased to 3 mg/kg/day after 4 weeks if there is no response or toxicity. Dosages should be adjusted for renal or hepatic impairment, age, and TPMT/NUDT15 enzyme activity.
Q2: What are the most serious side effects of Thioguanine?
A: Myelosuppression (decreased blood cell counts), hepatotoxicity (liver damage), infections, secondary malignancies, and severe allergic reactions are the most serious side effects.
Q3: Can Thioguanine be used during pregnancy?
A: Thioguanine is contraindicated during pregnancy due to its potential for teratogenic effects. Effective contraception should be used during treatment and for at least 6 months after the last dose.
Q4: How should Thioguanine be administered?
A: Thioguanine is administered orally, usually once daily. It is preferably taken on an empty stomach but can be taken with food if gastrointestinal upset occurs.
Q5: What should be monitored in patients taking Thioguanine?
A: Complete blood counts (CBC) with differential, liver function tests (LFTs), and TPMT/NUDT15 genotype should be monitored regularly. Close clinical observation is essential for early detection of side effects.
Q6: How does TPMT or NUDT15 enzyme activity affect Thioguanine dosing?
A: Patients with low or absent TPMT or NUDT15 activity are at significantly higher risk of severe myelosuppression and require substantial dose reductions. Testing for these deficiencies before starting thioguanine is highly recommended.
Q7: What are the signs of thioguanine toxicity?
A: Signs of toxicity include jaundice, unusual bleeding or bruising, fever, chills, weakness, sore throat, mouth sores, and severe gastrointestinal discomfort. Patients should be educated about these signs and instructed to report them immediately.
Q8: Can Thioguanine be used in patients with renal impairment?
A: Thioguanine should be used cautiously in patients with renal impairment. Dosage adjustments may be needed. Close monitoring of renal function and blood counts is essential.
Q9: Is there cross-resistance between Thioguanine and other drugs?
A: There is complete cross-resistance between thioguanine and mercaptopurine. If a patient has developed resistance to one of these drugs, they are likely resistant to the other.
Q10: How does Thioguanine interact with allopurinol?
A: While allopurinol inhibits the metabolism of mercaptopurine, it does not have the same effect on thioguanine. However, the combination may still increase the risk of myelosuppression. Hence caution and monitoring are advised when using these drugs concomitantly.
