Thioguanine

Thioguanine is an antineoplastic agent belonging to the pharmacological class of Antimetabolites.

Thioguanine is also referred to as Tioguanine.

Thioguanine is FDA-approved for treating Acute Nonlymphocytic Leukemia (ALL), a type of leukaemia.

Thioguanine undergoes incomplete absorption (30%) from the gastrointestinal tract, penetrating the CSF and crossing the placenta. The liver extensively metabolizes the drug and predominantly excretes metabolites through urine.

The most common side effects of Thioguanine include bone marrow failures, increased bilirubin in the blood, increased liver enzymes, enlarged liver, and increased uric acid levels in urine.

Thioguanine is available as oral tablets.

The molecule is available in India, the United States, Canada, the United Kingdom, Germany, Australia, Japan and Brazil.

Thioguanine is an antineoplastic agent belonging to the pharmacological class of Antimetabolites.

A purine antagonist is Thioguanine. It is a prodrug that is directly transformed intracellularly by the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to thioguanine monophosphate, or 6-thioguanylic acid (TGMP). Thioguanosine diphosphate (TGDP) and its triphosphates are produced by further converting TGMP and TGTP, or thioguanosine triphosphate. These nucleotides are incorporated into DNA and provide Thioguanine its cytotoxic impact. There is some immunosuppressive action of Thioguanine. Only the S phase of the cell cycle is suitable for Thioguanine.

Thioguanine reaches its peak concentration in the bloodstream approximately 8 hours after administration.

Thioguanine is available as a tablet.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

The physician recommends taking this medication orally once daily, preferably on an empty stomach.

Primary uses:

• Leukaemia, acute myeloid
• Leukemia, chronic myelogenous

Other uses:

• Brain tumours
• Breast cancer
• Lymphoma, non-Hodgkin

Thioguanine is indicated for the treatment of acute nonlymphocytic leukemias to induce remission and consolidate it.

Restrictions on Use

Because of the significant risk of liver damage, it is not advised for use during maintenance therapy or other comparable long-term continuous therapies.

Orally: Administer Mercaptopurine tablets orally with or without food. Swallow whole with water; it is advisable not to chew or crush the tablets. Do not take extra doses if a dosage is missed; take it as soon as you recall. As directed by the healthcare provider, adhere to the recommended dose standards.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Thioguanine is available as a tablet.

Dose Adjustment in Adult Patients:

Treatment for acute lymphoblastic leukaemia, acute myeloid leukaemia, and chronic myeloid leukaemia involves daily doses of 100–200 mg/m2 administered in short-term cycles at different treatment phases. The combination of various cytotoxic medications determines the treatment's dosage and duration.

In rare cases, as a single agent treatment, For four weeks, 2 mg/kg per day may be raised to 3 mg/kg per day under close observation if there is no leukocyte or platelet depression and the response is insufficient.

While on Thioguanine, managing side effects is possible through dietary adjustments. Patients should consume low-fat proteins like lean meats, fish, and poultry and a balanced diet of fruits and vegetables high in vital nutrients. Drinking lots of water regularly is crucial to staying hydrated, especially when some cancer treatments can cause dehydration. People should also maintain proper hygiene, wash their hands often, and keep their distance from individuals who are ill. Quitting smoking is also recommended.

The dietary restriction should be individualized as per patient requirements.

• History of severe hypersensitivity to Thioguanine or any of the excipients, especially prior resistance to 6-thioguanine or mercaptopurine.
• Pregnancy and lactation.
• Immunisation with live vaccines.

• Long-term continuous therapy poses a heightened risk of hepatotoxicity, portal hypertension, or sinusoidal obstruction syndrome. Close monitoring of liver function is imperative if symptoms of hepatotoxicity, such as hyperbilirubinemia or hepatomegaly, manifest. Therapy should be discontinued promptly.
• Dose-related bone marrow suppression is a consistent toxicity. Anaemia, leukopenia, thrombocytopenia, or a combination may occur. Withdrawal of Thioguanine at the first sign of a substantial fall in any blood element is crucial due to its potential delayed effect.
• Patients with repeated severe myelosuppression should be evaluated for thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency. Genotyping or phenotyping for TPMT and NUDT15 can identify reduced enzyme activity. Co-administration with TPMT-inhibiting drugs requires caution.
• Frequent evaluation of haemoglobin concentration, total white blood cell count, and platelet count are essential during thioguanine therapy. In cases of obscure fluctuations, bone marrow examination may be necessary. Dosage adjustments should consider not only absolute values but also the rapidity of changes.
• Myelosuppression during the induction phase of leukaemia is expected; modification or cessation of dosage depends on the disease response and available supportive facilities. Life-threatening infections and bleeding may result from thioguanine-induced granulocytopenia and thrombocytopenia.
• Adequate hydration and prophylactic allopurinol administration to minimize the common occurrence of hyperuricemia with treatment.
• Vigilant monitoring for infections (leukopenia) and bleeding (thrombocytopenia) is crucial throughout thioguanine therapy.

The adverse reactions related to Thioguanine can be categorized as:

• Common Adverse Effects: Fatigue, gastrointestinal disturbances such as nausea or vomiting, and myelosuppression
• Less Common Adverse Effects: Hepatotoxicity, rash, and elevated liver enzymes.
• Rare Adverse Effects: Severe hypersensitivity reactions, pancreatitis, or bone marrow suppression.

The clinically relevant drug interactions of Thioguanine are briefly summarized here.

Drug-Drug Interactions; Increased risk of radiation treatment or other myelotoxic medicines suppressing the bone marrow. Aminosalicylate derivatives (e.g., olsalazine, mesalazine, sulfasalazine) may increase the risk of TPMT deficiency. Busulfan increases the risk of oesophageal varices, portal hypertension, and nodular regenerative hyperplasia.

Potentially fatal: may raise the risk of infection and reduce the therapeutic benefit of live vaccinations.

The common side effects of Thioguanine include:

• Vomiting
• Nausea
• Bone marrow failure
• Stomatitis (Inflammation of the mouth)
• Increased bilirubin in the blood
• Increased liver enzymes
• Enlarged liver
• Loss of appetite
• Diarrhoea
• Hyperuricaemia (excess uric acid levels in the blood)

• Pregnancy

Pregnancy Category D (FDA): Use in cases where no safer medication is available, and life is in danger. Positive evidence of prenatal risk in humans.

There aren't enough reliable, well-controlled research on expectant mothers. These kinds of drugs have the potential to be teratogenic, so it's essential to consider the risks and benefits before using them while pregnant. Patients who use Thioguanine while pregnant or who get pregnant while taking Thioguanine should be informed of the risk to the developing baby. The medication should be postponed until beyond the first trimester of pregnancy whenever feasible.

Adequate contraceptive measures should be recommended when receiving Thioguanine for either spouse, as is the case with any cytotoxic chemotherapy. It is best to counsel women who are capable of having children not to get pregnant.

• Nursing Mothers

It is unknown if this medication is eliminated in human milk. The value of the medication to the mother should be considered when deciding whether to stop breastfeeding or to stop taking it altogether due to the possibility of tumorigenicity associated with Thioguanine.

• Pediatric Use

The safety and effectiveness of Thioguanine in pediatric patients have been indicated, primarily when it is used to manage specific forms of leukaemia.

Dose Adjustment

Acute Nonlymphocytic Leukemia

2 mg/kg daily PO

If there is no progress after four weeks, gradually increase to 3 mg/kg/day.

It can be used with prednisone, cytarabine, cyclophosphamide, and vincristine in multi-drug treatment.

• Geriatric Use

The number of patients 65 and older in thioguanine clinical trials was insufficient to assess if their responses differed from those of younger subjects.

Dose Adjustment in Kidney Impairment Patients:

Regarding Thioguanine in individuals with renal impairment, no information is currently accessible. When initiating Thioguanine in individuals with reduced renal function, it should be considered to lower the dosage.

Dose Adjustment in Hepatic Impairment Patients:

No information is available on how exposure to Thioguanine is affected by hepatic impairment. Because Thioguanine is primarily processed in the liver, hepatic impairment may increase exposure to it.

Patients with impaired hepatic function should have the option of lowering their initial thioguanine dosage.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Thioguanine.

Signs and Symptoms

Immediate nausea, vomiting, malaise, hypotension, diaphoresis, or delayed myelosuppression and azotaemia.

Management

No specific antidote exists for Thioguanine overdose. In the event of an overdose, promptly initiate appropriate supportive measures. Due to rapid intracellular incorporation into long-persisting active metabolites, dialysis is unlikely to clear the drug effectively. Administer appropriate blood transfusions for bleeding and antibiotics for sepsis. Consider inducing emesis for early detection of ingestion if accidental overdosage is promptly detected.

Pharmacodynamics:

Acute nonlymphocytic leukaemia is one of the leukaemia types that is treated with Thioguanine, an antineoplastic antimetabolite. Antimetabolites pose as purines or pyrimidines, subsequently used as DNA building blocks. They impede normal development and division during the "S" phase of the cell cycle by preventing these chemicals from being integrated into DNA. More than 30 years ago, Thioguanine was first synthesized and introduced into clinical trials. It is an analogue of 6-thiopurine, a purine base found naturally in guanine and hypoxanthine. Upon intracellular activation, a spurious purine base is incorporated into DNA. Its integration into RNA is associated with an extra cytotoxic impact. Mercaptopurine and Thioguanine do not cross-react. The cell cycle phase (S-phase) is unique to cytotoxicity.

Pharmacokinetics:

• Absorption: About 30% of the dosage given to Thioguanine is absorbed from the gastrointestinal system, exhibiting incomplete and variable absorption.
• Distribution: After entering the bloodstream, Thioguanine can cross the blood-brain barrier and enter the cerebrospinal fluid (CSF). Furthermore, the drug crosses the placenta.
• Metabolism: Thioguanine is rapidly and thoroughly metabolized in the liver, mainly with the help of the enzyme thiopurine S-methyltransferase (TPMT). Both active and inactive metabolites, including 2-amino-6-methylthioguanine, are produced by this metabolic pathway. Through a secondary metabolic route, xanthine oxidase oxidizes thioxanthine, which is then converted to thiouric acid.
• Excretion: Metabolites are Thioguanine's most commonly excreted forms, and elimination mainly occurs via the urinary system. The drugs are not subjected to dialysis.5–9 hours are the half-life of terminal elimination.

The terminal elimination half-life of Thioguanine is just 5 to 9 hours, which is relatively short.

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