Thioguanine Pharmacogenetics - Genetic Drug Testing Gene2Rx

Drug Overview

Thioguanine, marketed under the brand names Lanvis and Tabloid, is an oral thiopurine chemotherapeutic agent.

It is primarily used in the treatment of acute leukemias, including acute myeloid leukemia. Thioguanine is incorporated into DNA and RNA of rapidly dividing cells, causing strand breaks and inhibition of nucleic acid synthesis, which leads to cell death.

This mechanism of action makes thioguanine effective against malignant cells but also requires careful dosing to manage toxicity in healthy rapidly dividing tissues.

Relevant Genes and Their Roles

Two key genes influence the metabolism of thioguanine: TPMT and NUDT15. TPMT (thiopurine S-methyltransferase) inactivates thiopurines by adding a methyl group, reducing active metabolite levels. NUDT15 (nudix hydrolase 15) dephosphorylates thiopurine nucleotides, preventing excessive incorporation into DNA.

Variations that decrease enzyme activity can lead to higher concentrations of active thioguanine metabolites and an elevated risk of myelosuppression (reduction in white blood cells and platelets). Conversely, increased enzyme activity (rare for these genes) would lower drug levels and could reduce efficacy.

Impact of Genetics on Drug Response

Genetic variants in TPMT and NUDT15 create different metabolizer phenotypes—from poor to normal—that directly affect active metabolite concentrations. Poor metabolizers have very low enzyme activity, leading to accumulation of toxic metabolites and high risk of severe myelosuppression. Intermediate metabolizers have reduced activity and moderate risk, while normal metabolizers process the drug at expected rates and generally follow standard dosing.

Expected Clinical Effects of Genetic Variation

Ultra-rapid/Rapid Metabolizer

Effect on drug levels: Not commonly observed for TPMT or NUDT15 variants.
Clinical consequence: Faster than normal clearance; no specific dosing guidance.
Side effects: Standard risk of myelosuppression; typical monitoring applies.

Normal Metabolizer

Effect on drug levels: Standard active metabolite concentrations.
Clinical consequence: Expected therapeutic effect with standard dosing.
Side effects: Usual risk of neutropenia and leukopenia; monitor blood counts regularly.

Intermediate Metabolizer

Effect on drug levels: Moderately increased active metabolite concentrations.
Clinical consequence: Elevated risk of leukopenia, neutropenia, and myelosuppression.
Side effects: Moderate severity myelosuppression; may require dose reduction and more frequent blood count monitoring.

Poor Metabolizer

Effect on drug levels: Markedly increased active metabolite concentrations.
Clinical consequence: High risk of severe leukopenia, neutropenia, myelosuppression; potential for fatal toxicity without dose adjustment.
Side effects: Severe myelosuppression; requires significant dose reduction and intensive monitoring; for non-malignant conditions, consider non-thiopurine immunosuppressant alternatives.

Indeterminate/Not Available

Effect on drug levels: Unknown impact.
Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring.
Side effects: Standard risk profile; adjust based on clinical response.

Dosing Guidelines

The following dosing guidelines are based on the available guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC).

TPMT Dosing Guideline

Phenotype	Clinical Consequence	Guideline Recommendation
Normal Function	Normal active metabolite levels; typical risk of myelosuppression	Start with normal dose (e.g., 40–60 mg/m²/day). Adjust other myelosuppressive therapies as needed. Allow 2 weeks to steady state after each adjustment.
Intermediate Function	Moderately elevated metabolite levels; increased risk of myelosuppression	Start at 50–80% of normal dose (e.g., 20–48 mg/m²/day). Adjust based on myelosuppression. Allow 2–4 weeks to steady state after each adjustment.
Possible Intermediate Metabolizer	Moderately elevated metabolite levels; increased risk of myelosuppression	Start at 50–80% of normal dose (e.g., 20–48 mg/m²/day). Adjust based on myelosuppression. Allow 2–4 weeks to steady state after each adjustment.
Poor Function	Extremely high metabolite levels; risk of fatal toxicity	Reduce daily dose 10-fold and dose thrice weekly. Adjust based on myelosuppression. Allow 4–6 weeks to steady state. Consider alternative non-thiopurine therapy for non-malignant conditions.
Indeterminate	Unknown effect	No specific recommendation; follow standard dosing with monitoring.
Not available	Unknown effect	No specific recommendation; follow standard dosing with monitoring.

NUDT15 Dosing Guideline

Phenotype	Clinical Consequence	Guideline Recommendation
Normal Metabolizer	Normal risk of myelosuppression	Start with normal dose (40–60 mg/day). Allow 2 weeks to steady state and adjust based on blood counts.
Intermediate Metabolizer	Increased risk of myelosuppression	Start at 50–80% of normal dose. Adjust based on degree of myelosuppression. Allow 2–4 weeks to steady state.
Possible Intermediate Metabolizer	Increased risk of myelosuppression	Start at 50–80% of normal dose. Adjust based on degree of myelosuppression. Allow 2–4 weeks to steady state.
Poor Metabolizer	Greatly increased risk of myelosuppression	Reduce to 25% of normal dose. Allow 4–6 weeks to steady state. Consider alternative non-thiopurine therapy for non-malignant conditions.
Indeterminate	No CPIC guidance; unknown effect	Initiate therapy with recommended starting dose and monitor.
Not available	No CPIC guidance; unknown effect	Initiate therapy with recommended starting dose and monitor.

Alternative Treatment Options

For patients identified as poor metabolizers of TPMT or NUDT15—especially in non-malignant indications—CPIC guidelines suggest considering alternative non-thiopurine immunosuppressant therapies (for example, methotrexate or biologic agents). These are examples from published guidelines and do not constitute medical advice.

Thioguanine