Tacrolimus

Tacrolimus (brand name Prograf) is a potent immunosuppressive agent used to prevent organ transplant rejection. It belongs to the calcineurin inhibitor class and is available in oral and intravenous formulations.

This medication is most commonly prescribed to reduce the risk of rejection in kidney, liver, and heart transplant recipients. By dampening immune activity, tacrolimus helps ensure long‐term graft survival.

Tacrolimus works by binding to the intracellular protein FKBP-12 to form a complex that inhibits calcineurin, a phosphatase critical for T-lymphocyte activation. This blockade reduces the production of interleukin-2 and other cytokines, thereby suppressing the immune response.

The primary gene affecting tacrolimus pharmacokinetics is CYP3A5. This gene encodes an enzyme in the cytochrome P450 family responsible for the metabolism of tacrolimus in the liver and intestinal wall.

Individuals with functional CYP3A5 alleles (“expressers”) metabolize tacrolimus more quickly, leading to lower blood concentrations at standard doses. Those with nonfunctional alleles (“non-expressers”) have reduced metabolic activity and therefore higher drug levels. Metabolism refers to how the body chemically modifies a drug, and variations in CYP3A5 alter this process.

Genetic variations in CYP3A5 divide patients into phenotype groups—Normal (expressers), Intermediate, Poor (non-expressers), and Indeterminate/Not available—which influence tacrolimus clearance. Expressers clear the drug faster and often require higher starting doses, while non-expressers clear it more slowly and may need standard or lower doses. Accurate dosing guided by genotype can optimize efficacy and minimize toxicity.

Normal Metabolizer

• Effect on drug levels: Lower than expected at standard dose
• Clinical consequence: Reduced probability of reaching therapeutic concentrations; higher risk of rejection if underdosed
• Side effects: Similar to standard dosing; risk of rejection if dose not increased; severity is moderate, incidence depends on dose adjustment

Intermediate Metabolizer

• Effect on drug levels: Moderately reduced compared to standard dose
• Clinical consequence: Slightly increased risk of subtherapeutic exposure
• Side effects: Similar profile; potential for underexposure–related rejection if not adjusted; severity mild to moderate

Poor Metabolizer

• Effect on drug levels: Higher than expected at standard dose
• Clinical consequence: Increased risk of tacrolimus toxicity (nephrotoxicity, neurotoxicity)
• Side effects: Elevated risk of adverse events; severity can be significant if not monitored; frequency depends on blood levels

Indeterminate/Not available

• Effect on drug levels: Unknown
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring
• Side effects: Uncertain; monitor patient response and adjust as needed

The following dosing guidelines are based on CPIC recommendations for tacrolimus and CYP3A5 genotype, with supportive information from FDA labeling.

CYP3A5 Dosing Guideline

Examples of alternative immunosuppressants include cyclosporine and sirolimus. These are illustrative options from published guidelines and not personalized treatment advice.

• CPIC – Guideline for Tacrolimus and CYP3A5
• FDA – Table of Pharmacogenomic Associations