Generic Name

Tacrolimus

Brand Names

Prograf®, Advagraf®, Envarsus®) is a macrolide immunosuppressant used primarily to prevent organ rejection after solid‑organ transplantation and to treat certain autoimmune disorders such as autoimmune uveitis.

Mechanism

• Binding to FKBP‑12: Tacrolimus first binds to an intracellular immunophilin FK506 binding protein (FKBP‑12).
• Inhibition of calcineurin: The tacrolimus‑FKBP‑12 complex inhibits the phosphatase activity of calcineurin, blocking dephosphorylation of nuclear factor of activated T‑cells (NF‑AT).
• Reduced IL‑2 transcription: Without dephosphorylated NF‑AT, interleukin‑2 (IL‑2) gene transcription is suppressed, leading to diminished T‑cell proliferation and cytokine release.
• Immunosuppressive spectrum: By selectively targeting T‑cell activation, tacrolimus preserves B‑cell function, reducing the risk of some opportunistic infections compared to broader agents.

Pharmacokinetics

• Absorption: Oral bioavailability is *poor (10‑20 %)* and highly variable due to first‑pass metabolism and food interactions.
• Distribution: Highly lipophilic; extensive tissue binding, especially in adipose and liver; protein binding ~ 99 %.
• Metabolism: Predominantly by hepatic CYP3A4/3A5 and CYP3A5; polymorphisms in CYP3A5 affect clearance.
• Excretion: Primarily biliary (~ 80 %) and renal (~ 6 %) excretion; not a substrate for P‑gp.
• Steady‑state: Achieved after ~ 2–3 days; requires therapeutic drug monitoring.

Indications

• Solid‑organ transplantation
• Kidney, liver, heart, lung, or pancreas (primary or maintenance therapy)
• Autoimmune disorders
• Autoimmune uveitis (off‑label)
• Severe atopic dermatitis (select cases)
• Miscellaneous
• Experimental use in post‑bone‑marrow transplantation graft‑versus‑host disease prevention

Contraindications

• Absolute contraindications
• Known hypersensitivity to tacrolimus or macrolide antibiotics
• Severe hepatic dysfunction (elevated ALT/AST > 5× ULN)
• Precautions
• Concomitant CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, azoles) → ↑ tacrolimus levels
• CYP3A4 inducers (e.g., rifampin, St. John’s wort, phenytoin) → ↓ efficacy
• Recent use of high‑dose steroids or other immunosuppressants → augmented toxicity
• Pregnancy and lactation: Category D; use only if benefits outweigh risks
• Nephrotoxicity, neurotoxicity, hyperglycemia, hypertension, increased infection risk – monitor vitals and labs closely

Dosing

*Adjust dose downward in pregnancy, renal dysfunction, or high CYP3A4 inhibition.*

Adverse Effects

• Common
• Nephrotoxicity (acute tubular injury)
• Neurotoxicity (tremor, paresthesia, seizures)
• Hyperglycemia / diabetes onset
• Hypertension
• Oral ulcers, dysgeusia
• Increased risk of infections (viral, fungal)
• Hair loss, gingival hyperplasia
• Serious
• Progressive renal failure (requires dose reduction or discontinuation)
• Severe neurotoxicity (encephalopathy)
• Opportunistic infections: CMV, BK virus, Pneumocystis jirovecii
• Angiosarcoma & squamous cell carcinoma (rare, long‑term immunosuppression)

Monitoring

• Trough level (C0) — target 4–15 ng/mL depending on organ and time post‑transplant; adjust dose accordingly.
• Renal function: Serum creatinine, BUN, eGFR weekly for first month, then monthly.
• Blood pressure & glucose: Baseline and quarterly.
• Liver enzymes: ALT/AST, bilirubin bi‑weekly for first 3 months.
• CBC: Full counts monthly (especially for CMV, BK spectrum).
• Steroid synergy: Monitor for adrenal suppression if combined with steroids.
• Drug interactions: Re‑check concomitant meds; adjust for CYP3A4 modulators.

Clinical Pearls

• Food matters: Consistency in meal timing and fat content yields more predictable absorption. Patients should take tacrolimus on an empty stomach if experiencing GI upset, but be aware of reduced bioavailability (~ 30 %).
• Genotype guides: CYP3A5*3 carriers have slower clearance; start with lower doses and titrate to lower trough targets.
• Trough vs. peak: Rely on trough (C0) levels rather than peak (C1) for dose adjustments; peaks provide limited additional information.
• Eye safety: Even mild neuro‑ophthalmologic symptoms warrant prompt ophthalmology referral—tacrolimus can cause ocular toxicity.
• Renal transplant “window”: Early tacrolimus exposure (within first 2 weeks) is critical; avoid premature withdrawal even if BK virus is detected—use antivirals first, then reduce dose.
• Extended‑release for compliance: Envarsus® reduces dosing frequency and may improve adherence, but maintain trough target on a sliding scale.
• Drug‑drug interaction alerts in EHR: Enable mandatory stop‑warrants for high‑risk CYP3A4 inhibitors.
• Monitoring schedule: For solid‑organ recipients, build a dedicated “tacrolimus monitoring log”—document daily trough, dose changes, and lab values to prevent “blackout” periods in busy clinics.

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• References (for in‑depth reading, not included in the card)

1. Castle et al., *Clin Pharmacol Ther* 2023.

2. Fujino et al., *Transplantation** 2022.

3. FDA prescribing information for Prograf®, Advagraf®, Envarsus® (last updated 2025).