From the Guidelines
Tacrolimus toxicity is a serious concern that requires careful monitoring and management, with target trough levels typically ranging from 4-6 ng/mL for most patients beyond the first year after transplant, as recommended by the most recent guidelines 1. The therapeutic window for tacrolimus is narrow, and toxicity commonly manifests as nephrotoxicity, neurotoxicity (tremors, headaches, seizures), hyperglycemia, hypertension, and electrolyte abnormalities (particularly hyperkalemia). To prevent toxicity, regular blood level monitoring is essential, typically 2-3 times weekly immediately post-transplant, then decreasing in frequency as the patient stabilizes. Dose adjustments should be made gradually, typically by 20-25% increments. Some key points to consider in managing tacrolimus toxicity include:
- Monitoring blood work, including CBC count, renal function, glucose level, lipid profile, and potassium and magnesium levels, as well as frequent BP measurements after initiating tacrolimus 1.
- Being aware of drug interactions, as tacrolimus is metabolized by CYP3A4, and medications like azole antifungals, macrolide antibiotics, and calcium channel blockers can significantly increase tacrolimus levels 1.
- Avoiding grapefruit juice, which can also increase tacrolimus levels.
- Considering the use of renal sparing regimens, which include tacrolimus combined with either basiliximab induction and/or additional immunosuppressants, to minimize renal toxicity 1.
- Implementing prophylaxis against infections, such as Pneumocystis jiroveci, when using tacrolimus 1. If toxicity occurs, temporarily reducing or holding the dose is often necessary, with severe cases requiring temporary discontinuation. Tacrolimus toxicity occurs because the drug inhibits calcineurin, which not only provides immunosuppression but also affects other cellular functions throughout the body, explaining its diverse side effect profile. The most recent guidelines recommend targeting lower tacrolimus trough levels to preserve renal function, especially in patients at risk of post-transplant renal dysfunction 1. Overall, careful management of tacrolimus toxicity is crucial to minimize its adverse effects and ensure the best possible outcomes for patients.
From the FDA Drug Label
Tacrolimus, like other calcineurin inhibitors, can cause acute or chronic nephrotoxicity in transplant patients due to its vasoconstrictive effect on renal vasculature, toxic tubulopathy and tubular-interstitial effects. Nephrotoxicity was reported in clinical trials [see Adverse Reactions (6. 1)]. Acute renal impairment associated with tacrolimus toxicity can result in high serum creatinine, hyperkalemia, decreased secretion of urea and hyperuricemia, and is usually reversible. In patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range, consider dosage reduction or temporary interruption of tacrolimus administration The risk for nephrotoxicity may increase when tacrolimus is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors). Tacrolimus may cause a spectrum of neurotoxicities. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions [see Adverse Reactions (6.1,6. 2)]. As symptoms may be associated with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of tacrolimus if neurotoxicity occurs.
Key Toxicities of Tacrolimus:
- Nephrotoxicity: can cause acute or chronic nephrotoxicity, resulting in high serum creatinine, hyperkalemia, and decreased secretion of urea.
- Neurotoxicity: can cause a spectrum of neurotoxicities, including posterior reversible encephalopathy syndrome (PRES), delirium, seizure, and coma.
- Hyperkalemia: has been reported with tacrolimus use, and serum potassium levels should be monitored. The use of tacrolimus requires careful monitoring of its whole blood trough concentrations and renal function, as well as consideration of drug interactions that may increase the risk of toxicity 2.
From the Research
Tacrolimus Toxicity
- Tacrolimus is associated with various toxicities, including nephrotoxicity, neurotoxicity, new-onset diabetes mellitus after transplant (NODAT), and gastrointestinal toxicity 3.
- Elevated tacrolimus trough concentration (C0) has been linked to acute kidney injury occurrence and severity, as well as renal impairment 3.
- Neurotoxicity can occur at both therapeutic and supratherapeutic tacrolimus levels, and may present with symptoms such as neuro-encephalopathies, polyneuropathies, and changes in neurological status 3, 4.
- There is limited literature available on the pharmacologic management of tacrolimus-induced neurotoxicity, and no clear guidelines for treatment 4.
Comparison with Other Immunosuppressants
- Belatacept has been compared to tacrolimus in kidney transplantation, with similar longitudinal risk of mortality and allograft failure, but an increased risk of acute rejection in the first year posttransplant 5.
- Sirolimus has been compared to tacrolimus in simultaneous pancreas and kidney transplantation, with no difference in renal and pancreas graft survival at 5 years, but a high rate of sirolimus discontinuation due to adverse events 6.
Adverse Event Profile
- A pharmacovigilance study using the Japanese Adverse Drug Event Report (JADER) database found a significant association between tacrolimus use and colon cancer in heart transplant patients, bronchitis in kidney transplant patients, and seizure in liver transplant patients 7.
- The study also found that infectious disorders were commonly reported in solid organ transplant patients taking tacrolimus 7.