From the Guidelines
Elevated tacrolimus levels can be caused by several factors, primarily medication interactions and impaired renal function, with medications that inhibit the cytochrome P450 3A4 enzyme system being major contributors, as noted in studies such as 1.
Medication Interactions
Medications that inhibit the cytochrome P450 3A4 enzyme system are major contributors to elevated tacrolimus levels, including:
- Antifungals (fluconazole, voriconazole, ketoconazole)
- Macrolide antibiotics (erythromycin, clarithromycin)
- Calcium channel blockers (diltiazem, verapamil)
- Certain antivirals (ritonavir) These drugs compete with tacrolimus for metabolism, leading to increased blood concentrations, as discussed in 1 and 1.
Impaired Renal Function
Impaired renal function significantly affects tacrolimus levels because although the drug is primarily metabolized by the liver, reduced kidney function alters drug clearance and can lead to drug accumulation, as mentioned in 1.
Monitoring and Management
Regular therapeutic drug monitoring is essential when starting any potentially interacting medication or when renal function changes occur to prevent toxicity while maintaining immunosuppressive efficacy, with target trough levels ranging from 4-7 ng/ml during the first month, followed by 3-5 ng/ml, as recommended in 1.
Key Considerations
- Grapefruit juice should be avoided as it contains compounds that inhibit CYP3A4.
- Tacrolimus has a narrow therapeutic window, so even small changes in metabolism can lead to toxic levels, resulting in nephrotoxicity, neurotoxicity, and increased risk of infection.
- The use of renal sparing regimens, such as combining tacrolimus with other immunosuppressants, can help preserve renal function, as discussed in 1.
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. 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). Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of tacrolimus [see Drug Interactions (7.2)].
The tacrolimus level can increase due to:
- Medications:
- CYP3A inhibitors
- Calcium-channel blocking agents
- Other drugs associated with nephrotoxicity, such as:
- Aminoglycosides
- Ganciclovir
- Amphotericin B
- Cisplatin
- Nucleotide reverse transcriptase inhibitors
- Protease inhibitors
- Impaired renal function: Tacrolimus can cause nephrotoxicity, which may lead to elevated tacrolimus levels, especially if the renal function is already impaired 2.
From the Research
Factors Affecting Tacrolimus Levels
- Medications: Certain drugs can interact with tacrolimus, leading to increased levels. For example, nirmatrelvir/ritonavir (Paxlovid) can cause tacrolimus toxicity by inhibiting its metabolism via cytochrome P450 CYP3A4 3.
- Renal Function: Impaired renal function can affect tacrolimus levels, as the drug is primarily eliminated through the kidneys. However, the relationship between renal function and tacrolimus levels is complex and influenced by various factors, including the patient's overall health and other medications 4, 5.
Medication Interactions
- CYP3A4 Inhibitors: Drugs that inhibit CYP3A4, such as ritonavir, can increase tacrolimus levels by reducing its metabolism 3.
- CYP3A4 Inducers: Conversely, drugs that induce CYP3A4, such as phenytoin, can decrease tacrolimus levels by increasing its metabolism 3.
Monitoring Tacrolimus Levels
- Trough Concentrations: Measuring pre-dose tacrolimus concentrations (C0) is a common approach to monitoring tacrolimus levels. However, C0 may not always accurately reflect the patient's overall exposure to the drug 5, 6.
- Area Under the Curve (AUC): AUC-based monitoring can provide a more comprehensive understanding of tacrolimus exposure, but it is not always feasible in clinical practice 5, 6.