What drugs affect tacrolimus (FK506) levels?

From the Guidelines

Tacrolimus levels can be significantly affected by numerous medications, and it is crucial to monitor these interactions closely to avoid toxicity or rejection, as evidenced by the most recent study 1. When managing patients on tacrolimus, it is essential to consider the potential interactions with other medications that can affect its levels.

• Drugs that inhibit CYP3A4, such as antifungals (ketoconazole, fluconazole, voriconazole), macrolide antibiotics (erythromycin, clarithromycin), calcium channel blockers (diltiazem, verapamil), and protease inhibitors, can increase tacrolimus levels, potentially causing toxicity.
• Medications that induce CYP3A4, such as anticonvulsants (phenytoin, carbamazepine, phenobarbital), rifampin, and St. John's wort, can decrease tacrolimus levels, risking rejection. As noted in the study 1, high-fat meals may also decrease the oral absorption of tacrolimus, and St. John's wort may decrease its levels. Monitoring of tacrolimus levels is critical when starting or stopping interacting medications, and dose adjustments should be made as needed to maintain optimal levels and prevent adverse effects, as recommended in the guidelines 1. In addition to monitoring tacrolimus levels, it is also important to monitor blood work, including CBC count, renal function, glucose level, lipid profile, and potassium and magnesium levels, as well as blood pressure, as suggested in the study 1. Overall, careful management of tacrolimus interactions is essential to ensure the safety and efficacy of this medication, and clinicians should be aware of the potential interactions and take steps to monitor and adjust tacrolimus levels accordingly, as supported by the evidence 1.

From the FDA Drug Label

Table 15 displays the effects of other drugs on tacrolimus.

• Strong CYP3A Inducers: Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John’s wort may decrease tacrolimus whole blood trough concentrations and increase the risk of rejection.
• Strong CYP3A Inhibitors: Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, Schisandra sphenanthera extracts may increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions.
• Mild or Moderate CYP3A Inhibitors: Clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole may increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions.
• Other drugs, such as: Magnesium and aluminum hydroxide antacids, Metoclopramide may increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions.
• Mild or Moderate CYP3A Inducers: Methylprednisolone, prednisone may decrease tacrolimus whole blood trough concentrations.
• Caspofungin may decrease tacrolimus whole blood trough concentrations.
• Grapefruit or grapefruit juice may increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions.
• Cannabidiol may increase tacrolimus blood levels and increase the risk of adverse reactions suggestive of tacrolimus toxicity.
• Direct Acting Antiviral (DAA) Therapy may impact the pharmacokinetics of tacrolimus due to changes in liver function.

Drugs that affect tacrolimus levels:

• CYP3A inducers: may decrease tacrolimus levels, e.g., rifampin, phenytoin, carbamazepine, St John’s wort, methylprednisolone, prednisone, caspofungin
• CYP3A inhibitors: may increase tacrolimus levels, e.g., protease inhibitors, azole antifungals, antibiotics, nefazodone, letermovir, clotrimazole, erythromycin, fluconazole, calcium channel blockers, amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole, omeprazole
• Other drugs: may increase tacrolimus levels, e.g., magnesium and aluminum hydroxide antacids, metoclopramide, grapefruit or grapefruit juice, cannabidiol
• Direct Acting Antiviral (DAA) Therapy: may impact tacrolimus pharmacokinetics due to changes in liver function 2, 2, 2

From the Research

Drugs that Affect Tacrolimus Levels

• Rifampin has been shown to decrease tacrolimus blood concentrations by inducing the hepatic cytochrome P4503A4 system 3, 4
• Erythromycin, clarithromycin, clotrimazole, fluconazole, ketoconazole, and danazol have been shown to increase tacrolimus blood concentrations 4
• Other drugs that affect cytochrome P450 activity may also have significant effects on the pharmacokinetics of tacrolimus 4
• Tacrolimus itself may inhibit the metabolism of coadministered drugs, potentially leading to enhanced renal impairment 4

Factors that Influence Tacrolimus Metabolism

• Genetic factors can influence tacrolimus metabolism, with some patients being classified as poor or extensive metabolizers 5
• Different tacrolimus formulations, such as twice-daily immediate-release tacrolimus capsules or once-daily extended-release tacrolimus capsules, may have different pharmacokinetic profiles 5
• The area under the curve (AUC) of tacrolimus has been shown to be associated with efficacy and adverse effects, and may be a more accurate predictor of clinical outcomes than trough concentration (C0) 6

Monitoring Tacrolimus Levels

• Therapeutic drug monitoring is used to adjust the dosage of tacrolimus and optimize allograft function 3, 5
• The C0 value is commonly used to guide tacrolimus dosing, but may not always accurately reflect the AUC 6
• Bayesian estimation and machine learning are promising approaches for estimating the AUC of tacrolimus 6
• Microsampling devices may be a valuable alternative to venous blood sample collection for monitoring tacrolimus levels 6