What drugs interact with tacrolimus (immunosuppressant)?

From the Guidelines

Drugs that affect tacrolimus levels include those that inhibit or induce the CYP3A4 enzyme system, such as antifungals, macrolide antibiotics, calcium channel blockers, protease inhibitors, rifampin, phenytoin, carbamazepine, and St. John's wort. When managing patients on tacrolimus, it is crucial to consider potential drug interactions that can impact tacrolimus levels and, consequently, patient outcomes in terms of morbidity, mortality, and quality of life.

Key Interactions

• Drugs that inhibit CYP3A4, such as ketoconazole, erythromycin, and diltiazem, can increase tacrolimus levels, potentially leading to toxicity 1.
• Conversely, drugs that induce CYP3A4, including rifampin, phenytoin, and carbamazepine, can decrease tacrolimus levels, potentially resulting in subtherapeutic levels and transplant rejection 1.
• Other substances like St. John's Wort and grapefruit juice can also significantly affect tacrolimus levels by interacting with the CYP3A4 system 1.

Clinical Implications

• Monitoring of tacrolimus levels is essential when starting or stopping any medication that may interact with tacrolimus, especially during the first week of the interaction.
• Dose adjustments may be necessary to maintain therapeutic tacrolimus levels, which typically range from 5-15 ng/mL, depending on transplant type, time post-transplant, and individual patient factors.
• Healthcare providers should be vigilant about potential interactions and counsel patients on the importance of avoiding certain medications and substances while on tacrolimus to minimize risks to morbidity, mortality, and quality of life.

From the FDA Drug Label

When co-administering tacrolimus with strong CYP3A4 inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, phenytoin) Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when concomitant use of the following drugs with tacrolimus is initiated or discontinued Telaprevir: In a single dose study in 9 healthy volunteers, co-administration of tacrolimus (0. 5 mg single dose) with telaprevir (750 mg three times daily for 13 days) increased the tacrolimus dose-normalized Cmax by 9.3-fold and AUC by 70-fold compared to tacrolimus alone Boceprevir: In a single-dose study in 12 subjects, co-administration of tacrolimus (0. 5 mg single dose) with boceprevir (800 mg three times daily for 11 days) increased tacrolimus Cmax by 9.9-fold and AUC by 17-fold compared to tacrolimus alone Nelfinavir: Based on a clinical study of 5 liver transplant recipients, co-administration of tacrolimus with nelfinavir increased blood concentrations of tacrolimus significantly and, as a result, a reduction in the tacrolimus dose by an average of 16-fold was needed to maintain mean trough tacrolimus blood concentrations of 9. 7 ng/mL. Rifampin: In a study of 6 normal volunteers, a significant decrease in tacrolimus oral bioavailability (14±6% vs. 7±3%) was observed with concomitant rifampin administration (600 mg). Ketoconazole: In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). Voriconazole: Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased tacrolimus (0.1 mg/kg single dose) Cmax and AUCτ in healthy subjects by an average of 2-fold (90% CI: 1.9,2.5) and 3-fold (90% CI: 2.7,3.8), respectively Posaconazole: Repeat oral administration of posaconazole (400 mg twice daily for 7 days) increased tacrolimus (0.05 mg/kg single dose) Cmax and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01,2.42) and 4.5-fold (90% CI 4.03,5.19), respectively

The following drugs affect tacrolimus levels:

• CYP3A4 inhibitors: telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin, posaconazole
• CYP3A4 inducers: rifampin, phenytoin
• Other drugs: nelfinavir, magnesium and aluminum-hydroxide These drugs can increase or decrease tacrolimus levels, and may require dosage adjustments of tacrolimus 2, 2.

From the Research

Drugs that Affect Tacrolimus

• Rifampin has been shown to significantly reduce tacrolimus levels, despite the presence of multiple cytochrome P450 inhibitors 3
• The induction of the hepatic cytochrome P4503A4 system by rifampin can overcome the inhibitory effects of other drugs, such as diltiazem, fluconazole, and clarithromycin, on tacrolimus metabolism 3
• Tacrolimus itself has a mild inhibitory effect on CYP3A4 and 3A5 at high concentrations, but is unlikely to potentiate the effect of coadministered drugs through inhibition of their metabolism in the liver 4
• Genetic variants, such as CYP3A53 and CYP3A422, can significantly affect tacrolimus clearance and dose requirements, with patients homozygous for both variants requiring lower doses of tacrolimus 5
• The formulation of tacrolimus can also affect its susceptibility to drug-drug interactions, with prolonged-release formulations being less susceptible to interaction with strong CYP3A inhibitors, such as voriconazole 6

Factors that Influence Tacrolimus Metabolism

• Cytochrome P450 3A5 (CYP3A5) and cytochrome P450 3A4 (CYP3A4) are the primary enzymes responsible for tacrolimus metabolism 7, 5
• Genetic variants, such as CYP3A53 and CYP3A422, can reduce the production of functional CYP3A4 and CYP3A5 enzymes, leading to decreased tacrolimus metabolism 5
• Strong CYP3A inhibitors, such as voriconazole, can increase tacrolimus exposure, while inducers, such as rifampin, can decrease tacrolimus exposure 3, 6