How is tacrolimus dosage adjusted?

From the Guidelines

Tacrolimus dosage is adjusted based on trough levels, with typical levels of 6-10 ng/ml during the first month and 4-8 ng/ml thereafter.

Adjustment of Tacrolimus Dosage

• The dosage of tacrolimus is highly individualized and based on trough levels of the drug 1.
• Higher trough levels are sought initially after transplant when the risk of rejection is high, and lower levels are sought later when concerns about adverse effects start to predominate 1.
• Typical trough levels for tacrolimus are 5-15 ng/ml initially and levels of about 5 ng/ml after a year 1.
• However, more recent guidelines recommend tacrolimus trough levels of 6-10 ng/ml during the first month followed by 4-8 ng/ml thereafter 1.
• It is also recommended to combine tacrolimus with other immunosuppressive drugs, such as mycophenolate mofetil (MMF) or azathioprine (AZA), to allow for a lower range of tacrolimus trough levels and to help preserve renal function 1.
• The administration of basiliximab induction with delayed introduction of tacrolimus is strongly recommended in patients at risk of developing post-transplant renal dysfunction 1.
• Beyond the first year after transplant, most patients can be maintained on tacrolimus levels of 4-6 ng/ml (monotherapy) or lower if tacrolimus is combined with other immunosuppressants 1.

From the FDA Drug Label

Due to intersubject variability in tacrolimus pharmacokinetics, individualization of the dosing regimen is necessary for optimal therapy [see Dosage and Administration (2. 6)].

Table 15 displays the effects of other drugs on tacrolimus. * Tacrolimus dosage adjustment recommendation based on observed effect of co-administered drug on tacrolimus exposures [see Clinical Pharmacology (12. 3)], literature reports of altered tacrolimus exposures, or the other drug’s known CYP3A inhibitor/inducer status.

The tacrolimus dosage is adjusted based on the following factors:

• Whole blood trough concentrations: The dose is adjusted to maintain optimal trough concentrations.
• Concomitant drug administration: The dose is adjusted based on the effect of concomitantly administered drugs on tacrolimus exposures, such as:

• Strong CYP3A inducers: Increase tacrolimus dose and monitor whole blood trough concentrations.
• Strong CYP3A inhibitors: Reduce tacrolimus dose and adjust based on whole blood trough concentrations.
• Mild or moderate CYP3A inhibitors: Monitor whole blood trough concentrations and reduce tacrolimus dose if needed.

• Individualization: The dosing regimen is individualized due to intersubject variability in tacrolimus pharmacokinetics.
• Therapeutic drug monitoring: Is necessary to ensure that systemic exposure to tacrolimus is maintained, especially when converting between formulations or when co-administering with other drugs that may affect tacrolimus levels 2.

From the Research

Tacrolimus Dosage Adjustment

• Tacrolimus has a narrow therapeutic window, and its bioavailability varies considerably between patients, making dosage adjustment crucial 3.
• The dosage adjustment of tacrolimus is typically guided by the trough concentration (C0), but significant relationships between TAC C0 and clinical outcomes have seldom been reported or only with adverse events 4.
• The area under the curve (AUC) is associated with efficacy and, to a lesser extent, adverse effects, and AUC monitoring can help minimize tacrolimus-related toxicity 3, 4.

Factors Influencing Dosage Adjustment

• Genetic polymorphisms, such as CYP3A5 genotype, and clinical factors, such as hemoglobin, can influence tacrolimus concentrations and dosage adjustment 5, 6, 7.
• The CYP3A5 genotype is a significant determinant of tacrolimus dose-adjusted trough concentration, and individuals who express CYP3A5 generally have decreased dose-adjusted trough concentrations of tacrolimus 6, 7.
• Other factors, such as ABCB1 gene polymorphisms, can also affect tacrolimus trough concentrations and dosage adjustment 7.

Methods for Dosage Adjustment

• Bayesian estimation and machine learning are promising approaches for AUC monitoring and dosage adjustment 4.
• Microsampling devices can be used to collect blood samples for AUC monitoring, and individualized C0 targets can be estimated to guide dosage adjustment 4.
• A genotype-based dosing equation can be formulated to calculate the required starting daily dose of tacrolimus based on CYP3A5 and other gene polymorphisms 7.