How do you bridge subtherapeutic levels of Tacrolimus (FK506) to intravenous (IV) infusion?

From the Guidelines

To bridge subtherapeutic tacrolimus (tacro) levels to an intravenous (IV) drip, first calculate the total daily oral dose the patient is currently receiving, then convert to IV using a 1:4 ratio (IV dose should be approximately 1/4 of the oral dose), as recommended by recent guidelines 1. Start the IV infusion 12-24 hours after the last oral dose to prevent toxicity while maintaining therapeutic levels. For example, if a patient is taking 4 mg orally twice daily (8 mg total), the equivalent IV dose would be approximately 2 mg/day as a continuous infusion (0.08 mg/hour). Monitor tacrolimus levels frequently (daily initially) and adjust the infusion rate to achieve target therapeutic levels, which typically range from 5-15 ng/mL depending on transplant type, time post-transplant, and institutional protocols 1. The conversion is necessary because IV tacrolimus has higher bioavailability than oral formulations, which undergo first-pass metabolism in the liver. This approach helps maintain immunosuppression when oral administration is not feasible due to poor absorption, NPO status, or gastrointestinal dysfunction. It is also important to consider the use of renal sparing regimens, such as combining tacrolimus with other immunosuppressants, to minimize the risk of renal toxicity 1. Key considerations include:

• Calculating the equivalent IV dose based on the patient's current oral dose
• Starting the IV infusion at the right time to avoid toxicity
• Monitoring tacrolimus levels closely to adjust the infusion rate as needed
• Being aware of the potential for renal toxicity and taking steps to minimize this risk
• Considering the use of renal sparing regimens to reduce the risk of renal toxicity. The goal is to maintain therapeutic tacrolimus levels while minimizing the risk of adverse effects, particularly renal toxicity, as supported by the most recent and highest quality studies 1.

From the FDA Drug Label

The recommended starting dose of tacrolimus injection is 0.03 to 0.05 mg/kg/day in kidney or liver transplant, 0.01 mg/kg/day in heart transplant, given as a continuous intravenous infusion. Tacrolimus injection should be used only as a continuous intravenous infusion and should be discontinued as soon as the patient can tolerate oral administration. The first dose of tacrolimus capsules should be given 8 to 12 hours after discontinuing the intravenous infusion.

To bridge subtherapeutic tacrolimus (IV) to drip, the recommended starting dose is 0.03 to 0.05 mg/kg/day for kidney or liver transplant, and 0.01 mg/kg/day for heart transplant, given as a continuous intravenous infusion. The infusion should be discontinued as soon as the patient can tolerate oral administration, and the first dose of tacrolimus capsules should be given 8 to 12 hours after discontinuing the intravenous infusion 2.

From the Research

Bridging Subtherapeutic Tacrolimus Levels to Drip

To bridge subtherapeutic tacrolimus levels to drip, several factors need to be considered, including the patient's clinical status, the target blood concentration, and the conversion ratio from oral to intravenous administration.

• The target blood concentrations of tacrolimus during continuous intravenous infusion have been determined based on clinical experience, and it is desirable to set the steady-state concentration (C(ss)) so that the area under the curve (AUC) after intravenous infusion is equal to the AUC after oral administration (AUC(po)) 3.
• A formula has been proposed to calculate the target C(ss) from the trough level (C(TL)), AUC(po), and the area under the trough level (AUTL): C(ss) = C(TL) x (AUC(po)/AUTL) 3.
• The calculated target C(ss) of tacrolimus was 1.40 times that of C(TL), which was similar to the present clinical C(TL) 3.
• Physiologically based pharmacokinetic modeling has been used to establish the Css/Cmin ratio for tacrolimus across various clinical scenarios, and the results showed that the oral/intravenous dose ratio was 4.25, and the Css/Cmin ratio was 1.40 in healthy volunteers 4.
• The concomitant administration of cytochrome P450 3A inhibitors, such as itraconazole, can affect the pharmacokinetics of tacrolimus, and the Css/Cmin ratio can be altered 4.
• Tacrolimus dosing is typically guided by the trough concentration (C0), but significant relationships between TAC C0 and clinical outcomes have seldom been reported, and the AUC is associated with efficacy and adverse effects 5.
• The AUC/C0 ratio can vary significantly between patients, and individualized C0 targets can be estimated to improve the accuracy of tacrolimus dosing 5.
• In patients receiving concomitant isavuconazole after hematopoietic stem cell transplantation, the intravenous tacrolimus dose should be initiated at 0.017 mg/kg/day, and a 3.1:1 oral:intravenous conversion ratio can improve the chances of achieving target levels 6.
• The risk factors for subtherapeutic tacrolimus levels after conversion from continuous intravenous infusion to oral in children after allogeneic hematopoietic cell transplantation include ethnicity and ≥ 10 days of subtherapeutic tacrolimus levels in the first 30 days on intravenous therapy 7.

Key Considerations

• The conversion ratio from oral to intravenous administration should be carefully considered, and a 3.1:1 oral:intravenous conversion ratio may be appropriate in some cases 6.
• The patient's clinical status, including the presence of cytochrome P450 3A inhibitors, should be taken into account when adjusting the tacrolimus dose 4.
• Individualized C0 targets can be estimated to improve the accuracy of tacrolimus dosing, and the AUC/C0 ratio should be considered when adjusting the dose 5.
• Close monitoring of tacrolimus levels is necessary to ensure that the target concentration is achieved and maintained 6.