Update on the Use of Tacrolimus in Pediatrics

Kristi Higgins, PharmD


Pediatr Pharm. 2018;24(12) 

In This Article

Dosage Forms

Tacrolimus is commercially available in the United States as an immediate release oral capsule and IV formulation (Prograf®), an extended release capsule (Astagraf XL™), and an extended release tablet (Envarsus XR®). The contents of the immediate release capsule can also be compounded to form an oral suspension. In adult patients, the dosing conversions between agents are defined. If patients are converted from the immediate release oral formulation to the IV formulation, the oral dose is multiplied by ¼ to obtain the IV dose. When switching from an immediate release formulation of tacrolimus to Astagraf XL™, the dose conversion is 1:1. When switching from an immediate release formulation to Envarsus XR®, the dosing conversion is less straightforward, and is more similar to a 1:0.75 conversion, where 0.75 represents the Envarsus XR® formulation.

Recently, several studies analyzed the pharmacokinetics of switching from immediate release to extended release formulations of tacrolimus in pediatric patients. Lapeyraque and colleagues analyzed the conversion from twice daily immediate release tacrolimus to once daily Advagraf® (approved in Europe, listed as a 1:1 conversion in adults) in pediatric renal transplant patients between 6–20 years of age. Patients were converted on a 1:1 basis from their current total daily dose. AUC studies were performed over 24 hours by taking a blood sample immediately before drug administration and at a variety of time points after drug administration. The median total daily baseline tacrolimus dose was 0.11 mg/kg. The median AUC of twice daily dosing was 222.3 ng/mL compared to 197.5 ng/mL in daily dosing (p = 0.03). The median minimum concentration (Cmin) of twice daily dosing was 6.5 ng/mL, which was significantly higher than the Cmin for daily dosing of 5.6 ng/mL (p = 0.01). This study demonstrated that a 1:1 conversion from twicedaily to daily tacrolimus resulted in a sustained decrease in tacrolimus exposure as shown by a lower AUC and Cmin.[8] This indicates that when converting from twice-daily to daily tacrolimus regimens based on the current total daily dose, increased monitoring of drug levels is necessary to ensure therapeutic levels are maintained.

Quintero and colleagues evaluated the safety and efficacy of converting from twice daily to once daily tacrolimus in pediatric liver transplant patients. Patients were converted on a 1:1 basis from their current total daily dose. After conversion, doses were adjusted to maintain target trough levels. The mean daily tacrolimus dose was 0.09 mg/kg pre-conversion, with a significant increase to a mean of 0.11 mg/kg at three months after conversion (p < 0.001). Thirtyfive of the 55 (63.6%) patients needed modification of their original tacrolimus dose to maintain plasma trough levels during the first year after conversion. The average increase in dose was 0.013 mg/kg, representing an increase of 14.8% of the pre-conversion dose.[9] Patients were shown to have better adherence and similar safety profile post conversion. Both of these studies indicate that when converting pediatric patients from immediate to prolonged release tacrolimus, dose modifications may be required.

In February 2018, the first study was performed that randomized de novo pediatric patients to receive immediate release or prolonged release tacrolimus. The study included 44 pediatric patients undergoing kidney, liver or heart transplantation. Patients were randomized to receive either prolonged release tacrolimus once daily, or immediate release tacrolimus twice daily after transplantation. The dose and time after transplantation of the first tacrolimus administration, designated as Day 1, varied by organ transplanted (Table 1).

Subsequent doses were adjusted based on clinical evidence of efficacy, adverse events and achievement of recommended target whole blood trough levels (days 1–21: 10-20 ng/mL; days 22 onward: 5–15 ng/mL). Whole blood samples were collected before dosing and at a variety of time points post-dose on days 1, 7, and 28 to provide pharmacokinetic profiles.

The average whole blood concentration time curve for 24 hours after administration of prolonged release tacrolimus was smooth, whereas immediate release tacrolimus had a biphasic response. After the first dose of tacrolimus, systemic exposure (AUC) was approximately 35% lower in the group given the prolonged release group compared to those given the immediate release formulation. By day 28, once patients were at steady state after their last dose adjustment, the systemic exposure was similar for both formulations. The linear relationship between AUC and the concentration at 24 hours was also similar between the formulations. This indicates the same target trough levels will result in similar systemic exposure, and the same therapeutic drug monitoring method can be used.[4]

Based on currently available literature, it should be noted that when converting pediatric patients from twice daily to once daily formulations of tacrolimus, or starting them on a once daily regimen, daily drug monitoring is warranted until stable concentrations are achieved.