Conversion from twice- to once-daily tacrolimus in pediatric kidney recipients: a pharmacokinetic and bioequivalence study

Abstract

BackgroundThe objectives of this study were to investigate pharmacokinetic and pharmacogenetic parameters during the conversion on a 1:1 (mg:mg) basis from a twice-daily (Prograf) to once-daily (Advagraf) tacrolimus formulation in pediatric kidney transplant recipients.MethodsTwenty-four-hour pharmacokinetic profiles were analyzed before and after conversion in 19 stable renal transplant recipients (age 7–19 years). Tacrolimus pharmacokinetic parameters [area under the concentration-time curve (AUC0–24), minimum whole-blood concentration (Cmin), maximum whole-blood concentration (Cmax), and time to achieve maximum whole-blood concentration (tmax)] were compared between Tac formulations and between CYP3A5 and MDR1 genotypes after dose normalization.ResultsBoth AUC0–24 and Cmin decreased after conversion (223.3 to 197.5 ng.h/ml and 6.5 to 5.6 ng/ml; p = 0.03 and 0.01, respectively). However, the ratio of the least square means (LSM) for AUC0–24 was 90.8 %, with 90 % CI limits of 85.3 to 96.7 %, falling within bioequivalence limits. The CYP3A5 genotype influences the dose-normalized Cmin with the twice-daily formulation only.ConclusionsBoth tacrolimus formulations are bioequivalent in pediatric renal recipients. However, we observed a decrease in AUC0–24 and Cmin after the conversion, requiring close pharmacokinetic monitoring during the conversion period.

Immunosuppression in pediatric liver transplant recipients: Unique aspects

“…Studies in adult LT patients support the use of once‐daily extended‐release tacrolimus (Astagraf XL, Advagraf) with a similar safety and efficacy as standard tacrolimus . Data from small groups of pediatric patients who had kidney or living related donor LT show that both formulations were bioequivalent . There was a mild decrease in the area under the concentration‐time curve and whole‐blood concentration after conversion in pediatric renal recipients which may require closer drug level monitoring during the conversion period .…”

Choosing the right dose of tacrolimus

“…Tacrolimus is a new prolonged-release once-daily formulation of tacrolimus. Limited data (mainly pharmacokinetic data) were reported in children who had liver and renal transplants 11 12. It is recommended that patients receiving stable treatment with tacrolimus twice daily can be switched to tacrolimus once daily, on a daily milligram-for-milligram basis, followed with close TDM.…”

Update on the clinical utility of once-daily tacrolimus in the management of transplantation

“…Among pediatric kidney transplant recipients, AUC and trough were noted to decrease after conversion to once-daily tacrolimus 11,12. These differences were statistically significant in a PK study involving 34 patients11 and not statistically significant in another study involving 19 patients 12. C max was also not significantly different between formulations and CYP3A5 genotypes 12.…”

“…These differences were statistically significant in a PK study involving 34 patients11 and not statistically significant in another study involving 19 patients 12. C max was also not significantly different between formulations and CYP3A5 genotypes 12. PK studies conducted on 19 stable lung transplant patients converted to once-daily tacrolimus showed that the bioavailability of tacrolimus is similar with once- and twice-daily formulations.…”

“…The greater bioavailability of once-daily tacrolimus allowed similar AUC exposure using a dose that is about 30% lower than the twice-daily formulation 9,10. Among pediatric kidney transplant recipients, AUC and trough were noted to decrease after conversion to once-daily tacrolimus 11,12. These differences were statistically significant in a PK study involving 34 patients11 and not statistically significant in another study involving 19 patients 12.…”