New-Onset Diabetes After Transplantation in Renal Recipients: A Pilot Comparative Study of Immediate vs. Extended-Release Tacrolimus Formulation

Abstract

Tacrolimus is frequently used in immunosuppressive therapy in renal transplant patients and is characterized by high toxicity, a low therapeutic index, and great individual variability. For these reasons, correct dosing is important to ensure patient safety by reducing the incidence of adverse effects while maintaining an optimal blood level that prevents graft loss. New-onset diabetes after transplantation (NODAT) affects 15-30% of patients treated with tacrolimus, with potential differences between immediate-release (IR) and extended-release (ER) formulations. Objective: This study seeks to compare the incidence of NODAT between IR tacrolimus and ER tacrolimus formulations in renal transplant patients and correlate it with in vitro release characteristics. Methods: This is a retrospective pilot study including 66 renal transplant patients (33 IR tacrolimus, 33 ER tacrolimus) followed for 5 years. NODAT was defined according to standard criteria. In vitro dissolution testing was performed at pH values of 1.2, 4.5, and 6.8, with sampling at 15, 30, 60, 90, 120, and 360 min. Results: The obtained results do not indicate differences regarding the incidence of diabetes mellitus in patients treated with the two forms of tacrolimus. The determined NODAT incidence was 42.4% (ER tacrolimus) vs. 39.4% (IR tacrolimus), p = 0.802, and ER tacrolimus showed slower release without significant pH-dependent variations. Conclusions: No significant differences in NODAT incidence were identified between formulations. The release-clinical outcome correlation requires validation in larger multicenter studies. These results contribute to the evidence base for tacrolimus formulation selection in renal transplant patients and other associated pathologies.

Keywords: drug dissolution; extended release; immediate release; new-onset diabetes after transplantation; renal transplantation; tacrolimus.

Figure 1

Mechanism of action of TAC. The involvement of tacrolimus in the development of post-transplant diabetes mellitus. Legend: NFAT—nuclear factor of activated lymphocytes; IL—interleukin; FKBP-12—FK binding protein; NFAT—nuclear factor of activated T-cells; IL—interleukins; IFN–interferon.

Figure 2

Pharmacokinetic profiles of immediate-release (IR) and extended-release (ER) tacrolimus formulations. (A) Representative 24 h serum concentration profiles showing twice-daily immediate-release (IR-TAC, red line) versus once-daily extended-release (ER-TAC, blue line) tacrolimus. The green shaded area represents the optimal therapeutic range (5–15 ng/mL). IR-TAC shows characteristic biphasic peaks with greater fluctuations, while ER-TAC demonstrates more sustained levels with reduced variability. (B) Intra-patient variability comparison showing coefficient of variation (CV%) for trough levels. ER-TAC formulation demonstrates significantly lower variability compared to IR-TAC.

Figure 3

Scheme of processes that occur after administration of TAC capsule.

Figure 4

Multivariate logistic model characteristics.

Figure 5

Odds Ratio plot for NODAT predictors.

Figure 6

Flowchart for patient selection.