*Purpose: The purpose of this analysis was to quantify the impact of 2 tacrolimus pharmacokinetic profiles on functional changes within human islet cells using a novel microfluidic system. We hypothesize that the toxic effect of tacrolimus on human islet function and in vivo islet survival is dependent on tacrolimus pharmacokinetics. Tacrolimus extended-release (LCPT) has a unique pharmacokinetic profile demonstrated by a flatter curve due to the reduced and delayed peak concentration. The reduced peak concertation may result in less immunotoxicity on in-vitro islet cell function when compared to immediate-release tacrolimus (IR-TAC).

*Methods: A microfluidic biochip, designed specifically for studying islet cell physiology, was utilized to analyze differences in tacrolimus toxicity with variable concentration kinetics. Human islets were isolated from brain death donors with research consent. The tacrolimus concentration data generated from the phase 3b study in stable kidney transplant patients comparing LCPT to IR-TAC was used to generate comparable in vitro tacrolimus concentration profiles on human islet biochips. Glucose stimulated intracellular calcium, insulin secretion kinetics, and cell viability were measured to quantify the effect of tacrolimus concentration on islet cell toxicity.

*Results: Viability shown in Image 1, calcium influx in Image 2 and insulin secretion in Image 3.

*Conclusions: This analysis did not reveal any differences in islet cell viability between the 3 groups. The comparison of calcium influx induced by either 25 mM glucose or 30 mM KCI also showed no significant difference among the three groups. However, insulin secretion kinetics showed that IR-Tac had reduced glucose and KCL stimulated insulin secretion when compared to the control and the LCPT. Additional studies are needed to confirm this initial finding of improved insulin secretion with the flatter tacrolimus profile observed with LCPT.

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