*Purpose: It is well known that grapefruit juice (GFJ) interacts with many medications through an intestinal CYP3A-mediated interaction that does not involve hepatic CYP3A and is clinically significant, increasing tacrolimus concentrations by more than 10 ng/mL. In fact, GFJ has been proposed as a model to interrogate intestinal CYP3A4 mediated drug interactions. Tacrolimus extended release, LCP-Tacro (LCPT) utilizes Melt-Dose technology to avoid the high peaks associated with immediate release tacrolimus (IRT). By dispersing tacrolimus more distally in the intestine, there may be less opportunity for interaction with CYP3A enzymes in the intestine. The primary objective of this study is to characterize the drug interaction of GFJ with LCPT. Since CYP3A enzymes are concentrated in the proximal intestine, we hypothesize that GFJ will have a lower impact on LCPT PK compared to IRT. Secondary objective includes comparing the magnitude of GFJ interaction on tacrolimus versus midazolam PK.

*Methods: We conducted a prospective, single center, cross-over trial of 8 adult kidney transplant patients at least 3 months post-transplant taking a stable dose of LCPT. They received their LCPT dose with water or GFJ. A single oral dose of midazolam 3 mg was given as a positive control. There was a 2- 4 week wash-out period between each PK visit. Blood samples were taken pre-dose and post dose at 0.25, 0.5, 1, 2, 4, 6, 8, 10 or 12, and 24 hours. Each patient was fed the same low-fat meals to avoid variability due to food intake. Tacrolimus whole blood and midazolam plasma were analysed by LC-MS/MS. Pharmacokinetic parameters were assessed using Phoenix WinNonLin version 8.3.

*Results: Mean tacrolimus AUC was not significantly different after GFJ vs water (366 ± 98 vs 319 ± 48 ng*h/mL, p < 0.05, Wilcoxon signed rank). Mean tacrolimus Cmax was also not significantly different after GFJ vs water (21 ± 4 vs 25 ± 7 ng/mL, p = 0.15). In contrast, midazolam AUC was significantly different after GFJ vs water (68 ± 47 vs 42 ± 22 ng*h/mL, p = 0.05), demonstrating that GFJ did affect CYP3A enzymes.

*Conclusions: In conclusion, our results demonstrate that GFJ does not significantly affect LCPT pharmacokinetics and may be safely given to kidney transplant patients. This may serve as a model for other CYP3A substrates known to interact with tacrolimus.

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