Assessment of the Intestinal CYP3A Contribution to Drug Interactions with Extended-Release Tacrolimus (LCPT) Using Grapefruit Juice.

Grapefruit juice (GFJ) is a known inhibitor of intestinal cytochrome P450 3A (CYP3A) metabolism leading to increased exposure to CYP3A substrates such as tacrolimus. The extended-release tacrolimus formulation Envarsus (LCPT) exhibits prolonged absorption throughout the entire GI tract. Although a clinically significant drug-drug interaction occurs with immediate-release tacrolimus formulations, this has not been evaluated with extended-release formulations. This study assessed the impact of GFJ on LCPT in adult kidney transplant patients. Eleven adult kidney transplant recipients on a stable dose of LCPT were enrolled in a randomized crossover study. Participants were administered either GFJ or water during each pharmacokinetic visit, with midazolam used as a positive control. A washout period of 2-4 weeks was included between visits. Tacrolimus concentrations were determined using validated LC-MS/MS methods. Tacrolimus AUC0-24 was 28% higher with GFJ (GMR = 1.28, 90% CI 1.12-1.44) and Cmax was 73% higher (GMR = 1.73, 90% CI 1.46-2.00) compared to control. GFJ exhibited a clinically meaningful interaction with LCPT. However, the magnitude appears less than those reported with immediate-release formulations, suggesting the extended absorption profile of LCPT may affect susceptibility to drug interactions in the intestine.