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

Abstract 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 AUC 0–24 was 28% higher with GFJ (GMR = 1.28, 90% CI 1.12–1.44) and C max 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.