title: Assessment of tacrolimus absorption from the human intestinal tract: open-label, randomized, 4-way crossover study.
abstract: BACKGROUND
  Tacrolimus is an established immunosuppressant used for the prevention and treatment of allograft rejection in solid organ transplantation. An immediate-release oral formulation of tacrolimus has been commercially available since 1994 that is administered orally BID. To improve the compliance and quality of life of transplant patients, a once-daily modified release (MR) formulation is an attractive option. However, to be successful, the drug of interest must be sufficiently well absorbed from the distal region of the gastrointestinal tract.
  
  
  OBJECTIVE
  To facilitate the development of an MR formulation, we investigated the absorption of tacrolimus from different regions of the human gastrointestinal tract, proximal and distal small bowels, and ascending colon.
  
  
  METHODS
  The study was performed as an open-label, randomized, 4-way crossover design in 6 healthy white male subjects. For each subject, 1 mg (2 mg/mL) of tacrolimus solution in polyethylene glycol 400 was administered to each location in the gastrointestinal tract via a site-specific radiolabeled delivery capsule, which can release tacrolimus solution at specific sites of the gastrointestinal tract. Real-time visualization of capsule location and tacrolimus release at each target site was performed by using γ-scintigraphy. Blood samples were collected to determine tacrolimus levels in the blood. The pharmacokinetic parameters Cmax, Tmax after the capsule activation, AUC0-24, and mean residence time were determined from the concentration-time profiles.
  
  
  RESULTS
  Ten healthy male subjects underwent dosing. Six subjects completed all 4 treatments. Three adverse events (mild headache [n = 1], small amount of blood in stool [n = 1], and mild syncopal episode [n = 1]) that were possibly study drug related were reported in 3 different subjects. Tacrolimus was absorbed from not only the small intestine but also from the colonic region of the gastrointestinal tract. Although AUC0-24 values revealed some site-specific absorption tendencies, the mean AUC0-24 values obtained were similar regardless of the location of tacrolimus release from the capsule.
  
  
  CONCLUSIONS
  Tacrolimus was absorbed from the duodenum to the colon in these male subjects, although differences were observed in the value of AUC0-24, possibly due to variation in cytochrome P450 3A4 activity in the intestine. Although this study was conducted in small group of healthy fasting men, the present results indicate that tacrolimus is suitable for MR formulation development due to a wide absorption window throughout the intestine in humans.
authors.affiliation: Pharmaceutical Research and Technology Laboratories, Astellas Pharma Inc, Shizuoka, Japan; Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, Okayama, Japan. Electronic address: daisuke.tsunashima@astellas.com.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsunashima
authors.affiliation: Drug Metabolism Research Laboratories, Astellas Pharma Inc, Osaka, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Kawamura
authors.affiliation: Project Management, Astellas Pharma Inc, Tokyo, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Clinical Pharmacology, Astellas Pharma Inc, Tokyo, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Sawamoto
authors.affiliation: Medical Affairs Europe, Astellas Pharma Europe Ltd, Chertsey, Surrey, United Kingdom.
authors.forename: Nas
authors.initials: N
authors.lastname: Undre
authors.affiliation: Global Medical Affairs, Astellas Pharma, Northbrook, Illinois.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Brown
authors.affiliation: Chief Executive Office Operations, Astellas Pharma Europe Ltd, Chertsey, Surrey, United Kingdom.
authors.forename: Albert
authors.initials: A
authors.lastname: Groenewoud
authors.affiliation: Clinical Pharmacology, Astellas Pharma Global Development Inc, Northbrook, Illinois.
authors.forename: James J
authors.initials: JJ
authors.lastname: Keirns
authors.affiliation: Medical Sciences, Astellas Pharma Global Development Inc, Northbrook, Illinois.
authors.forename: John
authors.initials: J
authors.lastname: Holman
authors.affiliation: Quotient Clinical, Ruddington, Nottinghamshire, United Kingdom.
authors.forename: Alyson
authors.initials: A
authors.lastname: Connor
authors.affiliation: Quotient Clinical, Ruddington, Nottinghamshire, United Kingdom.
authors.forename: Hannah
authors.initials: H
authors.lastname: Wylde
authors.affiliation: Quotient Clinical, Ruddington, Nottinghamshire, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Wilding
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Ogawara
authors.affiliation: Pharmaceutical Research and Technology Laboratories, Astellas Pharma Inc, Shizuoka, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sako
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Higaki
authors.affiliation: IM/IDI Transplant, Astellas Pharma Global Development Inc, Northbrook, Illinois.
authors.forename: Roy
authors.initials: R
authors.lastname: First
mesh_terms: D001682:Biological Availability; D002214:Capsules; D044682:Colon, Ascending / Q000378:metabolism*; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems; D015902:Gamma Cameras; D005753:Gastric Mucosa / Q000378:metabolism*; D064368:Healthy Volunteers; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism*; D008297:Male; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D002214:Capsules; D016559:Tacrolimus
keywords: gastrointestinal; modified release; once daily; regional absorption; tacrolimus; γ-scintigraphy