title: Relative bioavailability of single doses of prolonged-release tacrolimus administered as a suspension, orally or via a nasogastric tube, compared with intact capsules: a phase 1 study in healthy participants.
abstract: Tacrolimus, an immunosuppressant widely used in solid organ transplantation, is available as a prolonged-release capsule for once-daily oral administration. In the immediate postsurgical period, if patients cannot take intact capsules orally, tacrolimus therapy is often initiated as a suspension of the capsule contents, delivered orally or via a nasogastric tube. This study evaluated the relative bioavailability of prolonged-release tacrolimus suspension versus intact capsules in healthy participants.
  
  
  
  A phase 1, open-label, single-dose, cross-over study.
  
  
  
  A single clinical research unit.
  
  
  
  In total, 20 male participants, 18-55 years old, entered and completed the study.
  
  
  
  All participants received nasogastric administration of tacrolimus 10 mg suspension in treatment period 1, with randomisation to oral administration of suspension or intact capsules in periods 2 and 3. Blood concentration-time profile over 144 hours was used to estimate pharmacokinetic parameters.
  
  
  
  Primary end point: relative bioavailability of prolonged-release intact capsule versus oral or nasogastric administration of prolonged-release tacrolimus suspension (area under the concentration-time curve (AUC) from time 0 to infinity post-tacrolimus dose (AUC0-∞); AUC measured until the last quantifiable concentration (AUC0-tz); maximum observed concentration (Cmax); time to Cmax(Tmax)). Tolerability was assessed throughout the study.
  
  
  
  Relative bioavailability of prolonged-release tacrolimus suspension administered orally was similar to intact capsules, with a ratio of least-square means for AUC0-tzand AUC0-∞of 1.05 (90% CI 0.96 to 1.14). Bioavailability was lower with suspension administered via a nasogastric tube versus intact capsules (17%; ratio 0.83; CI 0.76 to 0.92). Cmaxwas higher for oral and nasogastric suspension (30% and 28%, respectively), and median Tmaxwas shorter (difference 1.0 and 1.5 hours postdose, respectively) versus intact capsules (2.0 hours). Single 10 mg doses of tacrolimus were well tolerated.
  
  
  
  Compared with intact capsules, the rate of absorption of prolonged-release tacrolimus from suspension was faster, leading to higher peak blood concentrations and shorter time to peak; relative bioavailability was similar with suspension administered orally.
authors.affiliation: Astellas Pharma Europe Ltd, Chertsey, Surrey, UK.
authors.forename: Nasrullah
authors.initials: N
authors.lastname: Undre
authors.affiliation: NUVISAN GmbH, Neu-Ulm, Germany (former employee of Fujisawa GmbH, Munchen, Germany, now Astellas Pharma Europe Ltd).
authors.forename: James
authors.initials: J
authors.lastname: Dickinson
mesh_terms: D000293:Adolescent; D000328:Adult; D001682:Biological Availability; D002214:Capsules; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D006084:Graft Rejection / Q000097:blood / Q000517:prevention & control*; D064368:Healthy Volunteers; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D007441:Intubation, Gastrointestinal / Q000379:methods*; D008297:Male; D008875:Middle Aged; D013535:Suspensions / Q000008:administration & dosage / Q000493:pharmacokinetics; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D002214:Capsules; D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; D013535:Suspensions; D016559:Tacrolimus
keywords: healthy subjects; intact capsule; nasogastric tube; prolonged-release tacrolimus