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

OBJECTIVE: 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. DESIGN: A phase 1, open-label, single-dose, cross-over study. SETTING: A single clinical research unit. PARTICIPANTS: In total, 20 male participants, 18–55 years old, entered and completed the study. INTERVENTIONS: 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 AND SECONDARY OUTCOME MEASURES: 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 (AUC(0–∞)); AUC measured until the last quantifiable concentration (AUC(0–tz)); maximum observed concentration (C(max)); time to C(max) (T(max))). Tolerability was assessed throughout the study. RESULTS: Relative bioavailability of prolonged-release tacrolimus suspension administered orally was similar to intact capsules, with a ratio of least-square means for AUC(0–tz) and AUC(0–∞) 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). C(max) was higher for oral and nasogastric suspension (30% and 28%, respectively), and median T(max) was 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. CONCLUSIONS: 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.