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Abstract
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 (AUC0–∞); AUC measured until the last quantifiable concentration (AUC0–tz); maximum observed concentration (Cmax); time to Cmax (Tmax)). 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 AUC0–tz and 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). Cmax was higher for oral and nasogastric suspension (30% and 28%, respectively), and median Tmax 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.
- intact capsule
- healthy subjects
- nasogastric tube
- prolonged-release tacrolimus
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Footnotes
Contributors NU was involved in the conception and design of the study. JD was involved in project management of the study. Both authors were involved in the writing of the paper and approved the final version of the manuscript for submission.
Funding The study was funded by Fujisawa GmbH. Astellas Pharma was formed following the merger of Yamanouchi Pharmaceutical and Fujisawa Pharmaceutical in 2005. Astellas Pharma Europe BV is the manufacturer of prolonged-release tacrolimus (Advagraf). Editorial support was funded by Astellas Pharma Europe.
Competing interests The authors of this manuscript have the following disclosures: NU is employed by Astellas.
Ethics approval Local independent ethics committee.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement No additional data are available.