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

ObjectiveTacrolimus, 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.DesignA phase 1, open-label, single-dose, cross-over study.SettingA single clinical research unit.ParticipantsIn total, 20 male participants, 18–55 years old, entered and completed the study.InterventionsAll 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 measuresPrimary 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.ResultsRelative 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.ConclusionsCompared 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.

Pharmacokinetic Profile of Prolonged-Release Tacrolimus When Administered via Nasogastric Tube in De Novo Liver Transplantation: A Sub-Study of the DIAMOND Trial

“…A previous Phase I study [14] compared systemic exposure of tacrolimus after administration of the contents of prolonged-release tacrolimus capsules via intact capsules, oral suspension, or nasogastric suspension in healthy volunteers. The data indicated that administration of prolonged-release tacrolimus suspension, orally or via nasogastric tube, resulted in a faster absorption profile (shorter T max and higher C max ) compared with intact capsules.…”

“…The data indicated that administration of prolonged-release tacrolimus suspension, orally or via nasogastric tube, resulted in a faster absorption profile (shorter T max and higher C max ) compared with intact capsules. Mean exposure (estimated using AUC) was approximately 17% lower for nasogastric tube administration compared with intact capsules [14]. The authors speculated that incomplete tacrolimus absorption profiles were recorded for the participants who reached C max at the first blood-sampling time point, leading to an underestimation of the overall systemic exposure to tacrolimus.…”

“…When comparing the DIAMOND PK sub-study data for Day 1 with data from healthy volunteers [14], the median T max following nasogastric administration of prolonged-release tacrolimus on Day 1 in patients undergoing de novo liver transplantation was longer (2.5 h) vs. that in healthy volunteers (0.5 h). This suggests a more ‘normal’ absorption profile of prolonged-release tacrolimus when administered via nasogastric tube in liver transplant patients compared with healthy subjects.…”

“…In current clinical practice, this is also the case with the prolonged-release tacrolimus capsule formulation. It is, therefore, important to assess the PK profile of tacrolimus when the contents of prolonged-release capsules are administered via a nasogastric tube [14].…”

“…A previous Phase I study designed to assess the PK profile of tacrolimus administered to 20 healthy male volunteers found that when prolonged-release tacrolimus capsules were opened, and a suspension was prepared and administered via a nasogastric tube, there was a 28% increase in C max , a 75% faster T max , and a 17% lower AUC 0–∞ of tacrolimus relative to intact capsules [14]. The study suggested that creating a suspension of prolonged-release tacrolimus may dissolve the more immediate-release component of the formulation before administration, potentially resulting in a more rapid absorption rate compared with intact capsules [14]. However, the PK profile of prolonged-release tacrolimus administered by nasogastric tube immediately post-liver transplant has not previously been reported.…”