Pharmacokinetics of prolonged‐release tacrolimus and implications for use in solid organ transplant recipients

Tanzi, Maria G.; Undre, Nasrullah; Keirns, James J.; Fitzsimmons, William E.; Brown, Mark; First, M. Roy

doi:10.1111/ctr.12763

Cited by 24 publications

(35 citation statements)

References 32 publications

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“…However, single 10 mg doses of tacrolimus were well tolerated in all three administrations, with similar elimination half-lives and no marked differences in the interparticipant variability of systemic exposure. Owing to demonstrated dose proportionality14 and lack of therapeutic effect of the tacrolimus excipients, similar results can be expected with other prolonged-release tacrolimus capsule strengths.…”

Section: Discussionsupporting

confidence: 64%

“…This allows the tacrolimus to be delivered over a larger part of the gastrointestinal tract. These two components can be seen in the absorption profile as a rapid increase in mean whole blood tacrolimus concentration within the first hour postadministration due to the immediate-release component, followed by a steady decline in tacrolimus levels 14. In this study, the contents of prolonged-release tacrolimus capsules were prepared as a suspension in the pharmacy and then transferred to the clinic for dosing.…”

Section: Discussionmentioning

confidence: 99%

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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

Undre

Dickinson

2017

BMJ Open

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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.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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

Undre

Dickinson

2017

BMJ Open

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“…23 The initial intention to improve compliance by once-daily dosage needs to be demonstrated. 24 Henry 25 discussed the differing toxicities between CSA and tacrolimus.…”

Section: Discussionmentioning

confidence: 99%

Cognitive Evaluation in Liver Transplant Patients Under Calcineurin Inhibitor Maintenance Therapy

Heits

Keserovic

Mund

et al. 2017

Transplantation Direct

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BackgroundNeurological disorders due to calcineurin inhibitor (CNI) treatment pose a well-known problem after liver transplantation (LTx). In this study, the impact of CNIs on cognitive functioning during maintenance therapy was analyzed. A possible improvement of cognitive functioning, compliance and health-related quality of life (HRQoL) after conversion to a once-daily tacrolimus formulation was prospectively assessed.MethodsIn a cross-section analysis cognitive functioning of living donors (LD), waiting list patients and LTx patients was tested using a 4 times trail making test (4-TTMT). In a further investigator-initiated trial a possible improvement of cognitive functioning, HRQoL and compliance after conversion to the once-daily tacrolimus formulation was prospectively assessed over 1 year. HRQoL was assessed using an EORTC-QLQ C30 questionnaire and patient’s compliance was assessed by the Basel Assessment of Compliance with Immunosuppressive Medication Scales questionnaire. Correlated data were sex, age, time after surgery, liver disease, model of end-stage liver disease score, creatinine, CNI type, and CNI trough levels.ResultsTwo hundred eleven patients were included in this cross-section analysis. Twenty-seven patients agreed to participate in the investigator-initiated trial. LTx patients completed the 4-TTMT slower than living donor patients and faster than waiting list patients. Patients with twice daily cyclosporine A (CSA) formulation needed longer to finish the 4-TTMT than patients with the once-daily tacrolimus formulation. After drug conversion of a twice-daily CNI formulation to a once-daily tacrolimus formulation, CSA-treated patients needed longer to improve their cognitive functioning. HRQoL and compliance did not improve after drug conversion.ConclusionsPatients with once-daily tacrolimus formulation had a better psychomotor speed than CSA-treated patients. The conversion to once-daily tacrolimus formulation significantly improved cognitive functioning, but had no impact on HRQoL or compliance.

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“…Could the calcineurin inhibitor (Tacrolimus) be a candidate drug for the prevention of post-ERCP pancreatitis? The majority of patients in the LT group received calcineurin inhibitor for at least 3 days before ERCP and a level of drug concentration that may be effective for the prevention of post-ERCP was probably achieved at the time of ERCP since the steady-state of calcineurin inhibitor is achieved within 5 days [23]. Since many patients undergo ERCP on an emergent basis, whether a single or double dose of the calcineurin inhibitor before ERCP could be effective for post-ERCP pancreatitis prevention will require prospective study.…”

Section: Discussionmentioning

confidence: 99%

Effect of calcineurin inhibitor on post-endoscopic retrograde cholangiopancreatography pancreatitis in patients with liver transplantation: a propensity-matched cohort study

Easler

Hajj

et al. 2020

Korean J Intern Med

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Background/Aims: A calcineurin inhibitor may alter pancreatic function and inflammatory reaction. This study aimed to determine the possible pharmacologic effect of the calcineurin inhibitor, tacrolimus, on pancreatic function, and to determine its preventive effect on post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis in liver transplantation (LT) patients. Methods: The serum amylase and lipase values before and after LT were compared. The frequency of post-ERCP pancreatitis was compared between non-LT and LT patients, using propensity score matching method. Results: Median serum amylase values (normal range, 19 to 86 U/L) were 49.0 U/L (38.0 to 68.0) before LT and 27.0 U/L (19.3 to 36.8) after LT, and median serum lipase values (normal range, 7 to 59 U/L) were 40.0 U/L (26.5 to 54.0) before LT and 10.5 U/L (6.0 to 21.0) after LT. Both serum amylase and lipase values significantly decreased after LT (p < 0.001), and to a level comparable to chronic pancreatitis.There was a marginal significant difference between the non-LT and LT groups before the propensity score matching with respect to frequency of post-ERCP pancreatitis (16 [3.2%] in non-LT group vs. 2 [0.9%] in LT group, p = 0.069). After propensity score matching, a marginal significant difference still existed with respect to frequency of post-ERCP pancreatitis (7 [4.8%] in non-LT group vs. 1 [0.7%] in LT group, p = 0.067). Conclusions:The immunosuppression with calcineurin inhibitor may reduce not only the pancreatic enzyme dynamics but also inciting inflammatory event including post-ERCP pancreatitis.

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Pharmacokinetics of prolonged‐release tacrolimus and implications for use in solid organ transplant recipients

Cited by 24 publications

References 32 publications

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

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

Cognitive Evaluation in Liver Transplant Patients Under Calcineurin Inhibitor Maintenance Therapy

Effect of calcineurin inhibitor on post-endoscopic retrograde cholangiopancreatography pancreatitis in patients with liver transplantation: a propensity-matched cohort study

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