Assessment of Tacrolimus Absorption From the Human Intestinal Tract: Open-Label, Randomized, 4-Way Crossover Study

Tsunashima, Daisuke; Kawamura, Akio; Murakami, Manabu; Sawamoto, Taiji; Undre, N.; Brown, Mark; Groenewoud, Albert; Keirns, James J.; Holman, John; Connor, Alyson; Wylde, Hannah; Wilding, Ian R.; Ogawara, Ken Ichi; Sako, Kazuhiro; Higaki, Kazutaka; First, Roy

doi:10.1016/j.clinthera.2014.02.021

Cited by 45 publications

(34 citation statements)

References 28 publications

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“…Tacrolimus was shown to be able to be absorbed from the duodenum to the colon in six healthy white male subjects [76]. A change in the primary site of release of tacrolimus could potentially cause differences in the impact of gastrointestinal metabolic enzymes and gastrointestinal motility (affected by conditions such as diarrhoea or diabetes) on tacrolimus pharmacokinetics with the different formulations.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Clinical Pharmacokinetics of Once-Daily Tacrolimus in Solid-Organ Transplant Patients

Staatz

Tett

2015

Clin Pharmacokinet

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Tacrolimus is a pivotal immunosuppressant agent used in solid-organ transplantation. It was originally formulated for oral administration as Prograf(®), a twice-daily immediate-release capsule. In an attempt to improve patient adherence, retain manufacturer market share and/or reduce health care costs, newer once-daily prolonged-release formulations of tacrolimus (Advagraf(®) and Envarsus(®) XR) and various generic versions of Prograf(®) are becoming available. Tacrolimus has a narrow therapeutic index. Small variations in drug exposure due to formulation differences can have a significant impact on patient outcomes. The aim of this review is to critically analyse the published data on the clinical pharmacokinetics of once-daily tacrolimus in solid-organ transplant patients. Forty-three traditional (non-compartmental) and five population pharmacokinetic studies were identified and evaluated. On the basis of the stricter criteria for narrow-therapeutic-index drugs, Prograf(®), Advagraf(®) and Envarsus(®) XR are not bioequivalent [in terms of the area under the concentration-time curve from 0 to 24 h (AUC0-24) or the minimum concentration (C min)]. Patients may require a daily dosage increase if converted from Prograf(®) to Advagraf(®), while a daily dosage reduction appears necessary for conversion from Prograf(®) to Envarsus(®) XR. Prograf(®) itself, or generic immediate-release tacrolimus, can be administered in a once-daily regimen with a lower than double daily dose being reported to give 24-h exposure equivalent to that of a twice-daily regimen. Intense clinical and concentration monitoring is prudent in the first few months after any conversion to once-daily tacrolimus dosing; however, there is no guarantee that therapeutic drug monitoring strategies applicable to one formulation (or twice-daily dosing) will be equally applicable to another. The correlation between the tacrolimus AUC0-24 and C min is variable and not strong for all three formulations, indicating that trough measurements may not always give a good indication of overall drug exposure. Further investigation is required into whether the prolonged-release formulations have reduced within-subject pharmacokinetic variability, which would be a distinct advantage. Whether the effects of factors that influence tacrolimus absorption and pre-systemic metabolism (patient genotype status; gastrointestinal disease and disorders) and drug interactions differ across the formulations needs to be further elucidated. Most pharmacokinetic comparison studies to date have involved relatively stable patients, and many have been sponsored by the pharmaceutical companies manufacturing the new formulations. Larger randomized, controlled trials are needed in different transplant populations to determine whether there are differences in efficacy and toxicity across the formulations and whether formulation conversion is worthwhile in the longer term. While it has been suggested that once-daily administration of tacrolimus may improve patient compliance, further studies a...

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Section: Pharmacokineticsmentioning

confidence: 99%

Clinical Pharmacokinetics of Once-Daily Tacrolimus in Solid-Organ Transplant Patients

Staatz

Tett

2015

Clin Pharmacokinet

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“…Tacrolimus, a BCS class II compound (low solubility, high permeability), was administered as extended release formulation (which has become standard of care in our renal transplant patients) and likely has a large absorptive window over a substantial part of the intestine. Because CYP3A4 content in enterocytes decreases from proximal to distal intestine, tacrolimus absorption is at least comparable in the distal compared with the proximal intestine . If distal absorption of tacrolimus is less dependent on CYP3A4, this may blunt the effect of pharmacological CYP3A4 inhibition on the overall disposition of the drug.…”

Section: Discussionmentioning

confidence: 99%

In vivo CYP3A4 activity does not predict the magnitude of interaction between itraconazole and tacrolimus from an extended release formulation

Vanhove

Annaert

Knops

et al. 2018

Basic Clin Pharma Tox

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The magnitude of interaction between the CYP3A4 substrate tacrolimus and various CYP3A4 inhibitors is highly unpredictable. We investigated whether an individual's baseline in vivo CYP3A4 activity, assessed using the oral midazolam (MDZ) probe, could be used to predict the magnitude of drug-drug interaction between tacrolimus and the potent CYP3A4 inhibitor itraconazole. In a prospective single-arm open-label study, 16 healthy volunteers were administered single doses of MDZ and tacrolimus before and after a 4-day course of itraconazole. Itraconazole treatment resulted in a 9.0-fold decrease in MDZ apparent oral clearance (CL/F) and a 3.3-fold decrease in tacrolimus CL/F (P < 0.001 for each). MDZ CL/F and tacrolimus CL/F were positively correlated both at baseline (r = 0.582, P = 0.018) and after itraconazole (r = 0.811, P < 0.001). Furthermore, baseline MDZ CL/F was positively correlated to the fold change in MDZ CL/F resulting from CYP3A4 inhibition (r = 0.759, P = 0.001). However, no predictors of change in tacrolimus CL/F resulting from CYP3A4 inhibition were identified, including baseline MDZ CL/F (P = 0.453), baseline tacrolimus CL/F (P = 0.759) and fold change in MDZ CL/F between both phases (P = 0.274). In conclusion, baseline oral MDZ clearance does not predict the magnitude of interaction between tacrolimus and itraconazole.

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“…The study design for these simulations, including the proportion of male and female subjects tested, was based on the information reported in the reference clinical trial publications (Table ). (El Messaoudi et al, ; Snell et al, ; Tsunashima et al, ). The Simcyp simulator has a built‐in substrate profile for metformin.…”

Section: Methodsmentioning

confidence: 99%

“…Based on study design in reference (Tsunashima et al, ), proportion of males in simulation was 100%.…”

Section: Methodsmentioning

confidence: 99%

Application of physiologically based pharmacokinetic modeling to predict drug disposition in pregnant populations

Jogiraju

Avvari

Gollen

et al. 2017

Biopharm & Drug Disp

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Pregnancy is associated with numerous physiological changes that influence absorption, distribution, metabolism and excretion. Moreover, the magnitude of these effects changes as pregnancy matures. For most medications, there is limited information available about changes in drug disposition that can occur in pregnant patients, yet most women are prescribed one or more medications during pregnancy. In this investigation, PBPK modeling was used to assess the impact of pregnancy on the pharmacokinetic profiles of three medications (metformin, tacrolimus, oseltamivir) using the Simcyp® simulator. The Simcyp pregnancy-PBPK model accounts for the known physiological changes that occur during pregnancy. For each medication, plasma concentration-time profiles were simulated using Simcyp® virtual populations of healthy volunteers and pregnant patients. The predicted systemic exposure metrics (C , AUC) were compared with published clinical data, and the fold error (FE, ratio of predicted and observed data) was calculated. The PBPK model was able to capture the observed changes in C and AUC across each trimester of pregnancy compared with post-partum for metformin (FE range 0.86-1.19), tacrolimus (FE range 1.03-1.64) and oseltamivir (FE range 0.54-1.02). Simcyp model outputs were used to correlate these findings with pregnancy-induced alterations in renal blood flow (metformin, oseltamivir), hepatic CYP3A4 activity (tacrolimus) and reduced plasma protein levels and hemodilution (tacrolimus). The results illustrate how PBPK modeling can help to establish appropriate dosing guidelines for pregnant patients and to predict potential changes in systemic exposure during pregnancy for compounds undergoing clinical development.

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Assessment of Tacrolimus Absorption From the Human Intestinal Tract: Open-Label, Randomized, 4-Way Crossover Study

Cited by 45 publications

References 28 publications

Clinical Pharmacokinetics of Once-Daily Tacrolimus in Solid-Organ Transplant Patients

Clinical Pharmacokinetics of Once-Daily Tacrolimus in Solid-Organ Transplant Patients

In vivo CYP3A4 activity does not predict the magnitude of interaction between itraconazole and tacrolimus from an extended release formulation

Application of physiologically based pharmacokinetic modeling to predict drug disposition in pregnant populations

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