Conversion of Stable Liver Transplant Recipients From a Twice-Daily Prograf-Based Regimen to a Once-Daily Modified Release Tacrolimus-Based Regimen

Florman, Sander; Alloway, Rita R.; Kalayoğlu, Münci; Lake, K.; Bak, Thomas; Klein, Anders Bue; Klintmalm, Goran; Busque, Stéphan; Brandenhagen, D.; Lake, John R.; Wisemandle, K.; Fitzsimmons, William E.; First, M. Roy

doi:10.1016/j.transproceed.2004.11.086

Cited by 89 publications

(84 citation statements)

References 3 publications

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“…Three studies reported that within-subject variability [percentage coefficient of variation (% CV)] in AUC 0-24 or C min decreased significantly following conversion from Prograf Ò to Advagraf Ò [28,35,43], while two studies could find no significant difference [31,45]. Conversion from Prograf Ò to Advagraf Ò resulted in a significant reduction in within-subject variability in tacrolimus AUC 0-24 from 14.1 to 10.9 % (but no reduction in C min ) in a study involving 40 stable kidney transplant recipients, assessed using five AUC values for each dosing regimen [28], and a reduction in tacrolimus C min from 14.0 to 8.5 % in a study involving 129 stable kidney transplant recipients [35].…”

Section: Xrmentioning

confidence: 99%

“…Conversion from Prograf Ò to Advagraf Ò resulted in a significant reduction in within-subject variability in tacrolimus AUC 0-24 from 14.1 to 10.9 % (but no reduction in C min ) in a study involving 40 stable kidney transplant recipients, assessed using five AUC values for each dosing regimen [28], and a reduction in tacrolimus C min from 14.0 to 8.5 % in a study involving 129 stable kidney transplant recipients [35]. Two studies reported significantly less within-subject variation in exposure after conversion to MR tacrolimus but provided no actual numerical data [43,60]. Another study reported similar within-and betweensubject variability between Prograf Ò and Advagraf Ò formulations [31].…”

Section: Xrmentioning

confidence: 99%

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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: Xrmentioning

confidence: 99%

Section: Xrmentioning

confidence: 99%

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

Staatz

Tett

2015

Clin Pharmacokinet

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“…A new prolonged release formulation of tacrolimus was recently developed as a once-daily formulation (Advagraf Ò ) (First 2008;Florman et al 2005). Therapeutic regimens for transplants recipients are often complex, contributing to a high incidence of medication non compliance and as consequences an increased mortality and morbidity.…”

Section: Discussionmentioning

confidence: 99%

Prediction tacrolimus blood levels based on the Bayesian method in adult kidney transplant patients

Antignac

Fernandez

Barrou

et al. 2011

Eur J Drug Metab Pharmacokinet

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The use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. We have previously described a tacrolimus population pharmacokinetics model obtained in an adult kidney transplant cohort. The aims of the present study were (1) to validate that model using an external dataset and (2) to evaluate the prediction using a Bayesian method. Data were retrospectively collected from 34 adult patients receiving kidney transplantation. Trough blood concentrations of tacrolimus were predicted using the empirical Bayesian method with sparse samples obtained during the previous week. The system performance was evaluated by the mean prediction error (ME), mean absolute prediction error (MAE). and root mean square error (RMSE). Patients were administrated oral or intravenous tacrolimus as part of a triple immunosuppressive regimen with mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity and by routine therapeutic drug monitoring. In our previous model, clearance increased with post transplantation days and with prednisone dosage. Concentrations predicted by the population mean pharmacokinetic parameter values match well with observed concentrations during oral therapy. Bayesian prediction using trough concentrations obtained after 21 days of treatment significantly decreased ME, MAE, and RMSE compared with predictions from data including this period. After 21 days of treatment, there was an insignificant bias ME (0.22 ± 2.59 ng/ml), a reasonable precision MAE (1.97 ± 1.69 ng/ml) and RMSE (1.28 ± 0.58 ng/ml). The present study demonstrates the suitability of the Bayesian method for the prediction of trough blood concentrations of tacrolimus using only few samples in adult kidney transplantation recipients.

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“…The AUCs of tacrolimus are known to correlate highly with trough concentrations after dosing of a standard twice-daily formulation, it can easily be speculated that the AUC of tacrolimus may be associated Florman et al, 2005;Dansirikul et al, 2006;Masuda and Inui, 2006). Because AUC measurement for tacrolimus is complicated and AUC and efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…We have hypothesized that the maximal blood concentration (Cmax) of tacrolimus may be closely related to its toxicity. In addition, since there is a high correlation between the tacrolimus concentration-time area under the curve (AUC) and its trough concentration, tacrolimus concentration et al, 2005;Florman et al, 2005;Dansirikul et al, 2006;Masuda and Inui, 2006). If this hypothesis is valid, a sustainedrelease formulation would be less toxic because the Cmax would be lower.…”

Section: Introductionmentioning

confidence: 99%

Effect of pharmacokinetic profile on the pancreatic toxicity and efficacy of tacrolimus in rats

et al. 2008

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ABSTRACTmg/kg/day were given once daily for 8 days in the bolus intravenous injection groups. In the continuous intravenous infusion groups, tacrolimus was infused using an Alzet ® osmotic mini-pump for 9 days at the same doses. Pancreatic insulin content decreased dose-dependently in both the bolus intravenous injection -es caused by the two dosing regimens. At 0.03 mg/kg, continuous intravenous infusion did not cause glu--erance. The pharmacokinetic data indicated that continuous intravenous infusion resulted in a sustained blood drug concentration with an area under the curve (AUC) similar to that obtained with the bolus thoraxes of recipients. Tacrolimus doses of 0.01, 0.1, or 1 mg/kg/day were administered from day 0 to day 13. Both bolus intramuscular administration and continuous intravenous infusion prolonged skin allograft groups given the same doses. To summarize, the sustained-release of tacrolimus resulted in a steady blood drug concentration with an AUC similar to that of the bolus administration. In rats, it was better tolerated -tion (Cmax). These results indicate that the sustained-release formulation has the potential to improve the safety of tacrolimus.

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Conversion of Stable Liver Transplant Recipients From a Twice-Daily Prograf-Based Regimen to a Once-Daily Modified Release Tacrolimus-Based Regimen

Abstract: The steady-state tacrolimus exposure of MR tacrolimus once daily is equivalent to Prograf twice a day after a milligram-for-milligram conversion in stable liver transplant recipients.

Cited by 89 publications

References 3 publications

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

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

Prediction tacrolimus blood levels based on the Bayesian method in adult kidney transplant patients

Effect of pharmacokinetic profile on the pancreatic toxicity and efficacy of tacrolimus in rats

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