Pharmacokinetics of Tacrolimus in Kidney Transplant Recipients: Twice Daily Versus Once Daily Dosing (original) (raw)
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American Journal of Transplantation, 2009
Tacrolimus, a cornerstone immunosuppressant, is widely available as a twice-daily formulation (Tacrolimus BID). A once-daily prolonged-release formulation (Tacrolimus QD) has been developed that may improve adherence and impart long-lasting graft protection. This study compared the pharmacokinetics (PK) of tacrolimus in de novo kidney transplant patients treated with Tacrolimus QD or Tacrolimus BID. A 6-week, open-label, randomized comparative study was conducted in centers in Europe and Australia. Eligible patients received Tacrolimus QD or Tacrolimus BID. PK profiles were obtained following the first tacrolimus dose (day 1), and twice under steady-state conditions. As secondary objectives, efficacy and safety parameters were also evaluated. Sixty-six patients completed all PK profiles (34 Tacrolimus QD, 32 Tacrolimus BID). Mean AUC0–24 of tacrolimus on day 1 was approximately 30% lower for Tacrolimus QD than Tacrolimus BID (232 and 361 ng.h/mL, respectively), but was comparable by day 4. There was a good correlation and a similar relationship between AUC0–24 and Cmin for both formulations. Efficacy and safety data were also comparable over the 6-week period. Tacrolimus QD can be administered once daily in the morning on the basis of the same systemic exposure and therapeutic drug monitoring concept as Tacrolimus BID.
Advances in Therapy
Introduction: Different prolonged-release formulations of tacrolimus are available. To date, the pharmacokinetic (PK) profile of LCP-tacrolimus (LCPT; Envarsus Ò) has not been compared with PR-Tac (Advagraf Ò) in de novo kidney transplant recipients. These profiles will guide clinical recommendations for the initiation and dose titration strategies of once-daily tacrolimus formulations. Methods: This randomized, parallel-group, open-label, multicenter PK study randomized 75 de novo, adult, white kidney transplant recipients to LCPT 0.17 mg/kg/day (n = 37) or within the pre-defined therapeutic tacrolimus trough blood concentration range, with \ 12% in each group having below-target trough levels over the study period. LCPT demonstrated * 30% greater relative bioavailability [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 1.32 (p = 0.007); day 7, 1.25 (p = 0.051); day 14, 1.43 (p = 0.002)] and * 30% lower peak-to-trough percentage fluctuation of blood concentration [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 0.70 (p \ 0.001); day 7, 0.68 (p \ 0.001); day 14, 0.73 (p = 0.004)] in addition to longer time to maximum blood concentration (t max), lower maximum concentration (C max) and a consistently lower daily dose (* 40% dose reduction with LCPT vs. PR-Tac by day 28). Safety profiles were similar. Conclusion: In de novo kidney transplant recipients, prolonged-release formulations of tacrolimus can reach therapeutic concentrations in the immediate post-transplant period. LCPT has greater relative bioavailability and lower peak-to-trough fluctuation compared with PR-Tac.
Basic & Clinical Pharmacology & Toxicology, 2010
Monitoring of tacrolimus blood concentration is of utmost importance in the management of renal transplant recipients because of Narrow Therapeutic Index and highly variable pharmacokinetics. The aim of this study was to detect inter-patient pharmacokinetic variability of tacrolimus and to assess the predictability of individual tacrolimus concentrations at various times of the area under the curve (AUC) seeking to find the best sampling time to predict the exposure of tacrolimus in renal transplant recipients with triple therapy. This oral dose tacrolimus pharmacokinetics study was conducted in 18 Serbian renal transplant recipients on triple immunosuppressive therapy, including basiliximab. The first oral dose of tacrolimus (0.05 mg ⁄ kg) was given on day 5 post-transplant; blood concentration was measured by microparticle enzyme immunoassay method. Associations between each sampling time-point of concentrations and AUC 12 were evaluated by Pearson correlation coefficients. Abbreviated sampling equations were derived by multiple, stepwise regression analyses. The variance in the strength of association between predicted AUC (AUC p ) and AUC 12 was reflected by linear regression coefficients. AUC 12 showed remarkable inter-individual variations after the first oral dose of tacrolimus. The area of the maximum AUC was four times higher than that of the minimum AUC. C 4 seems to be an indicator of total body exposure to tacrolimus. Alternatively, the concentrations at 1.5, 4 and 8 hr as an abbreviated AUC were as good a predictor as a full pharmacokinetic study. Our results show a significant difference between men and women. A three-point sampling method seemed to be the best abbreviated AUC for a cost-effective tacrolimus monitoring strategy.
Pharmacokinetics of tacrolimus in adult renal transplant recipients
Drug Metabolism and Drug Interactions, 2012
Background: The success of an immunosuppressive drug therapy depends on the extent of exposure to the drugs (the blood levels and duration), which is measured as the area under the curve (AUC). Tacrolimus shows considerable variability in its pharmacokinetics, with poor correlation between the tacrolimus trough level and systemic exposure, as measured by the AUC of concentration time. Monitoring trough levels helps not only in reducing nephrotoxiicity but also in reducing the chances of acute rejection; although there is no international consensus, the trough concentration is used to determine dosing and the AUC for calculating the exposure of the patient to the drug. The major objective of this study was to find the best sampling time for an abbreviated AUC 0-6 (area under the concentration time curve) to predict the total body exposure to tacrolimus in adult renal transplantation recipients. Methods: The study involved retrospective analysis of 14 renal transplant patients (2 female and 12 male) that were on triple immunosuppressive therapy, methyl prednisolone, mycophenolate mofetil and tacrolimus. To determine trough concentrations, blood samples were collected before administration of tacrolimus (0 h) and at fixed time points of 2 h, 4 h and 6 h after administration of oral tacrolimus and analyzed in duplicate by microparticle enzyme immunoassay. AUC 0-6 was determined using the linear trapezoidal rule. The association between the blood concentration and AUC 6 were evaluated by the Pearson correlation coefficient. All statistical analyses were performed using the SPSS software (IBM Corp., NY, USA) program. Results: Trough levels were fairly consistent at 7.9-18 ng. h/mL in all the patients included in this study, and this did not show variation with age or sex. The AUC 0-6 was higher [202-290 ng/mL at 3-8 mg bis-daily (b.d.) dosage] in patients who received kidneys from cadavers compared to recipients from live donors (60.5-171 ng/ mL at 3-8 mg b.d. dosage), but the clinical significance of this is not known. The highest AUC 0-6 was 246 ng/mL, observed at 4.5 mg b.d. dosage. Dosages higher than 2 mg b.d. did not result in a noticeable increase in AUC 0-6. Peak blood levels of tacrolimus were obtained 4 h after administration. Conclusions: Trough level determination and a C2, C4 two-point limited sampling strategy may be useful to plan the dosing strategy and estimate the exposure of renal transplant patients to tacrolimus.
Transplantation Proceedings, 2011
Numerous evidence has been reported to support a safe 1:1 conversion from the twice-daily tacrolimus (Tac-T) to the once-daily tacrolimus regimen (Tac-O), but frequently there is a reduction in drug trough levels, which has been estimated by some authors to be about 20%. The relationship between Tac-O dosage and trough levels after conversion is not clear. The tacrolimus trough levels-to-dose ratio has been applied to better define the wide variability in doses and blood levels of tacrolimus. The aim of this study was to evaluate tacrolimus trough levels, tacrolimus daily dosage, and tacrolimus level-to-dose ratio during 1 year pre-postconversion follow-up in 31 stable kidney transplant patients who had received Tac-T therapy for over 6 months with stable renal function. They were converted to the same dosage of Tac-O. Patients before and after conversion were their own controls. The trough levels of tacrolimus showed a slight albeit significant reduction after conversion, remaining in the therapeutic range. Nineteen percent underwent an adjustment in total daily dosage after conversion versus 39% before conversion with no significant difference. No significant differences were detected in the total daily dose administered either by tacrolimus level-to-dose ratio before or after conversion. Kidney transplant recipients under Tac-O therapy were safely maintained using the same therapeutic monitoring as when receiving Tac-T.
Medical journal of Bakirköy, 2022
Objective: Tacrolimus is used in more than 80% of kidney transplant recipients due to its ability to avoid rejection. Irregularities in tacrolimus level may affect clinical outcomes by subjecting patients to adverse events associated with graft rejection or immunosuppressive therapy. There are two forms of tacrolimus; immediate-release (IR-T) and prolonged release (PR-T). This study is designed to compare the clinical follow-up of kidney transplant patients who are receiving prolonged-release (PR-T; Advagraf) and immediate-release (IR-T; Prograf) tacrolimus in the posttransplant first week. Methods: This study included 78 de novo, adult kidney transplant patients to prolonged-release tacrolimus 0.15 mg/kg/day (group 1, n=39) and immediate-release tacrolimus 0.15 mg/kg/day (group 2, n=39) for the first week in the posttransplant period. Demographic features, whole blood tacrolimus levels and kidney function were compared between the two groups. The presence of acute rejection and adverse events, antihypertensive drug use and arterial blood pressure of all patients were considered. Drug doses were determined according to the previously targeted tacrolimus level. SPSS 22 for Windows was used for statistical analysis. Results: Acute rejection was not seen in any patient and there were no adverse events in the posttransplant first week. However, group 2 patients were found to have higher tacrolimus levels on the posttransplant 1 st , 4 th and 7 th days (p=0.02, p=0.009 and p=0.013 respectively). Serum creatinine levels were significantly increased in group 2 patients on the posttransplant 7 th day (p=0.02). Systolic, diastolic or mean arterial blood pressure were not different between the groups. Conclusion: Prolonged-release tacrolimus is effective in preventing acute rejection when adequate blood levels are maintained, and appears promising as it makes it possible to avoid interindividual variation in absorption and early calcineurin inhibitor toxicity.
Hospital Pharmacology - International Multidisciplinary Journal, 2019
Introduction: Two most common pharmaceutical formulation of tacrolimus (Tac) used after kidney transplantation (Tx) are immediate-release one, administered twice-daily (Tac-TD), and prolonged-release one, administered once-daily (Tac-OD). Aim: The aim of this study was to compare daily doses, trough concentrations (C 0) and dose-adjusted trough concentrations (C 0 /D) of Tac between patients who administered diff erent drug formulations, Tac-TD or Tac-OD, during the fi rst year after Tx. Additionally, the aim of the study was to compare the distribution of C 0 within and beyond the target therapeutic range (8-12 ng/mL for the fi rst 90 days and 6-10 ng/mL afterwards) after the administration of diff erent drug formulations. Subjects and Methods: A retrospective pharmacokinetic study included 84 patients (56 on Tac-TD and 28 on Tac-OD), with a follow-up period between the fi rst and twelfth month post-transplantation. Following pharmacokinetic data were used: daily dose, daily dose according to patient's body weight, concentration C 0 and C 0 /D of Tac. Results: Тhe results of the study showed that patients on Tac-OD formulation had higher daily doses and higher C 0 during 4-6 months (p<0.01) and 7-12 months (p<0.01) after Tx. Patients on Tac-OD had lower C 0 /D during 4-6 months (p<0.05) and 7-12 months (p<0.01) after Tx. C 0 in Tac-TD patients was signifi cantly more frequently below the target range, whereas in Tac-OD patients C 0 was more frequently above the target range, while both patient groups had equal distribution of C 0 within the target range of Tac in the period between 4 th and 12 th month post-transplantation (p<0.01). Conclusions: The conducted research suggests that patients on Tac-OD preparation may require higher daily doses of Tac compared to patients on Tac-TD preparation in order to maintain optimal immunosuppression in the late post-transplant period.