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Mechanism of Action
Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin inhibited. This effect may prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression).
Table 6 summarizes the pharmacokinetic (PK) parameters of tacrolimus following oral administration of ASTAGRAF XL in healthy subjects and in kidney transplant patients. Whole blood tacrolimus concentrations in these pharmacokinetic studies were measured using validated HPLC/MS/MS assays.
Table 6: Pharmacokinetic Parameters of ASTAGRAF XL
Once Daily in Healthy Subjects and in Kidney Transplant Patients (Under Fasted
Conditions), and Statistical Comparison of PK Parameters with Prograf® Twice
|Population||N||ASTAGRAF XL Dosea||Dayb||Pharmacokinetic Parameters of ASTAGRAF XL and ASTAGRAF XL:Prograf ratio (90% CI for ratio)e|
|Cmaxc (ng/mL)||Tmaxd (hr)||AUC24c (ng•hr/mL)||C24g (ng/mL)|
|Healthy Subjects||24||4 mg||Day 1||6.2 ± 2.1||2.0 [1.0-5.0]||74 ± 22||2.3 ± 0.8|
|4 mg||Day 10||11.6 ± 3.4||2.0 [1.0-3.0]||155 ± 46||4.7 ± 1.5|
|Ratio (90% CI)|
|Day 1||0.67 (0.59 - 0.75)||1.02 (0.91 - 1.13)||0.81 (0.72 - 0.92)|
|Day 10||0.74 (0.69 - 0.80)||0.93 (0.87-0.99)||0.87 (0.81 - 0.94)|
|Adult||17||0.20 mg/kg||Day 1||26.0 ± 13.7||3.0 [2-24]||372 ± 202||12.1 ± 7.2|
|Kidney||0.19 mg/kg||Day 3||31.0 ± 13.9||2.0 [0.5-2.0]||437 ± 175||13.5 ± 5.6|
|De novof||0.18 mg/kg||Day 7||32.2 ± 10.2||2.0 [1-6]||405±117||11.4 ± 4.0|
|0.18 mg/kg||Day 14||32.7 ± 9.0||2.0 [1-4]||412± 109||11.2 ± 3.9|
|Ratio (90% CI)|
|Day 1||0.86 (0.63 - 1.19)||0.84 (0.63 - 1.12)||0.85 (0.59 - 1.17)|
|Day 3||0.93 (0.71 - 1.21)||1.05 (0.82 - 1.33)||1.04 (0.79 - 1.36)|
|Day 7||1.14 (0.95 - 1.38)||1.22 (1.02 - 1.46)||1.14 (0.90 - 1.44)|
|Day 14||1.27 (1.03 - 1.57)||1.21 (1.02 - 1.42)||0.99 (0.82 - 1.20)|
|Adult Kidney ( ≥ 6 months posttransplant)||60||5.2 mg/dayh||Day 14h||16.1 ± 5.3||2.0 [1.0 - 6.0]||222 ± 64||6.7 ± 1.9i|
|a Healthy adult subjects (actual administered dose of
ASTAGRAF XL and Prograf); Adult de novo kidney transplant patients (actual
group mean dose of ASTAGRAF XL, corresponding doses for Prograf on Days 1, 3, 7
and 14 were 0.20, 0.18, 0.16, and 0.17 mg/kg/day, respectively)
b Day of ASTAGRAF XL treatment and PK profiling
c Arithmetic means ± S.D.
d Median [range]
e Ratio of geometric least square means
f PK substudy of Study 2
g Tacrolimus trough concentration before the next dose
h same daily dose of ASTAGRAF XL for 14 day period
i the correlation coefficient of AUC24 to Cmin r= 0.88
In de novo adult kidney transplant recipients, the tacrolimus systemic exposure, as assessed by dose-adjusted AUC24, for ASTAGRAF XL once daily on Day 1 post-transplant was 16% lower when compared with Prograf twice daily. By Day 3 post-transplant, the dose-adjusted AUC24 was similar between the two formulations. On Day 14, the dose-adjusted AUC24 was 21% higher than Prograf, at comparable trough concentrations (C24).
Due to intersubject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy [see DOSAGE AND ADMINISTRATION].
Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics.
The presence of a meal affects the absorption of tacrolimus; the rate and extent of absorption is greatest under fasted conditions. In 24 healthy subjects, administration of ASTAGRAF XL immediately following a high-fat meal (150 protein calories, 250 carbohydrate calories, and 500 to 600 fat calories) reduced the Cmax, AUCt, and AUCinf of tacrolimus by approximately 25% compared with fasting values. Food delayed the median Tmax from 2 hours in the fasted state to 4 hours in the fed state; however, the terminal half-life remained 36 hours regardless of dosing conditions. The time when a meal is consumed also affected tacrolimus bioavailability. In 24 healthy subjects, when ASTAGRAF XL was administered 1.5 hours after consumption of a high-fat breakfast, tacrolimus exposure was decreased approximately 35%. Administration of ASTAGRAF XL 1 hour prior to a high-fat breakfast reduced tacrolimus exposure by 10%. ASTAGRAF XL capsules should be taken preferably on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal.
In 23 healthy subjects, a diurnal effect on the absorption of tacrolimus was observed. Evening dosing of ASTAGRAF XL reduced AUCinf by 35% relative to morning dosing. ASTAGRAF XL capsules should be taken consistently at the same time every morning.
The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a U.S. trial in which tacrolimus was administered as Prograf, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).
The desired pharmacological activity of tacrolimus is primarily due to the parent drug. Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31demethyl metabolite has been reported to have the same activity as tacrolimus.
The mean clearance following IV administration of tacrolimus is 0.040, and 0.083 L/hr/kg in healthy subjects, and adult kidney transplant patients, respectively. In man, less than 1% of the dose administered is excreted unchanged in urine.
In a mass balance study of IV-administered radiolabeled tacrolimus to 6 healthy subjects, the mean recovery of radiolabel was 77.8 ± 12.7% with the feces accounting for 92.4 ± 1.0% of the total recovery. The elimination half-life based on radioactivity was 48.1 ± 15.9 hours whereas it was 43.5 ± 11.6 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.029 ± 0.015 L/hr/kg and the mean clearance of tacrolimus was 0.029 ± 0.009 L/hr/kg. When administered orally (radiolabeled tacrolimus), the mean recovery of the radiolabel was 94.9 ± 30.7%. Fecal elimination accounted for 92.6 ± 30.7% and urinary elimination accounted for 2.3 ± 1.1% of the total radiolabel administered. The elimination half-life based on radioactivity was 31.9 ± 10.5 hours, whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and the mean clearance of tacrolimus was 0.172 ± 0.088 L/hr/kg.
The elimination half-life of tacrolimus after oral administration of 4 mg ASTAGRAF XL daily for 10 days was 37.9 ± 3.4 hours in 24 healthy subjects.
Renal and Hepatic Impairment
Tacrolimus pharmacokinetics following a single administration of Prograf injection (administered as a continuous IV infusion) were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9 ± 1.6 and 12.0 ± 2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in healthy subjects [see DOSAGE AND ADMINISTRATION, Use In Specific Populations].
Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations of Prograf. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in healthy subjects. Tacrolimus pharmacokinetics were studied in 6 patients with severe hepatic dysfunction (mean Pugh score: > 10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].
African-American patients may require higher ASTAGRAF XL doses to attain similar trough concentrations as Caucasian patients [see DOSAGE AND ADMINISTRATION, Use In Specific Populations, Clinical Studies].
The pharmacokinetics of tacrolimus have been studied following single IV and oral administration of Prograf in 10 African-American, 12 Latino-American, and 12 Caucasian healthy subjects. There were no significant pharmacokinetic differences among the three ethnic groups following a 4-hour IV infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean (±SD) tacrolimus Cmax in African-Americans (23.6±12.1 ng/mL) was lower than in Caucasians (40.2±12.6 ng/mL) and Latino-Americans (36.2±15.8 ng/mL) . Mean AUC0-inf tended to be lower in African-Americans (203±115 ng·hr/mL) than Caucasians (344±186 ng·hr/mL) and Latino-Americans (274±150 ng·hr/mL). The mean (±SD) absolute oral bioavailability (F) in African-Americans (12±4.5%) and Latino-Americans (14±7.4%) was lower than in Caucasians (19±5.8%). There was no significant difference in mean terminal half-life among the three ethnic groups (range from approximately 25 to 30 hours).
A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in total mg daily doses between male and female patients receiving ASTAGRAF XL in the kidney transplant trials. A retrospective comparison of pharmacokinetics in healthy subjects, and in kidney transplant patients indicated no gender-based differences.
Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when concomitant use of the following drugs with tacrolimus is initiated or discontinued [see DRUG INTERACTIONS].
In a study of 22 healthy male subjects, coadministration of a single 10 mg ASTAGRAF XL dose with rifampin (600 mg/day) for 12 days decreased mean AUCinf and Cmax of tacrolimus by 56% and 46%, respectively [see DRUG INTERACTIONS].
In a study of 24 healthy male subjects, coadministration of a 4 mg ASTAGRAF XL dose with ketoconazole (400 mg/day) for 9 days increased the mean AUCinf and Cmax of tacrolimus 7.5-fold and 4.6-fold, respectively [see DRUG INTERACTIONS].
In a single dose study in 9 healthy subjects, coadministration of tacrolimus (0.5 mg single dose, as tacrolimus immediate-release) with telaprevir (750 mg three times daily for 13 days) increased the tacrolimus dose normalized Cmax by 9.3-fold and AUC by 70-fold compared to tacrolimus alone [see DRUG INTERACTIONS].
In a single dose study in 12 subjects, coadministration of tacrolimus (0.5 mg single dose, as tacrolimus immediate-release) with boceprevir (800 mg three times daily for 11 days) increased tacrolimus Cmax by 9.9-fold and AUC by 17-fold compared to tacrolimus alone [see DRUG INTERACTIONS].
Based on a clinical study of 5 liver transplant recipients, coadministration of tacrolimus (as tacrolimus immediate-release) with nelfinavir increased blood concentrations of tacrolimus significantly and, as a result, a reduction in the tacrolimus dose by an average of 16-fold was needed to maintain mean trough tacrolimus blood concentrations of 9.7 ng/mL. It is recommended to avoid concomitant use of tacrolimus and nelfinavir unless the benefits outweigh the risks [see DRUG INTERACTIONS].
In a single-dose crossover study in healthy subjects, coadministration of tacrolimus (as immediate-release) and magnesium-aluminum-hydroxide resulted in a 21% increase in the mean tacrolimus AUC and a 10% decrease in the mean tacrolimus Cmax relative to tacrolimus administration alone [see DRUG INTERACTIONS].
Voriconazole (see complete prescribing information for VFEND®)
Repeat oral dose administration of voriconazole (400 mg every 12 hours for one day, then 200 mg every 12 hours for 6 days) increased tacrolimus (0.1 mg/kg single dose, as tacrolimus immediate-release formulation) Cmax and AUCτ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively [see DRUG INTERACTIONS].
Posaconazole (see complete prescribing information for Noxafil®)
Repeat oral administration of posaconazole (400 mg twice daily for 7 days) increased tacrolimus (0.05 mg/kg single dose, as immediate-release formulation) Cmax and AUC in healthy subjects by an average of 2-fold (90% CI: 2.01, 2.42) and 4.5-fold (90% CI 4.03, 5.19), respectively [see DRUG INTERACTIONS].
Caspofungin (see complete prescribing information for CANCIDAS®)
Caspofungin reduced the blood AUC0-12 of tacrolimus by approximately 20%, peak blood concentration (Cmax) by 16%, and 12-hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart, as immediate-release formulation) was administered on the 10th day of CANCIDAS® 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone [see DRUG INTERACTIONS].
The efficacy and safety of ASTAGRAF XL in de novo kidney transplantation were assessed in two randomized, multicenter, active-controlled trials (Study 1 and Study 2).
Study 1 -- Induction with Basiliximab
Study 1 was a randomized, open-label trial of ASTAGRAF XL (N=214) compared to Prograf (N=212), of 12 months duration conducted primarily in the US. Patients were stratified by donor type (living or deceased) and transplant history (primary or retransplant). All patients received basiliximab induction and concomitant treatment with MMF and corticosteroids. The population was 17 to 77 years of age, the mean age was 48 years; 64% of the study population was male; 73% were Caucasian, 22% were African-American, 2% were Asian, and 3% were categorized as other races. Living donors provided 49% of the organs. The most frequent diseases leading to transplantation were balanced between the groups and included nephrosclerosis/hypertensive nephropathy, diabetic nephropathy, glomerulonephritis, and polycystic kidney disease. Premature discontinuation from treatment at the end of one year occurred in 14% of ASTAGRAF XL patients and 16% of Prograf patients, primarily due to adverse reactions.
Study 2 -- No Induction
Study 2 was a randomized, double-blind trial, (designed to remain double-blind until the last patient enrolled had completed 24 weeks on study treatment) of ASTAGRAF XL (N = 331) compared to Prograf (N = 336), of 12 months duration conducted outside the US. The patient treatment assignments remained blinded for 12 months for 96% of the patients participating in the trial. Patients with a high immunologic risk defined as a PRA grade > 50% in the previous 6 months and/or with a previous graft survival of less than 12 months due to immunologic reasons were excluded, as were recipients of donor kidneys with cold ischemia time > 30 hours, or donor kidneys from a non heart-beating donor. All patients received concomitant treatment with MMF and corticosteroids without antibody induction. The population was 18 to 65 years of age; the mean age was 48 years; 63% of the study population was male; 82% were Caucasian, 5% were African-American, 2% were Asian, and 11% were categorized as other races. Living donors provided 27% of the organs. Premature discontinuation from treatment at the end of one year occurred in 24% of ASTAGRAF XL patients and 19% of Prograf patients, primarily due to adverse reactions.
In Study 1, the actual tacrolimus starting dose (given any time up to Day 2 post-transplant) of ASTAGRAF XL was higher than Prograf (0.15 mg/kg versus 0.1 mg/kg). In Study 2, the actual tacrolimus doses on Day 0 (0.1 mg/kg/day pre-operative) and Day 1 (0.2 mg/kg/day post-operative) were comparable between ASTAGRAF XL and Prograf. Thereafter, to achieve comparable mean tacrolimus trough concentrations (C24), higher total mean daily doses of tacrolimus were required for ASTAGRAF XL than Prograf (on average, by 15% in Study 1 and by 25% in Study 2).
In Study 1, African-American patients required higher ASTAGRAF XL doses to attain similar trough concentrations as Caucasian patients (Table 7).
Table 7: ASTAGRAF XL Doses and Mean Whole Blood Trough
Concentrations in African-American and Caucasian Kidney Transplant Patients in
|Time After Transplant||Caucasian Patients
|Dose (mg/kg)||Mean Trough Concentration (ng/mL)||Dose (mg/kg)||Mean Trough Concentration (ng/mL)|
Table 8 shows the observed tacrolimus whole blood trough concentrations measured at protocol-specified time points for ASTAGRAF XL in Study 1 and Study 2. In Study 1, the protocol-specified target tacrolimus whole blood trough concentrations (Ctrough) were 7-16 ng/mL for the first three months and 5-15 ng/mL thereafter.
Approximately 80% of ASTAGRAF XL patients maintained tacrolimus whole trough blood concentrations between 5 to 17 ng/mL during Months 1 through 2 and, then, between 4 to 12 ng/mL from Months 3 through 12. In Study 2, the protocol-specified target tacrolimus whole blood trough concentrations (Ctrough) were 10-15 ng/mL during the first month, 5-15 ng/mL from Month 2 to Month 6, and 5-15 ng/mL thereafter. Approximately 80% of ASTAGRAF XL patients maintained tacrolimus whole trough blood concentrations between 6 to 20 ng/mL during Months 1 through 2 and, then between 6 to 14 ng/mL from Months 3 through 12.
Table 8: Observed Tacrolimus Whole Blood Trough
Concentrations for ASTAGRAF XL Kidney Transplant Patients Evaluated in Studies
1 and 2
|Scheduled Visit||Median (P10-P90a) tacrolimus whole blood trough concentrations (ng/mL)|
|Study 1||Study 2|
|Day 3||9.6 (4.9 - 20.2)||13.8 (6.5 - 25.5)|
|Day 7||9.1 (4.4 - 16.8)||10.1 (5.5 - 17.3)|
|Day 14||10.0 (5.7 - 16.9)||10.8 (6.7 - 17.9)|
|Month 1||10.5 (5.6 - 17.1)||12.0 (7.5 - 17.6)|
|Month 2||9.4 (6.1 - 14.2)||11.1 (6.6 - 17.3)|
|Month 6||7.7 (4.4 - 11.5)||9.2 (5.7 - 13.5)|
|Month 12||7.2 (3.8 - 10.4)||8.0 (5.1 - 13.8)|
|a10th to 90th Percentile: range of Ctrough that excludes lowest 10% and highest 10% of Ctrough|
In Study 1, patients in each group started MMF at 1 gram twice daily. The MMF dose was reduced to less than 2 grams per day by Month 12 in 56% of patients in the ASTAGRAF XL group (Table 9). Approximately 57% of the MMF dose reductions were because of adverse reactions in the ASTAGRAF XL group [see ADVERSE REACTIONS].
In Study 2, patients in each group received MMF at 1 gram twice daily starting preoperatively. In a majority of the patients, the MMF dose was reduced to 0.5 grams twice daily starting after day 14 (Table 9).
Table 9: Distribution of
ASTAGRAF XL/MMF Patients (%) Based on Time-Averaged MMF Dosea
|Time period (Days)||Study 1||Study 2|
|Time-averaged MMF dosea||Time-averaged MMF dosea|
|Less than 2.0 (g/day)||2.0 (g/day)||Greater than 2.0 (g/day)||Less than 2.0 (g/day)||2.0 (g/day)||Greater than 2.0 (g/day)|
|a Time-averaged MMF dose = (total MMF dose)/(duration of treatment). A time-averaged MMF dose of 2.0 grams per day means that the MMF dose was not reduced in those patients during the time period.|
In Study 1, the efficacy failure rate including patients who developed biopsy-proven acute rejection (BPAR), graft failure, death, and/or lost to follow-up at 12 months, as well as the rates of the individual events, is shown in Table 10 for the intent to treat (ITT) population.
Table 10: Incidence of BPAR, Graft Loss, Death or Lost
to Follow-up at 12 Months
|Efficacy Failure||30 (14.0%)||32 (15.1%)|
|Biopsy Proven Acute Rejection||22 (10.3%)||16 (7.5%)|
|Graft Loss||5 (2.3%)||9 (4.2%)|
|Death||3 (1.4%)||9 (4.2%)|
|Lost to follow-up||3 (1.4%)||4 (1.9%)|
|Treatment Difference of efficacy failure compared to tacrolimus immediate-release/MMF group (95% CIa)||-1.1% (-7.8%, +5.6%)|
|a95% confidence interval calculated using normal approximation|
In Study 2, the Efficacy Failure rate including patients who developed biopsy-proven acute rejection (BPAR), graft failure, death, and/or lost to follow-up at 12 months, as well as the rates of the individual events, is shown in Table 11 for the ITT population. About 1% of randomized patients were not transplanted and were not included in the ITT analysis.
Table 11: Incidence of BPAR,
Graft Loss, Death or Lost to Follow-up at 12 Months
|Tacrolimus Immediate- Release/MMF
|Efficacy Failure||93 (28%)||78 (23%)|
|Biopsy Proven Acute Rejection||68 (21%)||54 (16%)|
|Graft loss||28 (9%)||24 (7%)|
|Death||10 (3%)||8 (2%)|
|Lost to follow-up||4 (1%)||7 (2%)|
|Treatment Difference of efficacy failure compared to tacrolimus immediaterelease/MMF group (95% CIa)||+4.9% (-1.7%, +11.5%)|
|a95% confidence interval calculated using normal approximation|
Last reviewed on RxList: 8/2/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Astagraf XL Information
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