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Original Clinical Science—General

Pharmacokinetics and Clinical Outcomes of Generic Tacrolimus (Hexal) Versus Branded Tacrolimus in De Novo Kidney Transplant Patients

A Multicenter, Randomized Trial

Arns, Wolfgang MD1; Huppertz, Andrea MD1,2; Rath, Thomas MD3; Ziefle, Stephan MD3; Rump, Lars C. MD4; Hansen, Anita MD4; Budde, Klemens MD5; Lehner, Lukas J. MD5; Shipkova, Maria MD6; Baeumer, Daniel PhD7; Kroeger, Irena PhD7; Sieder, Christian MD7; Klein, Thomas MD8; Schenker, Peter MD8

Author Information
doi: 10.1097/TP.0000000000001843

Generic formulations of immunosuppressive drugs are now widely prescribed for solid organ transplant recipients in many countries. Tacrolimus, the mainstay of most maintenance immunosuppressive regimens after transplantation, lost its patent in 2008. Since then, a number of generic preparations that are distributed either locally or internationally have been introduced. The generic substitution of tacrolimus or other immunosuppressants, however, is not straightforward, as stressed in statements from professional societies.1,2 The narrow therapeutic window of tacrolimus, and the vital importance of maintaining adequate immunosuppressive potency while avoiding potentially serious toxicity, means that close attention must be paid to the question of generic substitution of this and other immunosuppressive agents. Tacrolimus, a highly lipophilic molecule, is extensively metabolized after oral administration,3 and its exposure is affected by various factors such as food, cytochrome P450 3A4 and cytochrome P450 3A5, P-glycoprotein expression, liver function, race, and concomitant medications.4 Moreover, a time-dependent increase in its bioavailability is observed during the first few months posttransplant.5 Previous studies have reported that the pharmacokinetics of tacrolimus shows considerable variation in bioavailability both within6,7 and between patients.3,4

Recently, relevant differences in generic formulations of tacrolimus versus the reference drug (Prograf) after transplantation have been described.8,9 The most extensively studied preparation is the generic tacrolimus preparation produced by Sandoz, sold in Germany under the brand name Tacrolimus Hexal (TacHexal). A prospective, multicenter, randomized cross-over study in a cohort of stable renal transplant patients has confirmed that the pharmacokinetics of TacHexal is similar to the reference drug.10 Randomized trials comparing the tacrolimus pharmacokinetics and clinical outcomes associated with de novo use of the Sandoz generic product versus the reference drug, however, are lacking.

A randomized multicenter study was therefore undertaken to compare the pharmacokinetic profiles, renal function, efficacy, and safety of Sandoz generic tacrolimus (TacHexal) versus Prograf in de novo kidney transplant patients.


Study Design

This was a prospective, multicenter, parallel-group, open-label study in de novo kidney transplant patients randomly assigned to receive generic tacrolimus (TacHexal) or the reference tacrolimus formulation (Prograf) (EudraCT no. 2011-003795-36). The study was conducted in accordance with the Declaration of Helsinki after the approval by the institutional review board at each center. All participants provided written informed consent.

The first phase of the study evaluated pharmacokinetic parameters in a planned cohort of 60 evaluable patients and was undertaken at 5 transplant centers in Germany during October 2012 to August 2015. The primary objective of this phase was to demonstrate that the pharmacokinetics of the generic preparation was comparable to those of Prograf, as assessed by the ratio of the area under the curve (AUC)0-12h over the first month posttransplant. A second phase was planned in which the total population would be increased to 326 patients, with the primary objective of demonstrating noninferiority of renal function between treatment arms based on estimated glomerular filtration rate (eGFR) at month 6 posttransplant. During the first phase, however, many patients were unwilling to undergo the second or third 12-hour pharmacokinetic profiling required by the protocol, resulting in a high rate of patient dropouts. Therefore, the study sponsor decided not to initiate a planned second phase because the time to achieve the planned evaluable study population would be unacceptably long. Patients who had already been enrolled to the first phase were analyzed for phase II end points. All patients already enrolled were scheduled to attend a final study visit.

Eligibility Criteria

The study population comprised de novo adult recipients (aged 18-64 years) of a primary or secondary kidney transplant from a deceased, living-unrelated, or living-related donor aged younger than 65 years, with a cold ischemia time of less than 24 hours. Key exclusion criteria are shown in Table S1 (SDC,

Study Treatment

Randomization was performed using an automated, validated system, with stratification according to deceased or living donation. The investigators were informed of the randomization group by treatment allocation cards. The patients were randomized in a 1:1 ratio to generic tacrolimus (TacHexal, Hexal AG, Holzkirchen, Germany) or to the reference tacrolimus formulation (Prograf, Astellas Pharma GmbH, Munich, Germany). The starting dose was 0.15 mg/kg per day in both groups, adjusted to target a tacrolimus trough concentration (C0) of 8 to 12 ng/mL to month 3, 5 to 10 ng/mL during month 4, and 5 to 8 ng/mL thereafter until the end of the study. The patients were instructed to fast from 10:00PM on the day before each pharmacokinetic profiling. In addition, the patients were asked to avoid food intake for 1 hour before, and 2 hours after, administration of the study medication on the evening before pharmacokinetic profiling. On profiling days, the first tacrolimus dose of the day was not to be taken until 5 minutes after the first blood sample was drawn, and breakfast was not consumed until 90 minutes after the first dose. Consumption of grapefruit juice was prohibited for 1 hour before taking study medication throughout the study. In addition, grapefruit juice was not to be consumed at all on days when pharmacokinetic sampling was carried out. All patients were to receive basiliximab induction. In addition to tacrolimus, the maintenance immunosuppression regimen comprised enteric-coated mycophenolate sodium (Myfortic, Novartis Pharma AG, Basel, Switzerland) at a dose of 1440 mg/d and steroids (≥5 mg prednisolone or equivalent, according to local practice). All maintenance immunosuppressants, including tacrolimus, were to be taken in 2 divided doses, 12 hours apart.


Study visits were scheduled at baseline (≤7 days pretransplant), day 3, and day 10 posttransplant, and at months 1, 3 and 6. Tacrolimus morning predose concentrations (C0) were measured in whole blood at all study visits at an accredited central laboratory (Central Institute of Clinical Chemistry and Laboratory Medicine, Klinikum Stuttgart, Germany) using a validated liquid chromatography-tandem mass spectrometry system.11 A 12-hour pharmacokinetic profile was performed at day 3, day 10, and month 1 (with sampling predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose). A 4-hour profile was measured at months 3 and 6 (with sampling predose and at 0.5, 1, 1.5, 2, 3, and 4 hours postdose).

Pharmacokinetic Data

The following pharmacokinetic variables for tacrolimus were determined during the first phase of the study: the dose-normalized AUC0-12h, peak concentration (Cmax), average concentration over the 12 hours after dosing (Cav), C0, time to Cmax (tmax), peak-trough fluctuation, and oral clearance on day 3, day 10, and month 1. The values for AUC0-12h, Cmax, Cav, C0 (to month 1), and AUC0-4h were dose normalized. Pharmacokinetic analyses were based on the pharmacokinetic population, defined as those patients from whom an evaluable plasma concentration time profile was obtained over a 12-hour interval at month 1.

Tacrolimus concentrations were measured locally, and dose adjustments were made on the basis of these measurements. All concentrations below the limit of quantification were imputed by half the value of the limit of quantification before statistical analysis. Actual blood sampling times were used during analysis.

Study End Points

The primary end point of the first phase of the study was dose-normalized AUC0-12h at month 1 posttransplant. The secondary end points were the ratio of dose-normalized AUC0-12h at days 3 and 10 for TacHexal versus AUC0-4h at months 3 and 6 for Prograf; the ratio of dose-normalized Cmax for TacHexal versus for Prograf over the first month posttransplant; C0 at day 3 and day 10 and at months 1, 3, and 6; the incidence of treatment failure (defined as biopsy-proven acute rejection [BPAR], graft loss, or death) at month 1; renal function as assessed by eGFR (Nankivell, Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI], Cockcroft-Gault, and Modification of Diet in Renal Disease [MDRD] formulas) at month 1 posttransplant; and safety and tolerability at month 1.

Statistical Analysis

The primary variable for the first phase of the study was the dose-normalized AUC0-12h at month 1 posttransplant. The sample size calculation estimated that 27 evaluable patients in each group would provide 80% power to reject the null hypothesis that the ratio of the means of TacHexal versus Prograf was (a) less than 0.80 and (b) greater than 1.25 (NQuery Version 6.1; Statistical Solutions, Cork, Ireland). This estimate assumed that the means of the 2 groups were equivalent and that if the expected ratio of means was 1.00 the coefficient of variation for TacHexal would be 0.25.

The primary variable, dose-normalized AUC0-12h at month 1 posttransplant, was compared between treatment groups by applying an analysis of variance (ANOVA) model to log-transformed, dose-normalized values for tacrolimus AUC0-12h. The ANOVA model included treatment, stratum (ie, deceased vs living donor), and center as fixed factors. The ratio and 90% confidence interval (CI) values for geometric means were obtained by back transformation of the least squares (LS) mean difference between the 2 treatment groups (SAS Proc Mixed, SAS Institute, Cary, NC).

The primary efficacy variable of the planned second phase of the study was eGFR assessed by the Nankivell formula at month 6 posttransplant, compared by analysis of covariance (ANCOVA) with treatment and center as factors and baseline eGFR as covariate, with no imputation for missing values. Noninferiority of TacHexal to Prograf was to be confirmed if the lower limit of the 2-sided 95% CI for the treatment difference based on LS mean values included the predefined noninferiority margin of −7 mL/min.12 As a prespecified sensitivity analysis, the ANCOVA analysis was repeated using the last observation carried forward (LOCF) method to impute for missing data. Pharmacokinetic analyses to month 1 posttransplant were based on the subset of patients with evaluable pharmacokinetic profiles at the time point in question. Pharmacokinetic data at months 3 and 6 were based on the intent-to-treat (ITT) population, comprising all randomized patients who underwent transplantation. Analyses of renal function and efficacy outcomes were also based on the ITT population. Safety analyses were based on all randomized, transplanted patients who received at least 1 dose of study drug and provided at least 1 postbaseline safety assessment.


Patient Population

In total, 81 patients were enrolled and randomized (TacHexal, 37; Prograf, 44). Two patients randomized to the TacHexal group and 5 patients randomized to the Prograf group were not transplanted and did not receive study drug, such that the safety population included 74 patients. One patient randomized to Prograf was excluded from the ITT population because TacHexal was given in error. Of the 73 patients in the ITT population, 51 completed the 6-month study, and all but 1 patient (in the Prograf group) remained on study medication at month 6 (Figure 1). The most frequent reason for discontinuation was withdrawal of consent.

Patient disposition.

Baseline characteristics were generally similar between treatment groups (Table 1). Pretransplant donor-specific antibodies were not detected in any patient.

Study population characteristics (ITT population)

Pharmacokinetic Analysis

The mean (SD) tacrolimus daily dose during month 1 posttransplant was 12.4 (3.3) mg in the TacHexal group and 13.2 (3.3) mg in the Prograf group; corresponding values for months 1 and 3 were 8.8 (3.7) mg and 9.1 (4.0) mg, respectively. Evaluable pharmacokinetic profiles were available at day 3, day 10, month 1, month 3, and month 6 in 38, 38, 43, 51, and 52 patients, respectively. Observed nondose normalized pharmacokinetic values are summarized in Table S1, SDC, At month 1, mean (SD) AUC0-12h was 210 (59) ng·h·mL−1 in the TacHexal group versus 208 (88) ng·h·mL−1 in the Prograf group. Observed pharmacokinetic values are summarized in Table S2, SDC, Mean (SD) tacrolimus C0 in the TaxHexal group was 13.3 (3.1), 12.5 (5.6), and 7.8 (3.1) ng/mg at months 1, 3, and 6, respectively, compared to 12.3 (4.9) 10.1 (3.7), and 8.0 (2.2) in the Prograf group. The tacrolimus plasma concentrations versus time profiles in evaluable patients at month 1 according to the treatment group are shown in Figure 2. The correlations between tacrolimus C0 and AUC0-12h for TacHexal and Prograf, respectively, were r = 0.937 and r = 0.942 (P = 0.451) at day 3, r = 0.641 and r = 0.449 (P = 0.214) at day 10, and r = 0.767 and r = 0.899 (P = 0.081) at month 1.

Tacrolimus plasma concentrations versus time profiles at month 1 posttransplant in patients randomized to TacHexal or Prograf. Mean values are shown. Vertical bars indicate standard deviations.

The primary end point, dose-normalized AUC0-12h at month 1 posttransplant, was comparable for TacHexal or Prograf treatment. The back-transformed geometric means of the adjusted log-transformed values (ANOVA) were 18.99 for TacHexal versus 20.48 ng·h·mL−1 per mg dose for Prograf, with a ratio of 1.08 [90% CI 0.84; 1.38]; P = 0.605. Analysis at day 3 and day 10 also showed no significant differences between the TacHexal and Prograf back-transformed geometric means (Table 2), or for observed values (Figure 3A). Dose-normalized AUC0-12h increased between day 10 and month 1, a change that was significant for both TacHexal (P < 0.001) and Prograf (P = 0.004) (Figure 3A). Dose-normalized Cmax values were also statistically similar between the TacHexal and Prograf groups at day 3, day 10 and month 1 when compared using the ANOVA approach (Figure 3B, Table 2).

ANOVA analysis of tacrolimus pharmacokinetics in de novo kidney transplant patients randomized to TacHexal or Prograf (pharmacokinetic population)
Box and whisker plots for (A) the dose-normalized AUC0-12h and (B) the dose-normalized Cmax at day 3, day 10, and month 1 posttransplant in de novo kidney transplant patients randomized to TacHexal or Prograf (ITT population). Boxes represent the interquartile range. Horizontal lines indicate the median. Crosses indicate the mean. Vertical lines indicate maximum and minimum values excluding outliers. Circles indicate outliers.

The observed values of the pharmacokinetic parameters at day 3, day 10 and month 1 are summarized in Table 3. The dose-normalized Cmax was slightly higher in the TacHexal group on days 3 and 10, but similar by month 1. No other parameter showed a relevant difference at both day 3 and day 10, and all parameters were comparable between groups at month 1.

Observed dose-normalized tacrolimus pharmacokinetic parameters in de novo kidney transplant patients randomized to TacHexal or Prograf (pharmacokinetic population)

At month 3, the mean (SD) dose-normalized tacrolimus AUC0-4h was 10.76 (3.58) ng·h·mL−1 per mg dose and 11.27 (6.48) ng·h·mL−1 per mg dose in the TacHexal and Prograf groups, respectively; corresponding values at month 6 were 11.34 (5.86) ng·h·mL−1 per mg dose and 11.20 (5.88) ng·h·mL−1 per mg dose, respectively. The mean (SD) C0 at month 3 was 12.5 (5.6) and 10.1 (3.7) ng/mL for TacHexal and Prograf, respectively, at month 3, with values of 7.8 (3.1) and 8.0 (2.2) ng/mL, respectively, at month 6.

Renal Function

The observed values of eGFR (Nankivell) by treatment group are shown in Figure 4. At month 6, the mean (SD) eGFR was 72.1 (16.4) mL/min per 1.73 m2 in the TacHexal group versus 63.4 (13.8) mL/min per 1.73 m2 in the Prograf group (the data were available in 24 TacHexal and 27 Prograf patients). ANCOVA analysis showed that TacHexal was noninferior to Prograf for eGFR at month 6; the difference was 9.1 mL/min per 1.73 m2 (95% CI, 0.3-17.9 mL/min per 1.73 m2) (P < 0.001 for noninferiority) and indeed showed superiority (P = 0.044 for superiority) (LS mean values). When the analysis was repeated applying the LOCF method, noninferiority was confirmed (difference, 2.2 mL/min per 1.73 m2; 95% CI, −7.8 to 12.2 mL/min/1.73 m2; P = 0.035 for noninferiority; P = 0.659 for superiority).

Observed eGFR values to month 6 posttransplant in de novo kidney transplant patients randomized to TacHexal or Prograf (no imputation for missing values). Values are shown as mean (SD).

Estimation of GFR at month 6 according to the CKD-EPI, MDRD, and Cockcroft-Gault formulas confirmed noninferiority for TacHexal versus Prograf (Table 4). The Cockcroft-Gault formula data showed superiority for the TacHexal arm (P = 0.020), which was not observed with the CKD-EPI or MDRD formulas.

Efficacy and renal outcomes at month 6 posttransplant in de novo kidney transplant patients randomized to TacHexal or Prograf (ITT population)


BPAR occurred in 5.7% of TacHexal-treated patients (2/35; 1 borderline on day 15 and 1 grade IA on day 149) and 7.9% of Prograf-treated patients (3/38; three grade IIA, on day 11, month 3, and day 11) by month 6. At the visit before BPAR, dose-normalized AUC values were 6.0 and 16.1 ng·h·mL−1 per mg dose, respectively, for the 2 patients in the TacHexal group, and 8.3, 15.2, and 9.7 ng·h·mL−1 per mg dose, respectively, for the 3 patients in the Prograf arm. All episodes of BPAR were treated. There were no deaths or graft losses in the TacHexal group. One patient in the Prograf group lost her graft because of BPAR and underwent retransplantation, and another patient in the Prograf arm died because of unknown causes (Table 4). Thus, the composite efficacy end point of BPAR, graft loss, or death occurred in 2 TacHexal patients (2 BPAR) and 4 Prograf patients (2 BPAR, 1 BPAR/graft loss, and 1 death).

Safety and Tolerability

Almost all patients experienced 1 or more adverse event by month 6 (TacHexal, 97.1% [34/35]; Prograf, 100.0% [38/38]), with serious adverse events in 37.1% of the TacHexal-treated patients (13/35) and 42.1% of Prograf-treated patients (16/38). The pattern of adverse events showed no marked difference between groups (Table S3, SDC,

Laboratory values at month 6 showed no relevant differences between treatment groups (Table S4, SDC, Median blood pressure values at month 6 were comparable (TacHexal, 129/80 mmHg; Prograf, 131/80 mmHg).


In this randomized trial of de novo kidney transplant patients, tacrolimus pharmacokinetics was similar for the TacHexal and Prograf formulations. The primary pharmacokinetic variable, AUC0-12h at month 1 posttransplant, showed no statistically significant differences between the 2 treatment arms. Other pharmacokinetic parameters measured up to month 6 posttransplant also showed no relevant variations between treatment groups. The correlation between C0 and AUC did not indicate any substantial difference between treatment arms. It should be stressed that these findings apply only to the TacHexal formulation and should not be extrapolated to other generic formulations of tacrolimus.

Standard bioequivalence studies, which use a crossover design to avoid variation due to patient-specific factors and include adequate washout periods (eg, ≥5 half lives of the drug under investigation),13,14 are generally unfeasible in transplantation. In general, bioequivalence is tested in healthy volunteers or stable maintenance patients. For the Sandoz formulation, high-quality comparative pharmacokinetic data are available from a randomized, 2-part crossover pharmacokinetic study in maintenance patients performed by Alloway and colleagues,10 albeit with only a 2-week duration for each sequence. The study was performed in 68 kidney transplant patients with stable graft function (mean, 4.1 years posttransplant). Patients received the Sandoz generic tacrolimus or Prograf for a 14-day period, which was then switched to the other product, with pharmacokinetic monitoring at the end of each phase. As in the current study, the mean dose-normalized values for AUC0-12h and Cmax, as well as for C0, were similar for both the products. Regulatory bioequivalence criteria require that the 90% CIs for the ratio of geometric means for the generic versus the originator drug be within the range 0.80 to 1.25 for AUC and Cmax15 (or 90%-111% for AUC according to European Medicines Agency criteria13). These criteria were met in the study by Alloway et al10: AUC0-12h, 1.02 (90% CI, 97%-108%; P = 0.486) and Cmax, 1.09 (90% CI, 101%-118%; P = 0.057). In our cohort of newly transplanted patients, the upper 90% CI values were higher than these ranges. This is not unexpected because intrapatient and interpatient variability of tacrolimus is higher in de novo patients than in patients in the maintenance phase.15 In the first weeks, posttransplant dose adjustments are frequently required because steady state is often not yet reached. This will have applied equally to both treatment arms and will therefore not have distorted the between-group comparison but makes achievement of tight bioequivalence criteria unlikely. It is well established that renal function, metabolic parameters, hematocrit, and albumin change rapidly after kidney transplantation, all of which are known to influence tacrolimus pharmacokinetics,16,17 with dramatic changes in the hepatic metabolism of tacrolimus in the first few months posttransplant. In our analysis, this was confirmed by the increase in AUC0-12h and other exposure parameters over the first month posttransplant. Thus, although it is important to assess the pharmacokinetics of generic tacrolimus in the early posttransplant period versus the reference product, it is questionable whether strict bioequivalence criteria, developed for stable patients or healthy volunteers but not the postoperative setting, are applicable in this period. Nevertheless, appropriate statistical testing, as applied here, is essential to evaluate the pharmacokinetic similarity of different tacrolimus products.

Consistent with our findings, an appropriately designed bioequivalence study of the tacrolimus generic formulation Tacni, undertaken in elderly de novo transplant patients, also showed statistically similar tacrolimus pharmacokinetics to the originator drug, but the upper values for 90% CIs in that trial again exceeded Food and Drug Administration18 and European Medicines Agency criteria.19 The current study was not designed as a bioequivalence study, and establishing bioequivalence was not an objective. In addition, the first phase of this study was hampered by a high rate of patient dropouts, largely arising from the requirement for extended 12-hour blood sampling on 3 separate pharmacokinetic profiling days. Therefore, the primary pharmacokinetic analysis was underpowered (a maximum of 43 patients instead of the planned 54 patients). Given the high interpatient variability of tacrolimus, this explains the larger-than-expected CI values. The assumed coefficient of variation used for the sample size calculation (0.25) was substantially lower than that observed in either treatment group. Thus, it was not possible for bioequivalence criteria to be met in this early posttransplant pharmacokinetic study because of the wide variation of tacrolimus pharmacokinetics and low patient numbers.

Clinical outcomes data from the study should be regarded as exploratory, because the larger second phase of the study was not performed. Nevertheless, given the paucity of existing studies, even within this limited population (N = 73), the results are of interest. The TacHexal formulation was associated with no difference in risk for BPAR or any other efficacy end point or in the incidence of safety events including discontinuation of the study due to adverse events. Observed eGFR at month 6 was higher with TacHexal than with Prograf based on the Nankivell formula, but this was not confirmed using LOCF imputation for missing values or when GFR was estimated based on the MDRD or CKD-EPI formulas. It seems clear, however, that renal function was at least equivalent with either formulation. Although published data comparing clinical data in de novo transplant patients receiving Prograf versus the Sandoz generic preparation are sparse, consistent with our findings previous studies suggest that the 2 products are associated with similar efficacy and safety.8,9,20 In a retrospective single-center analysis, Connor et al20 found no significant differences in BPAR, tacrolimus-related toxicity, cytomegalovirus infection, delayed graft function, or graft or patient survival at 6 months posttransplant in a series of 99 de novo kidney transplant patients. Moreover, a nonrandomized sequential study of 94 patients undergoing liver transplantation at a single center observed no significant differences in efficacy or safety end points between Prograf and the Sandoz generic preparation.8 Lastly, Melilli et al9 recently reported no differences in tacrolimus C0, concentration/dose ratio, acute rejection, delayed graft function, or renal function at 6 months posttransplant in 60 kidney transplant patients treated de novo with the Sandoz generic formulation when compared with historical controls given reference tacrolimus.

The results observed here cannot be applied to other generic tacrolimus preparations for which pharmacokinetic assessments versus the reference drug in transplant populations are less extensive than those for Sandoz generic tacrolimus.21 It should also be noted that careful monitoring of tacrolimus exposure is mandatory if patients are switched from Prograf to TacHexal. Although planned conversion has been performed without efficacy or safety concerns,22-25 altered tacrolimus exposure has been reported in cases where patients were inadvertently switched from Prograf to a generic product without appropriate monitoring.26,27

In conclusion, the pharmacokinetic profiles of the TacHexal formulation and the reference drug Prograf were statistically similar in this cohort of de novo kidney transplant patients, and C0 showed a similar degree of correlation with AUC. Within the limited scope of this small population and time frame of the study, no efficacy or safety differences were detected between the TacHexal and Prograf preparations, and renal function was at least comparable under TacHexal. These results are not necessarily applicable to other generic tacrolimus preparations, for which comparative studies versus Prograf should be undertaken.


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