The Impact of Conversion From Prograf to Generic Tacrolimus in Liver and Kidney Transplant Recipients With Stable Graft Function

Authors


Raman Venkataramanan, rv@pitt.edu

Abstract

Bioequivalence of the recently available generic tacrolimus formulation, manufactured by Sandoz, to the reference product (Prograf; Astellas Pharma, Tokyo, Japan) has been demonstrated in healthy subjects. However, the safety and efficacy of substitution with generic tacrolimus in transplant patients have not been evaluated. Tacrolimus trough concentrations and indices of liver and kidney function were recorded before and after generic substitution in 48 liver and 55 kidney transplant recipients. In liver transplant patients, the mean tacrolimus concentration/dose (C/D) ratio (±SD) was 184.1 (±123.2) ([ng/mL]/[mg/kg/day]) for the reference product and 154.7 (±87.8) ([ng/mL]/[mg/kg/day]) for the generic product (p < 0.05). The mean C/D-ratios in kidney transplant patients were 125.3 (±92.7) and 110.4 (±79.2) ([ng/mL]/[mg/kg/day]) for the reference and generic products, respectively (p < 0.05). Actual trough concentrations declined by an average of 1.98 ng/mL in liver and 0.87 ng/mL in kidney transplant patients following the switch, after accounting for all significant covariates. No change was observed in biochemical indices of liver or kidney function and no cases of acute rejection occurred following the substitution. These results suggest that transplant patients currently taking the reference tacrolimus formulation may be safely switched to the Sandoz-generic product provided trough concentrations are closely monitored following the substitution.

Introduction

The contribution of tacrolimus to effective immunosupression in solid organ transplantation is well established (1–4). Tacrolimus is a potent immunosuppressive drug with a narrow therapeutic index, and several studies have demonstrated that therapeutic drug monitoring provides information of predictive value for managing the risks of concentration-related rejection and toxicities (5–7).

In August 2009, the US Food and Drug Administration (FDA) approved the first generic formulation of tacrolimus, manufactured by Sandoz (Holzkirchen, Germany) (8). The use of generic medications is widespread and represents a viable cost-saving opportunity in the face of rising health care costs (9). However, while economics is the driving force behind utilization of generic drug products, patient welfare must remain the principal consideration. Currently there is a paucity of data related to the safety and efficacy of switching transplant patients from the reference tacrolimus product (Prograf; Astellas Pharma, Tokyo, Japan) to the recently available generic formulation. Therefore, in the present study, the impact of generic substitution on predose tacrolimus trough concentrations and indices of liver and kidney function was investigated in clinically stable liver and kidney transplant recipients.

Materials and Methods

Study design

This single-center, retrospective, nonrandomized study was conducted at the University of Pittsburgh Medical Center in Pittsburgh, Pennsylvania. Information used for analyses was obtained through databases maintained by the University of Pittsburgh Starzl E. Transplantation Institute, under the auspices of, and with formal approval by, the Institutional Review Board of the University of Pittsburgh (IRB 0307037). Research data were coded to prevent the identification of subjects.

Inclusion/exclusion criteria

Inclusion criteria included (i) age > 18 years, (ii) liver transplant recipient at least 6 months posttransplant or kidney transplant recipient at least 3 months posttransplant, (iii) switched from the reference tacrolimus product to the generic formulation (Sandoz) from August 2009 to April 2010, and (iv) on a stable dose of tacrolimus for at least 14 days prior to the switch, with preswitch trough concentrations within 25% of the intraindividual mean during this period. Patients were excluded if they had less than three tacrolimus trough concentrations before and after the switch to the generic product, or if they had a change in coprescribed medications known to interfere with the metabolism of tacrolimus during the study period.

Monitoring

All subjects received care in the outpatient transplant clinic where tacrolimus trough concentrations, weight, total bilirubin, albumin, serum creatinine, alkaline phosphatase, ALT, AST, GGTP and graft rejection status was routinely monitored. Patients were followed for a minimum of 14 days and a maximum of 90 days before and after the generic conversion. All patients were instructed to take tacrolimus doses at specified times to ensure accurate determination of trough concentrations. At the time of the switch from the reference to generic product, a 1:1 dose conversion was employed and the dose of generic tacrolimus was then adjusted at the discretion of the treating physician to maintain trough concentrations within the therapeutic range. The tacrolimus concentration to dose (C/D) ratio, expressed as the concentration divided by daily weight-adjusted dose ([ng/mL]/[mg/kg/day]), was calculated for each trough concentration.

Immunosupression

In liver transplant patients, the immunosuppressive regimen included methylprednisolone 1 g perioperatively, followed by tacrolimus twice daily immediately postoperatively. Patients with poor renal function, defined as serum creatinine > 2.5 mg/dL or urine output < 30 mL/h, received basiliximab induction and mycophenolate mofetil immediately postoperatively, with tacrolimus started when renal function or neurologic function improved. Patients with a positive cross-match received a rapid steroid taper over 3 months with tacrolimus and mycophenolate mofetil immediately postoperatively. Target 12-h tacrolimus trough levels in liver transplant recipients were 10–12 ng/mL for the first 3 months, 8–10 ng/mL for months 3–6 and 6–8 ng/mL thereafter.

The immunosuppressive regimen in kidney transplant patients included methylprednisolone 2 g perioperatively with alemtuzumab induction, followed by tacrolimus twice daily as monotherapy. Hepatitis C virus-positive patients received basiliximab induction followed by tacrolimus and mycophenolate mofetil. Target 12-h-tacrolimus trough levels in all kidney transplant recipients were 9–10 ng/mL for the first 3 months and 5–7 ng/mL thereafter.

Analytical methodology

Tacrolimus concentrations were determined in whole blood using a validated sensitive and specific high-performance liquid chromatography mass spectrometric (HPLC-MS/MS) method. The coefficient of variation of the method at our laboratory was < 10% in the linear range of 1–40 ng/mL.

Statistical analysis

Results were presented as mean (± SD). Student's paired t-test was used to analyze both tacrolimus C/D-ratios for each drug product, and liver and kidney biochemical parameters before and after conversion to the generic product. Linear mixed-effects models examining the influence of covariates on actual tacrolimus trough concentrations were constructed using bivariate analyses and Akaike's Information Criterion, Schwarz's Bayesian Criterion and likelihood-ratio χ2 tests. Continuous covariates included tacrolimus dose, patient age, time posttransplant, albumin, total bilirubin and serum creatinine. Patient gender and the use of generic tacrolimus were analyzed as categorical covariates. Covariates found to be significant predictors in bivariate analyses were subsequently tested in multivariate analyses to test if they remained statistically significant after controlling for all other variables. The threshold of statistical significance was set at 5% (α= 0.05).

Results

Data from 103 patients (48 liver transplant and 55 kidney transplant recipients) were available. Patient demographic information is presented in Table 1. A total of 746 tacrolimus trough concentrations were included in the analysis. In liver transplant recipients, actual trough concentrations ranged from 2.0 to 15.7 ng/mL with the reference tacrolimus product and 2.0–15.1 ng/mL with generic tacrolimus. In kidney transplant recipients, actual trough concentrations ranged from 3.4 to 21.1 ng/mL with the reference product and 2.8–22.2 ng/mL with generic tacrolimus.

Table 1.  Patient demographics
 Mean (± SD)RangeFrequency (%)
Liver transplant recipients (n = 48)
Patient age (years)60.6 (10.9)23.8–82.5 
Graft age (months)100.4 (70.3)   6.5–235.6 
Gender
 Male (n = 27)  56.3
 Female (n = 21)  43.7
Patient weight (kg)82.9 (23.7) 41.6–128.5 
Time followed presubstitution (days)48.8 (25.3) 14.5 – 87.7 
Time followed postsubstitution (days)58.3 (21.6)17.5–89.6 
Kidney transplant recipients (n = 55)
Patient age (years)49.9 (15.1)20.6–81.4 
Graft age (months)48.1 (41.6)  3.1–181.1 
Gender
 Male (n = 31)  56.4
 Female (n = 24)  43.6
Patient weight (kg)85.7 (23.5) 32.0–141.3 
Time followed presubstitution (days)47.1 (26.1)15.2–87.6 
Time followed postsubstitution (days)50.3 (25.7)15.2–89.1 

No appreciable change was observed in biochemical indices of liver function (total bilirubin, albumin, alkaline phosphatase, ALT, AST, GGTP) or kidney function (serum creatinine, BUN) following conversion from the reference product to generic tacrolimus. Additionally, no cases of acute rejection occurred in either the liver or kidney transplant groups during the study period (Table 2).

Table 2.  Biochemical parameters and acute rejection episodes pre- and postconversion to generic tacrolimus in liver and kidney transplant recipients
 Liver transplant recipients (n = 48)Kidney transplant recipients (n = 55)
PreconversionPostconversionpPreconversionPostconversionp
  1. Data are presented as mean (±SD); ALT, alanine transaminase; AST, aspartate aminotransferase; GGTP, gamma-glutamyltransferase; BUN, blood urea nitrogen.

Total bilirubin (mg/dL)0.84 (0.59)0.78 (0.50)0.520.58 (0.29)0.59 (0.27)0.82
Alkaline phosphatase (U/L)138.6 (111.7)146.3 (137.8)0.5898.9 (38.7)96.5 (36.9)0.75
Albumin (g/dL)3.66 (0.56)3.54 (0.54)0.593.98 (0.41)3.99 (0.36)0.9
ALT (U/L)42.6 (30.6)37.3 (24.7)0.3627.8 (20.0)27.1 (17.3)0.84
AST (U/L)43.6 (40.71)39.9 (33.9)0.5523.2 (9.4)23.1 (9.1)0.92
GGTP (U/L)102.3 (163.3)106.4 (226.4)0.9265.7 (135.0)64.3 (134.1)0.96
Serum creatinine (mg/dL)1.61 (1.24)1.63 (1.32)0.911.54 (0.78)1.52 (0.79)0.91
BUN (mg/dL)22.23 (8.81)23.42 (9.18)0.5325.1 (11.9)23.9 (10.4)0.59
Episodes of acute rejection0000

There was a high degree of variability in the weight-adjusted tacrolimus doses used in both liver and kidney transplant patients (Figure 1). The mean weight-adjusted daily tacrolimus doses used to maintain therapeutic trough concentrations were not significantly different between the reference and generic products in the liver transplant group (0.039 vs. 0.041 mg/kg/day, p > 0.05) or the kidney transplant group (0.087 vs. 0.091 mg/kg/day, p > 0.05). A total of 43 patients experienced a dose adjustment after the substitution, with 51.2% of these patients having an increase in tacrolimus dose and 48.8% experiencing a dose reduction.

Figure 1.

Daily tacrolimus doses used in liver (A) and kidney (B) transplant recipients. Colored bars represent the reference product (Prograf, Astellas Pharma Inc., Tokyo, Japan) and open bars represent generic tacrolimus (Sandoz).

In both liver and kidney transplant patients, the tacrolimus concentration/dose (C/D) ratio differed significantly from the reference to the generic product. In the liver transplant group, the mean C/D-ratio (±SD) was 184.1 (±123.2) ([ng/mL]/[mg/kg/day]) for the reference product and 154.7 (±87.8) ([ng/mL]/[mg/kg/day]) for the generic product (p < 0.05). The mean C/D-ratios in the kidney transplant group were 125.3 (±92.7) and 110.4 (±79.2) ([ng/mL]/[mg/kg/day]) for the reference and generic products, respectively (p < 0.05). Overall, 24 patients (23.3%) had more than a 20% decrease in the C/D ratio and seven patients (6.8%) had more than a 20% increase in the C/D ratio following the switch.

The percent change in average actual tacrolimus concentrations following generic substitution in a subgroup of patients who remained on the same dosing regimen over the entire observational period (n = 60) is displayed in Figure 2. In the liver transplant subgroup (n = 30), tacrolimus weight-adjusted dose, albumin, creatinine and use of generic tacrolimus were significantly correlated with tacrolimus trough concentrations at the p < 0.005 level, patient age was significant at the p < 0.01 level, and time posttransplant and total bilirubin were significant at the p < 0.025 level. In the final multivariate model, weight-adjusted dose, albumin, total bilirubin and use of generic tacrolimus were significantly correlated with trough concentrations. After controlling for all other significant independent variables, the average change in tacrolimus whole blood trough concentrations associated with use of generic tacrolimus was –1.98 ng/mL (95% confidence interval –3.05 to –0.92, p < 0.005) (Table 3).

Figure 2.

Percent change in the mean whole blood tacrolimus trough concentrations following generic substitution in liver (top) and kidney (bottom) transplant recipients when the dosing regimen remained constant.

Table 3.  Summary of covariate effects on tacrolimus trough concentrations in liver transplant recipients
 BivariateMultivariate backward stepwise elimination
Bp95% CIBp*95% CI
LowerUpperLowerUpper
  1. Dependent variable: Tacrolimus whole blood trough concentrations in liver transplant recipients; *p-value derived from the difference in –2 log likelihood of (a) model with all remaining predictors and (b) model with the predictor in the row omitted; B, unstandardized (raw) coefficient; CI, confidence interval; NS, not significant.

Tacrolimus dose (per mg/70 kg)0.45<0.005 0.030.870.57<0.0050.290.85
Patient age (per year)−0.08<0.01−0.14−0.02NS
Female (gender)0.50NS−0.981.98
Time posttransplant (per year)−0.14<0.025−0.25−0.03NS
Albumin (per g/dL)−1.29<0.005−2.44−0.14−0.77 <0.005−1.38−0.16
Total bilirubin (per mg/dL)0.09<0.025−0.030.210.18<0.010.130.23
Creatinine (per mg/dL)−0.38<0.005−0.890.14NS
Use of generic tacrolimus−1.511<0.005−2.29−0.73−1.98 <0.005−3.05−0.92

In the kidney transplant subgroup (n = 30), tacrolimus weight-adjusted dose, total bilirubin, creatinine and the use of generic tacrolimus were significantly correlated with trough concentrations at the p < 0.005 level. Tacrolimus dose, total bilirubin and the use of generic tacrolimus remained significant in the multivariate model. After controlling for all other significant covariates, the average change in tacrolimus whole blood trough concentrations associated with use of generic tacrolimus was –0.87 ng/mL (95% confidence interval –1.47 to –0.27, p < 0.005) (Table 4).

Table 4.  Summary of covariate effects on tacrolimus trough concentrations in kidney transplant recipients
 BivariateMultivariate backward stepwise elimination
Bp95% CIBp*95% CI
LowerUpperLowerUpper
  1. Dependent variable: Tacrolimus whole blood trough concentrations in kidney transplant recipients; * p-value derived from the difference in –2 log likelihood of (a) model with all remaining predictors and (b) model with the predictor in the row omitted; B, unstandardized (raw) coefficient; CI, confidence interval; NS, not significant.

Tacrolimus dose (per mg/70 kg)0.22<0.0050.030.41 0.26<0.0050.040.48
Patient age (per year)0.01NS−0.030.05
Female (gender)−0.032NS−1.2821.218
Time posttransplant (per year)−0.075NS−0.2630.113
Albumin (per g/dL)0.01NS−0.140.16
Total bilirubin (per mg/dL)2.39<0.0050.074.72 2.35<0.0050.074.62
Creatinine (per mg/dL)0.70<0.005- 1.042.44NS
Use of generic tacrolimus−0.94<0.005−1.54−0.35−0.87<0.005−1.47−0.27

Discussion

Generic substitution of tacrolimus with the Sandoz-generic formulation resulted in an average reduction of 15.9% and 11.9% in the concentration/dose (C/D) ratio in liver and kidney transplant patients, respectively, following conversion from the innovator tacrolimus product (Prograf; Astellas Pharma, Tokyo, Japan). In addition, in those patients who remained on the same tacrolimus dosing regimen over the observational period, actual mean tacrolimus trough concentrations declined by an average of 1.98 ng/mL in liver transplant patients and 0.87 ng/mL in kidney transplant patients following the switch, after accounting for all significant covariates. Nevertheless, generic substitution of tacrolimus appears safe when accompanied by vigilant therapeutic drug monitoring, as graft function remained stable, and no acute rejection episodes occurred during the observational period.

The US FDA characterizes a generic drug as the same as a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use. In order to introduce a new generic product to the market, a pharmaceutical company must submit an Abbreviated New Drug Application (ANDA) to the FDA, which does not require preclinical or clinical data to establish safety and efficacy. Rather, an ANDA must demonstrate bioequivalence, defined by the FDA as ‘the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study’ (10).

The US FDA accepts two products as bioequivalent if the 90% confidence interval of the relative mean maximum blood concentration (Cmax) and the area under the plasma concentration versus time curve (AUC(0-t) or AUC(0-∞)) of the test to reference product is within 80–125%. A typical bioequivalance study employs a single dose, two-way crossover design in 24–40 healthy subjects, depending on pharmacokinetic variability of the test compound, and data in the intended patient population are not required. However, transplant patients are vastly different from healthy subjects secondary to multiple comorbidities and concomitant pharmacotherapy which may influence drug disposition. Indeed, differences exist in the mean clearance and half life of tacrolimus following IV administration between healthy volunteers and adult liver and kidney transplant patients (11).

In a randomized, two-way crossover study in 39 healthy volunteers in the fed state, the 90% CI of the AUC(0-∞) of Sandoz tacrolimus capsules to the reference product was 92.0–99.3% (12). Tacrolimus trough concentrations are considered a surrogate marker of AUC, and if standard bioequivalence criteria are applied to the results of the present study, the 90% CIs for the mean ratio of generic to Prograf trough concentrations are 86.9–95.7% in liver transplant patients and 90.4–96.6% in kidney transplant patients, both of which fall within the FDA's acceptable range for bioequivalence.

Concerns have been raised that the FDA's ‘one size fits all’ approach to bioequivalence may be insufficient to ensure the safety and efficacy of generic immunosuppressive drugs in transplant patients, as these medications have a narrow therapeutic index with a diminutive difference between therapeutic and toxic concentrations. The American Society of Transplantation supports the availability of generic immunosuppressive medications but stresses that bioequivalence should be demonstrated in at-risk populations during the drug approval process (13). In addition, the American Society of Transplant Surgeons has taken the position that bioequivalence testing of generic immunosuppressive products is essential in transplant recipients (14).

In the United States, the average annual patient cost for standard tacrolimus-based immunosupression regimens is substantial (15). High-medication costs may play a role in noncompliance, estimated between 15% and 25% in transplant recipients, which puts patients at risk for rejection and graft loss (16–23). At our institution, the acquisition costs for the 1 mg and 5 mg generic tacrolimus products (Sandoz) are 26% less than the reference product. Patient medication costs and copays are also expected to decrease when the generic product is dispensed in the outpatient setting. Consequently, the use of generic tacrolimus may increase medication compliance and result in favorable patient outcomes. On the other hand, our results suggest that heightened therapeutic drug monitoring is necessary following generic substitution and these costs may offset the savings of the generic product in the short term. In light of these complexities, pharmacoeconomic analyses evaluating generic tacrolimus substitution in solid organ transplantation are warranted.

At the time the study was conducted, only one generic tacrolimus formulation (Sandoz) was on the market. At the present time several additional generic products are now available in the United States, and the most significant risk may be if patients are switched from one generic product to another, potentially resulting in a difference in AUC or Cmax of >20%.

The current study has a few limitations. First, the study population were outpatients and compliance with the tacrolimus regimen was not directly assessed. Second, this study used measured trough concentrations to compare the brand name and generic product. There are conflicting data regarding the correlation between tacrolimus trough concentrations and AUC, with most studies reporting a reasonable correlation (r2= 0.6–0.95) (24–27) and a few studies demonstrating a poor correlation (r2 < 0.5) (28,29). Finally, acute rejection may take months to manifest clinically in the setting of subtherapeutic immunosupression, but the follow-up period in this study was brief, with some patients followed for as few as 15 days after the switch to the generic tacrolimus product.

In summary, switching from the reference tacrolimus product to a generic formulation (Sandoz) resulted in lower C/D ratios and a small but significant drop in tacrolimus concentrations in liver and kidney transplant recipients. Despite this finding, transplant patients currently taking the reference tacrolimus formulation can be safely switched to the Sandoz generic product provided trough concentrations are closely monitored following the substitution.

Disclosure

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

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