• Open Access

Conversion from twice daily tacrolimus capsules to once daily extended-release tacrolimus (LCP-Tacro): Phase 2 trial of stable liver transplant recipients

Authors


  • Some of the data were presented at the 2008 American Transplant Congress in Toronto, Canada, and at the 2012 American Transplant Congress in Boston, MA.

  • The ClinicalTrials.gov identifier for this study is NCT00608244.

  • Funding for this study was provided by Veloxis Pharmaceuticals.

  • Rita R. Alloway received grant funding from Veloxis Pharmaceuticals; Devin E. Eckhoff, W. Kenneth Washburn, and Lewis W. Teperman have nothing to disclose.

Abstract

LCP-Tacro is an extended-release formulation of tacrolimus designed for once-daily dosing. Studies in renal transplantation demonstrate greater bioavailability with similar safety and efficacy vs. twice-daily tacrolimus capsules. In this phase 2 study, adult stable liver transplant patients on tacrolimus capsules (Prograf) twice-daily were converted to tacrolimus tablets (LCP-Tacro) once-daily; patients continued on LCP-Tacro once-daily for days 8–21; target trough levels were 5–15 ng/mL; 24-hour pharmacokinetic (PK) assessments were done on days 7 (baseline pre-switch), 14, and 21. A 6 month extension study phase evaluated PK and safety following a total of 52 weeks of LCP-Tacro. Fifty-seven patients completed LCP-Tacro dosing in the core study; 43 completed the extension phase. The mean conversion ratio was 0.71 (Prograf:LCP-Tacro). PK data demonstrated consistent exposure (AUC) at the lower conversion dose. Cmax, Cmax/Cmin ratio, percent fluctuation and swing were significantly (P<0.001) lower and Tmax significantly (P<0.001) longer for LCP-Tacro vs. Prograf. AUC24 and Cmin correlation coefficients after 7 and 14 days of therapy were ≥0.93. There were no significant differences in PK parameters at week 26 vs. 14. One patient experienced an unrelated serious adverse event (SAE) during the core study and discontinued. There were six unrelated SAEs in the extension and 1 possibly related (rejection) that resolved; there were 3 discontinuations due to AEs during the extension. In this study, patients were safely converted from Prograf twice-daily to LCP-Tacro. The greater bioavailability of LCP-Tacro allowed for once-daily dosing and similar (AUC) exposure at a dose approximately 30% less than the total daily dose of Prograf. LCP-Tacro displayed significantly lower peak and peak-trough fluctuations. LCP-Tacro administered over one year was well tolerated with no new safety concerns. Liver Transpl 20:564–575, 2014. © 2014 AASLD.

Tacrolimus is a cornerstone of the immunosuppression drug regimen used for solid organ transplantation. Tacrolimus was approved as prophylaxis against organ rejection in patients receiving allogeneic liver transplants by the US Food and Drug Administration in April 1994 under the brand name Prograf (tacrolimus capsules, Astellas Pharma US, Inc.). Today, the majority of liver transplant recipients are initiated on tacrolimus as part of their immunosuppression regimen.[1]

Although Prograf capsules have been proven to be highly effective in preventing graft rejection,[2] the drug exhibits significant inter- and intra-individual variability in its absorption and metabolism of tacrolimus.[3] Thus, the standard dosing or total daily dose (TTD) is not an accurate predictor of drug exposure, and tacrolimus trough blood concentrations must be measured to ensure efficacy and safety.[4] Furthermore, Prograf exhibits relatively low bioavailability of tacrolimus (22% ± 6% in adult liver transplant patients) as a result of a combination of poor water solubility, the presystemic metabolism of tacrolimus in the gastrointestinal tract, and the activity of the P-glycoprotein efflux pump found in the enterocytes of the gastrointestinal tract.[5]

In addition to the management of tacrolimus blood levels being complicated by variable intra- and interpatient absorption, interactions with food and concomitant medications, and the relatively low bioavailability of tacrolimus from the Prograf formulation, twice daily dosing is indicated for Prograf. Dosing multiple times per day is associated with an increased risk for poor adherence.[6-9] In a recent study,[10] nearly two-thirds of adult liver transplant recipients reported being nonadherent to their medications. In renal transplantation, poor adherence to immunosuppression drugs is associated with acute rejection and, ultimately, graft loss.[11] In stable liver transplant recipients converted from Prograf to a once daily version of tacrolimus, improved medication adherence was demonstrated.[12]

LCP-Tacro tablets (Envarsus, Veloxis Pharmaceuticals, Hørsholm, Denmark) is a unique extended-release formulation of tacrolimus designed for once daily administration. LCP-Tacro was developed with a proprietary MeltDose drug delivery technology (Veloxis Pharmaceuticals) designed to enhance the bioavailability of drugs with low water solubility. The MeltDose process enhances the absorption of drug substances by the creation of a solid dispersion (or a solid solution) of the drug substance through a physical process called controlled agglomeration. Extended-release products are designed to release their medications in a controlled manner at a predetermined rate and location and for a predetermined duration to achieve and maintain optimum therapeutic blood levels of the drugs. Two important parameters to be considered when the controlled delivery of drugs is being evaluated are fluctuation and swing.[13, 14] The fluctuation percentage is the peak-to-trough change in the drug concentration around the average concentration (Cavg), and the swing percentage is the peak-to-trough change in the drug concentration relative to the minimum concentration (Cmin). Less fluctuation and swing are desirable in a controlled-release drug. Reduced fluctuations in drug plasma concentrations may result in a more continuous effect, and the avoidance of high peak concentrations may reduce the incidence and/or intensity of drug toxicity–related adverse events (AEs).[15]

LCP-Tacro demonstrated greater tacrolimus bioavailability and similar exposure [area under the curve (AUC)] at a dose approximately 30% less than the TTD of Prograf as well as significantly less fluctuation and swing in comparison with Prograf in stable kidney transplant recipients converted to LCP-Tacro.[16] The efficacy of LCP-Tacro has been shown to be noninferior in comparison with Prograf in kidney transplantation.[17] The present study compared the pharmacokinetic (PK) and safety profile of once daily LCP-Tacro tablets to that of twice daily Prograf capsules in stable liver transplant recipients. Long-term safety and tolerability were evaluated during an open-label, 50-week extension phase.

Patients and Methods

Study Design and Conduct

This was a 3-sequence, open-label, multicenter, prospective study of stable liver transplant patients (Fig. 1).

Figure 1.

Study design. *Trough levels (ie, C24 values) were to be at least 24 hours apart. †Weeks since the start of LCP-Tacro in the core study.

After study enrollment, each patient was monitored for 7 days on a fixed dose of twice daily Prograf capsules to ensure stable tacrolimus trough concentrations between 5 and 12 ng/mL. On day 7, a 24-hour PK assessment was conducted for each patient, and blood samples were taken before dosing and at the following hours after dosing: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 12.5, 13, 13.5, 14, 15, 16, 20, and 24. On day 8, each patient was converted to once daily LCP-Tacro tablets with no dose changes allowed; the dose conversion ratio target was 0.70, and the ratio ranged from 0.66 to 0.80 (because of the nominal dosage strengths of LCP-Tacro that were available). The patients continued on a fixed dose of LCP-Tacro for the second week of the study (days 8-14). Tacrolimus trough blood levels (Cmin values) were obtained once between days 9 and 11 and once between days 11 and 13 with at least 48 hours between the 2 measurements to ensure that tacrolimus blood concentrations remained between 5 and 15 ng/mL. On days 14 and 21, a 24-hour PK assessment was conducted; blood samples were taken before dosing and at the following hours after dosing: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, and 24. For the purpose of summarizing the data, PK results were summarized according to the planned timing for the PK samples (ie, days 7, 14, and 21). One dose adjustment was allowed during the study period on day 15 for patients whose mean tacrolimus trough levels changed more than 25% from the mean tacrolimus trough levels during the initial 7 days of the study. For those patients, the LCP-Tacro dose could be adjusted up or down by 25% on the morning of day 15. If a patient's trough levels were maintained between 5 and 15 ng/mL during study days 8 to 14 without any need for a change in the study drug dose, the patient proceeded to study days 15 to 21 on the same fixed dose of once daily LCP-Tacro tablets. Tacrolimus trough blood levels were obtained once between days 16 and 18 and once between days 18 and 20, with at least 48 hours between the 2 measurements. On the morning of day 22, the patients were converted back to their regular maintenance regimen of twice daily Prograf capsules except for those patients continuing to the extension phase of the study. A follow-up safety visit was conducted on day 53.

After the core study, eligible subjects could enter an open-label extension phase in which they were maintained on LCP-Tacro for an additional 50 weeks at a dose determined by each center's standard of care. The recommended whole blood trough level was 5 to 15 ng/mL. A 24-hour PK assessment was performed in week 26; blood samples were taken before dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, and 24 hours after dosing.

Participants

All participants provided written consent for participation; this study was conducted in accordance with the Helsinki Declaration of 1975. The study protocol received a priori approval by the appropriate institutional review committee.

Inclusion and Exclusion Criteria

Eligible participants were adult (18- to 65-year-old) liver transplant recipients at least 6 months after transplantation with serum creatinine levels ≤ 2.5 mg/dL and liver function test results [serum bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and gamma-glutamyltransferase] ≤ 2 times the upper limit of normal before enrollment who were on oral Prograf therapy as part of their maintenance immunosuppression therapy. The Prograf dose had to be been stable with tacrolimus trough levels between 5 and 12 ng/mL for 4 or more weeks before enrollment. Patients could continue to take mycophenolate mofetil (CellCept, Roche Laboratories, Nutley, NJ) or delayed-release mycophenolic acid tablets (Myfortic, Novartis Pharmaceuticals Corp., East Hanover, NJ) as long as the doses had been stable for 4 weeks or more before enrollment. The exclusion criteria included the receipt of any transplanted organ other than the liver, a white blood cell count ≤ 2.3 × 109/L, a total Prograf dose for 24 hours < 3 mg, the use of any drug interfering with tacrolimus metabolism, sirolimus use within the 3 months before screening, acute rejection requiring antibody therapy within the 6 months before enrollment, treatment for acute rejection within the 30 days before enrollment, a recurrent hepatitis C virus infection, active treatment with antiviral therapy, and any gastrointestinal disorder that may have affected the absorption of tacrolimus.

Primary Objective

The primary objective of the study was to assess and compare the PK parameters [maximum concentration (Cmax), concentration at 24 hours (C24), and AUC] and safety of LCP-Tacro tablets and Prograf capsules.

Secondary Objectives

The secondary objectives of the study were to determine the mean conversion ratio of twice daily Prograf capsules to once daily LCP-Tacro tablets and to evaluate the safety of LCP-Tacro versus Prograf. Safety was evaluated through the monitoring of AEs, serious adverse events (SAEs), vital signs, clinical laboratory test results, physical examinations, and electrocardiograms (ECGs).

Sample Size Determination

The sample size was calculated on the basis of the endpoint of the equivalence of the natural logarithm–transformed AUC24 under the following assumptions: two 1-sided tests, equivalence limits of 80% to 125%, and a common standard deviation of 0.220. If the sample in each group had been 18, a 2-group design would have had 80% power to reject the null hypothesis that the test mean and the standard mean were not equivalent. For this 1-sample study, the estimated sample size needed per group was doubled to get the best estimate for the true sample size needed; when we took into consideration a dropout rate of approximately 30%, the total estimated patient population was 50.

Statistical Analysis

All demographic data, PK parameters, laboratory data, and AEs were summarized with descriptive statistics.

PK parameters [AUC24, Cmax, Cmin, Cavg, and time of the maximum concentration (Tmax)] were calculated from blood concentration–time data via noncompartmental analysis. An analysis of variance was performed on natural logarithm–transformed PK parameters and on untransformed parameters (fluctuation and swing percentages and Cmax/Cmin). The model included treatment as a factor. The ratios of geometric least squares means and 90% confidence intervals were calculated for AUC24, Cmax, and Cmin for the following 3 comparisons: day 14 LCP-Tacro versus day 7 Prograf, day 21 LCP-Tacro versus day 7 Prograf, and day 21 LCP-Tacro versus day 14 LCP-Tacro.

Pairwise treatment comparisons were made for Tmax with the Wilcoxon signed-rank test. The mean shift between the 2 treatments was estimated with the median unbiased Hodges-Lehmann estimate. The degree of correlation between AUC24 and Cmin was quantified by the calculation of the Pearson correlation coefficient; both parameters were natural logarithm–transformed before the correlation analysis.

RESULTS

Patient Disposition and Baseline Characteristics

There were 59 patients enrolled from 12 centers. Fifty-seven of the 59 patients who were enrolled and started on LCP-Tacro completed the study (one patient discontinued the study because of an SAE, and another patient discontinued the study for an administrative or other reason). More than half of the patients were male (56%). The mean age was 49.8 ± 11.15 years; most patients were white (78%), and 15% were black (Table 1). Forty-nine patients enrolled in the extension study and received at least 1 dose of the study medication, and 43 patients completed the extension study [the reasons for discontinuation of the extension phase were AEs (n = 3), an administrative or other reason (n = 1; the patient moved out of state), noncompliance with the protocol (n = 1), and withdrawal of consent (n = 1)].

Table 1. Demographic and Baseline Characteristics
CharacteristicIntent-to-Treat Subjects (n = 59)
Male [n (%)]33 (55.9)
Age (years) 
Mean ± standard deviation49.8 ± 11.15
Median52.0
Minimum to maximum20.0-66.0
Race [n (%)] 
White46 (78.0)
Black9 (15.3)
Other4 (6.8)
Not Hispanic or Latino [n (%)]50 (84.7)
Time from transplant to study (months) 
Mean ± standard deviation49.4 ± 41.9
Median32.2
Minimum to maximum6.7-171.4
Most common medical history [n (%)] 
Hepatic cirrhosis10 (16.9)
Chronic hepatic failure10 (16.9)
Cirrhosis alcoholic9 (15.3)
Hepatitis C7 (11.9)
Hepatitis B7 (11.9)

PK Results

The results of the relative tacrolimus bioavailability analysis between the different time points (days 7, 14, and 21) demonstrated that an approximately 30% lower dose of LCP-Tacro was associated with similar AUC24 (ratio of geometric means (RGM) for day 14 versus day 7 = 94.43%; RGM for day 21 versus day 7 = 102.98%) and trough levels (Cmin) (RGM for day 14 versus day 7 = 92.28%; day 21 versus day 7 = 99.44%) to Prograf but a lower peak (Cmax) (RGM for day 14 versus day 7 = 70.02%; day 21 versus day 7 = 74.86%). Comparisons of days 21 and 14 demonstrated consistency for LCP-Tacro with respect to tacrolimus concentrations (ie, AUC24 values; RGM for day 21 versus AQ6 day 14 = 109.06%), peak levels (ie, Cmax values; RGM for day 21 versus day 14 = 106.91%), and trough levels (ie, Cmin values; RGM for day 21 versus day 14=107.76%).

In terms of specific PK parameters, Cmax values (P < 0.001) and fluctuation (P < 0.001) and swing percentages (P < 0.001) were significantly lower for LCP-Tacro tablets administered once daily versus twice daily therapy with Prograf, whereas Tmax was significantly longer (P < 0.001; Table 2). Figure 2 shows the characteristic fluctuation in the tacrolimus concentration (approximately 6-16 ng/mL) with Prograf and the smaller fluctuation (approximately 7-12 ng/mL) with LCP-Tacro on days 14 and 21. AUC24 and Cmin were significantly correlated (P < 0.001) at each time point (days 7, 14, and 21), and the correlation coefficients between AUC24 and Cmin on days 14 and 21 (LCP-Tacro) were numerically higher than that on day 7 (Prograf), but the magnitude of the difference was not statistically significant. Cmax values, Cmax/Cmin ratios, and fluctuation and swing percentages were significantly higher (P < 0.001) on day 7 (Prograf) versus day 14 (LCP-Tacro) and day 21 (LCP-Tacro; Table 2).

Table 2. Tacrolimus PK Parameters on Days 7, 14, 21, and 26
 Geometric Mean (% CV)Treatment EffectaGeometric Mean (% CV)Treatment Effecta
Twice Daily Prograf CapsulesOnce Daily LCP-Tacro TabletsDay 7 Versus Day 14Day 7 Versus Day 21Day 14 Versus Day 21Extension Phase: Once Daily LCP-Tacro TabletsDay 26 Versus Day 14
Day 7 (n = 57)Day 14 (n = 57)Day 21 (n = 56)Week 26 (n = 44)Day 14 (n = 44)
  1. a

    The treatment effect was derived from an analysis of variance of natural logarithm–transformed parameters except for Tmax; the treatment effect for Tmax was based on the Wilcoxon signed-rank test.

  2. b

    The data are reported as arithmetic means and standard deviations.

  3. c

    Ninety percent confidence intervals for the ratios of means are presented in parentheses.

  4. d

    The data are reported as medians with minimums and maximums in parentheses.

  5. e

    The fluctuation is the degree of plasma concentration fluctuation during the dosing interval with respect to Cavg [ie, 100 × (Cmax − Cmin)/Cavg].

  6. f

    The swing is the degree of plasma concentration swing during the dosing interval with respect to Cmin [ie, 100 × (Cmax − Cmin)/Cmin].

TDD (mg/day)b6.10 ± 2.944.42 ± 2.104.76 ± 2.46   4.62 ± 2.494.51 ± 2.17 
PK parameters         
AUC[24] (ng/hour/mL)196.43 (29.78)185.48 (30.25)202.29 (36.82)0.36 (85.16%-104.70%)c0.64 (92.84%-114.24%)c0.17 (98.31%-120.98%)c175.75 (35.54)192.21 (28.11)0.15 (82.45%-101.39%)c
Cmax (ng/mL)16.86 (42.02)11.80 (32.66)12.62 (43.39)<0.001<0.0010.3811.59 (36.09)12.22 (32.14)0.44
Cmin (ng/mL)6.40 (30.76)5.91 (37.38)6.37 (38.44)0.260.940.295.36 (43.64)6.11 (33.22)0.08
Cavg (ng/mL)8.18 (29.77)7.72 (30.27)8.42 (36.82)0.360.640.177.32 (35.62)8.01 (28.11)0.15
Cmax/Cmin ratiob2.75 ± 0.812.12 ± 0.832.08 ± 0.67<0.001<0.0010.76   
Tmax (hours)d1.50 (0.50-20.00)6.00 (1.00-16.00)6.00 (1.03-16.00)<0.001<0.0010.604.99 (1.47-24.00)6.01 (1.50-16.00)0.24
Fluctuation (%)be133.34 ± 56.1879.19 ± 47.1276.58 ± 40.95<0.001<0.0010.7689.45 ± 56.4078.64 ± 43.180.23
Swing (%)bf174.87 ± 80.70112.44 ± 83.36107.97 ± 67.32<0.001<0.0010.76134.49 ± 102.45110.61 ± 73.610.14
Pearson linear correlation coefficient between AUC[24] and Cmin0.8950.9350.935   0.9220.914 
Figure 2.

Mean whole blood tacrolimus concentrations in patients on days 7, 14, and 21 and in week 26 versus time (n = 44).

Black patients tended to have higher mean AUC24 values, Cmax values, and degrees of fluctuation and swing in comparison with nonblack patients (Table 3). However, there were too few black patients for any statistical analyses to be performed according to ethnicity.

Table 3. Tacrolimus PK Parameters: Black and Nonblack Patients
 Black SubjectsNonblack Subjects
Prograf Capsules (Twice Daily)LCP-Tacro Tablets (Once Daily)Prograf Capsules (Twice Daily)LCP-Tacro Tablets (Once Daily)
Day 7 (n = 9)Day 14 (n = 9)Day 21 (n = 9)Day 7 (n = 48)Day 14 (n = 48)Day 21 (n = 47)
  1. NOTE: Statistical testing was not performed because of the small number of black patients.

  2. a

    The data are reported as arithmetic means and standard deviations.

  3. b

    The data are reported as medians with minimums and maximums in parentheses.

  4. c

    The fluctuation is the degree of plasma concentration fluctuation during the dosing interval with respect to Cavg [ie, 100 × (Cmax − Cmin)/Cavg].

  5. d

    The swing is the degree of plasma concentration swing during the dosing interval with respect to Cmin [ie, 100 × (Cmax − Cmin)/Cmin].

TDD (mg/day)a8.22 ± 3.965.67 ± 2.746.44 ± 3.575.71 ± 2.584.18 ± 1.794.48 ± 2.09
PK parameters      
AUC[24] (ng/hour/mL)205.09 (41.44)194.91 (33.22)189.76 (33.86)194.85 (26.99)183.77 (29.88)204.78 (37.43)
Cmax (ng/mL)18.73 (46.10)13.22 (32.10)12.48 (34.49)16.53 (41.21)11.55 (32.70)12.64 (45.07)
Cmin (ng/mL)6.51 (41.03)5.96 (38.92)5.65 (32.46)6.38 (28.70)5.90 (37.49)6.51 (38.92)
Cavg (ng/mL)8.53 (41.51)8.11 (33.34)7.89 (33.87)8.12 (26.96)7.65 (29.89)8.53 (37.42)
Cmax/Cmin ratioa2.89 ± 0.342.46 ± 1.312.28 ± 0.642.72 ± 0.872.06 ± 0.712.04 ± 0.68
Tmax (hours)b1.47 (1.00-8.00)6.00 (1.50-12.48)4.27 (1.50-8.02)1.50 (0.50-20.00)6.00 (1.00-16.00)6.00 (1.03-16.00)
Fluctuation (%)ac145.58 ± 31.6395.09 ± 67.7288.80 ± 36.22131.04 ± 59.6376.21 ± 42.5274.24 ± 41.74
Swing (%)ad189.49 ± 33.60145.70 ± 131.11127.56 ± 63.63172.12 ± 86.71106.20 ± 71.43104.22 ± 68.01

The overall systemic exposure (AUC24) to LCP-Tacro in week 26 was approximately 9% lower than that on day 14, Cmax was approximately 5% lower in week 26 versus day 14, and Cmin was approximately 12% lower in week 26 versus day 14, but the differences in these 3 PK parameters were not statistically significant (P > 0.05) between the 2 time points. The fluctuation and swing percentages were higher in week 26 versus day 14, but the differences between the time points were not statistically significant. The mean Tmax value was 4.99 hours in week 26 and 6.01 hours on day 14 (P = 0.24). AUC24 and Cmin were significantly correlated (P < 0.001) on day 14 and in week 26. Figure 2 shows the mean tacrolimus whole blood concentration–time profiles for day 14 and week 26 and demonstrates the similarity between the LCP-Tacro PK profiles at the different time points. The RGMs demonstrated that AUC24 (91.43%), Cmax, (94.86%) and Cmin (87.70%) were similar for day 14 and week 26. The lack of significant PK differences between days 14 and 21 and week 26 suggests that LCP-Tacro is not associated with significant tacrolimus accumulation. If the numeric increases in the AUC, Cmax, and Cmin values were indications of some accumulation, the accumulation was small and not statistically significant.

Safety

Extent of Exposure

Figure 3 displays the mean daily doses of tacrolimus during the study periods. The mean daily dose of tacrolimus for the preswitch study period of Prograf was 6.1 ± 2.94 mg. The mean daily doses of tacrolimus for the postswitch study periods of LCP-Tacro dosing were 4.4 ± 2.10 mg for days 7 to 14 and 4.8 ± 2.46 mg for days 14 to 21. Trough levels were stable during the various study periods and within the 5 to 15 ng/mL range (the mean level ranged from 6.9 to 8.2 ng/mL, and the median level ranged from 6.2 to 7.8 ng/mL). If the mean tacrolimus trough levels changed more than 25% from the mean tacrolimus trough levels during the initial 7 days of the study, the LCP-Tacro dose could be adjusted up or down by 25% on the morning of day 15. A total of 23 subjects had a dose adjustment for this reason during study days 15 to 21; 1 subject had a dose adjustment due to an AE unrelated to the study drug (mildly elevated liver function test results that recovered/resolved). The subject stayed in the study and completed the extension phase of the study.

Figure 3.

Tacrolimus mean daily doses and trough levels during the study.

During the extension phase of the study, the mean daily dose of tacrolimus was 4.6 ± 2.37 mg. The mean trough levels ranged from 6.8 to 8.2 ng/mL (the median levels ranged from 6.8 to 7.8 ng/mL) throughout the extension phase.

AEs

Table 4 summarizes the occurrence of AEs by drug exposure during the core study and during the extension phase of the study. During the core study, 59% and 14% of the patients experienced an AE during exposure to LCP-Tacro and Prograf, respectively. During the extension phase, 90% of the patients experienced an AE. Overall, most AEs were mild or moderate and were not considered related to the study drugs.

Table 4. AEs During the Study
 2012 Study (PK Phase) 
LCP-Tacro (n = 59)Prograf (n = 59)Extension Phase: LCP-Tacro (n = 49)
  1. NOTE: The data are reported as numbers of subjects and percentages.

All AEs35 (59.3)8 (13.6)44 (89.8)
Relation to study drug   
Not related20 (33.9)8 (13.6)34 (69.4)
Related15 (25.4)010 (20.4)
Severity   
Mild22 (37.3)6 (10.2)16 (32.7)
Moderate11 (18.6)1 (1.7)21 (42.9)
Severe2 (3.4)1 (1.7)7 (14.3)
AEs occurring in ≥5% of patients   
Fatigue6 (10.2)08 (16.3)
Headache4 (6.8)1 (1.7)8 (16.3)
Diarrhea3 (5.1)04 (8.2)
Peripheral edema3 (5.1)03 (6.1)
Upper respiratory tract infection3 (5.1)1 (1.7)2 (4.1)
Back pain3 (5.1)03 (6.1)
Dizziness4 (6.8)1 (1.7)1 (2.0)
Tremor4 (6.8)1 (1.7)1 (2.0)
Nausea3 (5.1)01 (2.0)
Pyrexia01 (1.7)3 (6.1)
Urinary tract infection1 (1.7)03 (6.1)
Pruritus004 (8.2)
Contusion3 (5.1)00
Insomnia003 (6.1)

AEs that occurred in ≥5% of the patients included fatigue, dizziness, tremor, nausea, pyrexia, upper respiratory infection, urinary tract infection, pruritus, insomnia, back pain, headache, diarrhea, and peripheral edema. Most AEs were mild or moderate.

During the core study, 1 patient experienced an SAE that was unrelated to the treatment and discontinued the study because of the event. One other patient discontinued the study because of an AE. There were 6 unrelated SAEs in the extension and 1 possibly related SAE (rejection) that was resolved; there were 3 discontinuations due to AEs during the extension. No patients experienced graft loss or death during the core study or extension phase.

Clinical Laboratory Values and Vital Signs

There were no clinically significant changes in clinical laboratory variables or vital signs. Mean values for most of the laboratory results remained within the expected ranges for liver transplant recipients. Figure 4 displays the values of liver function tests during the course of the study periods. The mean changes from the baseline to week 52 were 0.26 ± 11.31 U/L for AST, −2.11 ± 11.42 U/L for ALT, 2.30 ± 18.64 U/L for alkaline phosphatase; and −6.42 ± 65.20 U/L for gamma-glutamyltransferase. The mean change in the total bilirubin level was 0 mg/dL.

Figure 4.

Liver function tests during the study: AST, ALT, and alkaline phosphatase.

DISCUSSION

In this phase 2 prospective study, stable adult liver transplant recipients were safely converted from traditional twice daily Prograf capsules to a fixed dose of once daily LCP-Tacro tablets, and the required dose was approximately 30% less than the TTD of Prograf. The greater bioavailability of LCP-Tacro allows once daily dosing with similar systemic exposure and trough levels achieved. In comparison with Prograf, LCP-Tacro results in more consistent exposure over the course of 24 hours; specifically, Tmax is longer, and peak and peak-to-trough fluctuations and swing values are reduced. This PK profile is characteristic of LCP-Tacro and was seen also in our previous conversion trial for kidney transplantation: the Cmax values, Cmax/Cmin ratios, and fluctuation and swing percentages were significantly lower for LCP-Tacro versus Prograf, and Tmax was significantly longer.[16] The robust correlation between AUC24 and Cmin with LCP-Tacro demonstrates that the current practice of therapeutic drug monitoring of Cmin as a measure of tacrolimus exposure can also be applied to LCP-Tacro. In addition to the increased tacrolimus bioavailability associated with LCP-Tacro, the reduced peak-to-trough fluctuations found for LCP-Tacro versus Prograf and the excellent interday reproducibility for PK parameters suggest a tighter and more consistent relationship between the dose given and the tacrolimus exposure level for LCP-Tacro versus Prograf. This aspect has the potential to simplify the management of the liver transplant patient and may result in less intrasubject variability and fewer dose changes and thus more time spent within the targeted therapeutic range; this hypothesis remains to be tested.

Although outcomes of liver transplantation are excellent, with the cumulative incidence of rejection less than 20% in the first year,[18] late complications such as renal failure are of concern.[19] LCP-Tacro was formulated with the proprietary MeltDose technology with the goal of improving dosing convenience and potentially the tolerability of tacrolimus for kidney transplant patients. The hypothesis was that LCP-Tacro would offer once daily administration and a flatter PK profile that would be potentially beneficial in mitigating peak-related effects such as nephrotoxic and neurotoxic effects of tacrolimus. Tacrolimus neuro- and nephrotoxicities are usually linked to higher doses as well as higher peak levels. Because of the reduction in peak-to-trough fluctuations, the lower Cmax values, and the longer Tmax values of LCP-Tacro versus Prograf, LCP-Tacro may offer transplant patients experiencing peak-related tacrolimus-induced toxicities an alternative to part of their immunosuppressive regimen.

Results from the extension phase of the study demonstrate that the PK profile of LCP-Tacro after 6 months of therapy is comparable to that after 14 days of therapy. The safety profile observed with a combined total of 52 weeks of LCP-Tacro treatment in the setting of stable liver transplants was consistent with findings generally observed in such patients. One patient experienced mild acute rejection that responded to glucocorticoid treatment, and that patient was able to continue treatment with LCP-Tacro.

Black patients tended to have a higher exposure to tacrolimus with a greater degree of fluctuation in blood concentrations of tacrolimus in comparison with nonblack patients. The PK differences between blacks and nonblacks seen in this study were consistent with widely reported differences in tacrolimus absorption and metabolism reported from other studies. It is well documented that, largely because of a high frequency of the CYP3A5 genetic polymorphism (which acts to increase the clearance and lower the oral bioavailability of tacrolimus), blacks require higher tacrolimus drug doses to achieve the same drug level achieved by nonblacks.[20-26] Specifically, the wild-type gene CYP3A5*1, which allows significant production of cytochrome P450 3A5, is reportedly absent in 60% to 90% of nonblacks and yet is present in 55% of blacks. This may partially account for lower tacrolimus troughs and higher tacrolimus dose requirements among blacks.[27] The results suggest that the lower dosing benefit and favorable PK profile associated with LCP-Tacro were evident in both nonblacks and blacks who were converted from Prograf. However, the small number of black patients in this study precluded statistical testing of LCP-Tacro and Prograf among black patients.

Results from the extension study demonstrate that the overall systemic exposure, the peak systemic exposure, and the tacrolimus trough levels were similar after 6 months of therapy and 14 days of therapy.

Furthermore, the degrees of fluctuation and swing and the median Tmax values were not statistically significantly different between week 26 and day 14 of therapy. A statistically significant correlation between AUC24 and Cmin was seen for week 26 and day 14.

In this study, most AEs were mild or moderate; they did not significantly differ between the drug groups; and the incidence, type, and severity of AEs were within the range expected for this patient population. Most of the AEs were not related to the study drugs, and there was no specific AE or unexpected trend of AEs that indicated a tacrolimus-related event. Overall, no new safety concerns related to LCP-Tacro were raised by the results of this study. Although most of the AEs were reported when patients were converted from Prograf to LCP-Tacro, this could reflect an increased awareness and reporting of AEs from clinicians due to the starting of a new medication. Importantly, the incidence of AEs decreased in the extension phase despite the continued treatment. Laboratory values, including liver and renal function values, remained stable during the study.

In addition to the benefits of the enhanced PK parameters associated with LCP-Tacro, the once daily dosing of LCP-Tacro may also help to optimize tacrolimus therapy in liver transplantation. Maintaining effective immunosuppressive drug levels is essential to preventing rejection, and a lack of adherence to prescribed immunosuppression drug regimens is a barrier to successful transplant outcomes.[11, 28] Unfortunately, a lack of adherence has been reported to be common in transplant recipients.[29-31] A greater dose frequency is inversely related to medication adherence.[8, 9, 32, 33] Thus, the once daily dosing afforded by LCP-Tacro may be associated with increased medication adherence. Well-designed studies are needed to evaluate this potential advantage of once daily LCP-Tacro.

The findings of this article appear to contrast with those of other publications[12, 34, 35] in which a 1:1-mg conversion was associated with lower tacrolimus trough levels when stable liver patients were converted from Prograf to Advagraf, another once daily tacrolimus formulation. On the contrary, all patients in this study, blacks and nonblacks, benefited from a lower TTD and consistent trough levels immediately upon conversion and throughout the course of the 1-year study. Whether de novo liver transplant patients require a higher initial starting dose to rapidly achieve therapeutic tacrolimus levels remains to be tested.

The results from this study demonstrated that stable liver transplant patients could be converted to LCP-Tacro tablets with a mean conversion ratio of 0.71 (ie, a fixed dose approximately 30% less than the TTD of Prograf). LCP-Tacro showed greater bioavailability and lower peak and peak-to-trough fluctuations in the steady state and overall flatter kinetics in comparison with Prograf. The PK profile of LCP-Tacro after 6 months of therapy was comparable to that after 14 days of therapy, and no new safety concerns were observed during this 1-year study.

ACKNOWLEDGMENT

The following investigators were involved in this study: Hugo Vargas, M.D. (Mayo Clinic, Phoenix, AZ); Lewis W. Teperman, M.D. (New York University Langone Medical Center, New York, NY); Rita R. Alloway, Pharm.D. (University of Cincinnati Medical Center, Cincinnati, OH); Devin E. Eckhoff, M.D. (University of Alabama, Birmingham, AL); W. Kenneth Washburn, M.D. (University of Texas Health Science Center, San Antonio, TX); Russell Wiesner, M.D. (Mayo Clinic Hospital, Rochester, MN); A. Osama Gaber, M.D. (Methodist Hospital, Houston, TX); Richard B. Freeman, Jr., M.D. (Tufts New England Medical Center, Boston, MA); Robyn Chudzinski, Pharm.D. (Beth Israel Deaconess Medical Center, Boston, MA); John Lake, M.D. (University of Minnesota Medical Center, Minneapolis, MN); Juan Del Rio Martin, M.D. (Recanati/Miller Transplantation Institute, Mt. Sinai School of Medicine, New York, NY); and Andreas G. Tzakis, M.D. (University of Miami, Miami, FL). Medical writing support, directed by the authors, was provided by Kristin Kistler, Ph.D. (Evidera).

Abbreviations
AE

adverse event

ALT

alanine aminotransferase

AST

aspartate aminotransferase

AUC

area under the curve

AUC24

area under the curve at 24 hours

C24

concentration at 24 hours

Cavg

average concentration

Cmax

maximum concentration

Cmin

minimum concentration

CV

coefficient of variation

ECG

electrocardiogram

H&C

hematology and chemistry

PK

pharmacokinetic

RGM

ratio of geometric means

SAE

serious adverse event

SE

standard error

TDD

total daily dose

Tmax

time of the maximum concentration

Ancillary

Advertisement