Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Mammalian target of rapamycin (mTOR) kinase inhibitors. ATC code: L04AH02.

Mechanism of action
Everolimus, a proliferation signal inhibitor, prevents allograft rejection in rodent and non-human primate models of allotransplantation. It exerts its immunosuppressive effect by inhibiting the proliferation, and thus clonal expansion, of antigen-activated T cells, which is driven by T cell-specific interleukins, e.g. interleukin-2 and interleukin-15. Everolimus inhibits an intracellular signalling pathway, which is triggered upon binding of these T cell growth factors to their respective receptors, and which normally leads to cell proliferation. The blockage of this signal by everolimus leads to an arrest of the cells at the G1 stage of the cell cycle.


At the molecular level, everolimus forms a complex with the cytoplasmic protein FKBP-12. In the presence of everolimus, the growth factor-stimulated phosphorylation of the p70 S6 kinase is inhibited. Since p70 S6 kinase phosphorylation is under the control of FRAP (also called mTOR), this finding suggests that the everolimus-FKBP-12 complex binds to and thus interferes with the function of FRAP. FRAP is a key regulatory protein that governs cell metabolism, growth and proliferation; disabling FRAP function thus explains the cell cycle arrest caused by everolimus.

Everolimus thus has a different mode of action to ciclosporin. In preclinical models of allotransplantation, the combination of everolimus and ciclosporin was more effective than either compound alone.

The effect of everolimus is not restricted to T cells. It inhibits growth factor-stimulated proliferation of hematopoietic as well as non-hematopoietic cells in general, such as vascular smooth muscle cells.
Growth factor-stimulated vascular smooth muscle cell proliferation, triggered by injury to endothelial cells and leading to neointima formation, plays a key role in the pathogenesis of chronic rejection.
Preclinical studies with everolimus have shown inhibition of neointima formation in a rat aorta allotransplantation model.

Clinical efficacy and safety
Renal transplantation
Certican in fixed doses of 1.5 mg/day and 3 mg/day, in combination with standard doses of ciclosporin for microemulsion and corticosteroids, was investigated in two Phase III de novo adult renal transplant trials (B201 and B251). Mycophenolate mofetil (MMF) 1 g b.i.d was used as comparator. The co- primary composite endpoints were efficacy failure (biopsy-proven acute rejection, graft loss, death or loss to follow-up) at 6 months, and graft loss, death or loss to follow-up at 12 months. Certican was, overall, non-inferior to MMF in these trials. The incidence of biopsy-proven acute rejection at 6 months in the B201 study was 21.6%, 18.2%, and 23.5% for the Certican 1.5 mg/day, Certican 3 mg/day and MMF groups, respectively. In study B251, the incidences were 17.1%, 20.1%, and 23.5% for the Certican 1.5 mg/day, Certican 3 mg/day and MMF groups, respectively.

Reduced allograft function with elevated serum creatinine was observed more frequently among subjects using Certican in combination with full-dose ciclosporin for microemulsion than in MMF patients. This effect suggests that Certican increases ciclosporin nephrotoxicity. Drug concentration- pharmacodynamic analysis showed that renal function was not impaired with reduced exposure to ciclosporin, while conserving efficacy for as long as the blood trough everolimus concentration was maintained above 3 ng/ml. This concept was subsequently confirmed in two further Phase III studies (A2306 and A2307, including 237 and 256 patients, respectively), which evaluated the efficacy and safety of Certican 1.5 mg and 3 mg per day (initial dosing; subsequent dosing based on target trough concentration ≥3 ng/ml) in combination with reduced exposure to ciclosporin. In both studies, renal function was preserved without compromising efficacy. In these studies, however, there was no non- Certican comparative arm. A Phase III, multicentre, randomised, open-label, controlled trial (A2309) has been completed in which 833 de novo renal transplant recipients were randomised to one of two Certican regimens, differing by dosage, and combined with reduced-dose ciclosporin or a standard regimen of sodium mycophenolate (MPA) + ciclosporin, and treated for 12 months. All patients received induction therapy with basiliximab pre-transplant, and on Day 4 post-transplant. Steroids were given as required post-transplant.

Starting dosages in the two Certican groups were 1.5 mg/day and 3 mg/day, given in two divided doses., subsequently modified from Day 5 onwards to maintain target blood trough everolimus concentrations of 3-8 ng/ml and 6-12 ng/ml, respectively. Sodium mycophenolate dosage was 1.44 g/day. Ciclosporin dosages were adapted to maintain target blood trough concentration windows as shown in Table 6. The actual measured values for blood concentrations of everolimus and ciclosporin (C0 and C2) are shown in Table 7.

Although the higher-dosage Certican regimen was as effective as the lower-dosage regimen, the overall safety was poorer, and so the higher-dosage regimen is not recommended.
The lower-dosage regimen for Certican is recommended (see section 4.2).

Table 6     Study A2309: Target ciclosporin blood trough concentration windows 
Target ciclosporin C0              Mo 1              Mo 2-3              Mo 4-5           Mo 6-12 (ng/ml)
Certican groups                   100-200             75-150              50-100            25-50 MPA group                         200-300            100-250             100-250           100-250 
Table 7     Study A2309: Measured trough blood concentrations of ciclosporin and everolimus 
Trough                              Certican groups                             MPA concentrations                      (low-dose ciclosporin)                 (standard ciclosporin) (ng/ml)
Certican 1.5 mg           Certican 3.0 mg           Myfortic 1.44 g
Ciclosporin         Co           C2           Co           C2          Co           C2 Day 7        195 ± 106 847 ± 412 192 ± 104 718 ± 319 239 ± 130 934 ± 438 Month 1         173 ± 84    770 ± 364    177 ± 99     762 ± 378 250 ± 119 992 ± 482 Month 3         122 ± 53    580 ± 322    123 ± 75     548 ± 272 182 ± 65 821 ± 273 Month 6         88 ± 55     408 ± 226     80 ± 40     426 ± 225 163 ± 103 751 ± 269 Month 9          55± 24     319 ± 172     51 ± 30     296 ± 183 149 ± 69 648 ± 265 Month 12        55 ± 38     291 ± 155     49 ± 27     281 ± 198 137 ± 55        587± 241 Everolimus          (Target Co 3-8)          (Target Co 6-12)                  - Day 7               4.5 ± 2.3                 8.3 ± 4.8                     - Month 1               5.3 ± 2.2                 8.6 ± 3.9                     - Month 3               6.0 ± 2.7                 8.8 ± 3.6                     - Month 6               5.3 ± 1.9                 8.0 ± 3.1                     - Month 9               5.3 ± 1.9                 7.7 ± 2.6                     - Month 12              5.3 ± 2.3                 7.9 ± 3.5                     - Numbers are mean ± SD of measured values with C0 = trough concentration, C2 = value 2 hours post- dose.

The primary efficacy endpoint was a composite failure variable (biopsy-proven acute rejection, graft loss, death or loss to follow-up). The outcome is shown in Table 8.


Table 8       Study A2309: Composite and individual efficacy endpoints at 6 and 12 months (incidence in ITT population)
Certican 1.5 mg       Certican 3.0 mg           MPA 1.44 g
N=277                N=279                  N=277
% (n)                 % (n)                 % (n)
6 mo      12 mo      6 mo        12 mo       6 mo     12 mo
Composite endpoint (1     0
19.1 (53) 25.3 (70) 16.8 (47) 21.5 (60) 18.8 (52) 24.2 (67) criterion)
0.4%       1.1%     -1.9%
Difference % (Certican - MPA)                                          -2.7%         -         - (-6.2,     (-6.1,    (-8.3,
95% CI                                                            (-9.7, 4.3)     -         - 6.9)       8.3)      4.4)
Individual endpoints (20 criteria)
Treated BPAR                    10.8 (30) 16.2 (45) 10.0 (28) 13.3 (37) 13.7 (38) 17.0 (47) Graft loss                       4.0 (11) 4.3 (12) 3.9 (11) 4.7 (13)           2.9 (8)   3.2 (9) Death                             2.2 (6)    2.5 (7)   1.8 (5)      3.2 (9)    1.1 (3)   2.2 (6) Loss to follow-up                3.6 (10) 4.3 (12)     2.5 (7)      2.5 (7)    1.8 (5)   3.2 (9) Combined endpoints (2 criteria)
0

Graft loss / Death               5.8 (16) 6.5 (18) 5.7 (16) 7.5 (21) 4.0 (11) 5.4 (15) Graft loss / Death / Loss to FU 9.4 (26) 10.8 (30) 8.2 (23) 10.0 (28) 5.8 (16) 8.7 (24) mo = months, 10 = primary, 20 = secondary, CI = confidence interval, non-inferiority margin was 10% Composite endpoint: treated biopsy-proven acute rejection (BPAR), graft loss, death, or loss to follow-up (FU)

Changes in renal function, as shown by calculated glomerular filtration rate (GFR) using the MDRD formula, are shown in Table 9.

Proteinuria was assessed at scheduled visits by spot analysis of urinary protein/creatinine (see Table 10). A concentration effect was shown relating proteinuria levels to everolimus trough concentrations, particularly at Cmin values above 8 ng/ml.

Adverse events reported more frequently in the recommended (lower-dosage) Certican regimen than in the MPA control group have been included in Table 4. A lower frequency of viral infections was reported for Certican-treated patients, resulting principally from lower reporting rates for CMV infection (0.7% vs. 5.95%) and BK virus infection (1.5% vs. 4.8%).

Table 9     Study A2309: Renal function (MDRD-calculated GFR) at 12 months (ITT population)

Certican 1.5 mg      Certican 3.0 mg       MPA 1.44 g
N=277                N=279             N=277
12-month mean GFR (ml/min/1.73 m2)               54.6                  51.3             52.2 Difference in mean (everolimus -                 2.37                 -0.89              - MPA)                                          (-1.7, 6.4)          (-5.0, 3.2)           - 95% CI
12-month GFR missing value imputation: graft loss = 0; death or loss to follow-up for renal function = LOCF1 (last-observation-carried-forward approach 1: End of Treatment (up to Month 12)).
MDRD: modification of diet in renal disease


Table 10      Study A2309: Urinary protein to creatinine ratio

Category of proteinuria (mg/mmol) sub- normal%(n) mild%(n)         nephrotic%(n)        nephrotic%(n)
Treatment             (<3.39)       (3.39-<33.9) (33.9-<339)           (>339) Month 12    Certican 1.5 mg       0.4 (1)       64.2 (174)    32.5 (88)            3.0 (8) (TED)       Certican 3 mg         0.7 (2)       59.2 (164)    33.9 (94)            5.8 (16) MPA 1.44 g            1.8 (5)       73.1 (198)    20.7 (56)            4.1 (11) 1 mg/mmol = 8.84 mg/g
TED: Treatment endpoint (Mo 12 value or last observation carried forward) 
In a 24-month, randomised, multicenter, open-label, 2-arm study (A2433), 2,037 adult recipients with low immunological risk were randomised within 24 hours of renal transplantation to receive either everolimus and reduced CNI (EVR+rCNI) or MPA and standard CNI (MPA+sCNI). In the EVR+rCNI group, the starting dose of everolimus was 3 mg/day as 1.5 mg b.i.d (when given with tacrolimus) or 1.5 mg/day as 0.75 mg b.i.d (when given with ciclosporin). Incidence rates of all efficacy endpoints at month 12 and month 24 are summarized in Table 11. The safety findings are consistent with the known safety profiles of everolimus, MPA, ciclosporin and tacrolimus. The incidence of viral infections such as CMV and BKV infections was 28 (2.8%) and 59 (5.8%) respectively, in the EVR+rCNI group, and 137 (13.5%) and 104 (10.3%) respectively, in the MPA+sCNI group.

Table 11     Study A2433: Comparison between treatments for incidence rates of the composite endpoints (full analysis set)
Efficacy     EVR+ MPA+ Difference             P    EVR+      MPA+ Difference           P endpoints    rCNI     sCNI      (95% CI)    value  rCNI       sCNI      (95%   CI)   value N=       N=                        N = 1022      N=
1022    1015                                     1015
Month 12                              Month 24 eGFR <         489      456         3.0     0.187    489        443         4.2      0.067 50mL/min/ (47.9) (44.9)         (-1.4, 7.3)        (47.9)     (43.7)    (-0.3, 8.7) 1.73m2 or tBPAR# tBPAR,         146      131         1.4     0.353    169        147         0.8      0.782 graft loss,  (14.4) (13.0)      (−1.6, 4.4)        (18.0)     (17.3)   (−4.6, 6.1) or death tBPAR          107       91         1.6     0.243    118         98         0.7      0.794 (10.8)    (9.2)    (−1.1, 4.2)        (12.8)     (12.1)   (−4.4, 5.8) Graft loss     33        28         0.5     0.542     37         32         0.5      0.572 (3.3)    (2.8)    (−1.0, 2.0)         (3.7)      (3.2)   (−1.1, 2.1) Death            20       28         -0.8       0.234        32        36         −0.5        0.634 (2.0)    (2.8)    (−2.2, 0.5)              (3.7)      (4.2)    (−2.7, 1.6) Graft loss       51        54        -0.3       0.732        67        65           0.0       0.970 or death         (5)     (5.4)    (-2.3,1.6)               (7.1)      (7.1)     (-2.5, 2.6) eGFR <           456      424         2.9       0.201       474       423           4.7       0.040 50mL/min/      (44.6)   (41.8)    (-1.5, 7.2)             (46.4)     (41.6)     ( 0.2, 9.2) 1.73m2#


95% CI and p-value to test for no difference ([EVR+rCNI] – [MPA+sCNI] = 0); endpoint highlighted with # is compared using raw incidence rates, other endpoints are compared using Kaplan-Meier incidence rates;
tBPAR: treated biopsy-proven acute rejection; CI: confidence interval; eGFR: estimated glomerular filtration rate; EVR: everolimus; MPA: mycophenolic acid; rCNI: reduced-exposure calcineurin inhibitor; sCNI: standard-exposure calcineurin inhibitor

Cardiac transplantation
In the Phase III cardiac study (B253), both Certican 1.5 mg/day and 3 mg/day, in combination with standard doses of ciclosporin for microemulsion and corticosteroids, was investigated vs. azathioprine (AZA) 1-3 mg/kg/day. The primary endpoint was a composite of the incidence of acute rejection ≥ISHLT grade 3A, acute rejection associated with haemodynamic compromise, graft loss, patient death or loss to follow-up at 6, 12 and 24 months. Both doses of Certican were superior to AZA at 6, 12 and 24 months. The incidence of biopsy-proven acute rejection ≥ISHLT grade 3A at month 6 was 27.8% for the 1.5 mg/day group, 19% for the 3 mg/day group and 41.6% for the AZA group,
respectively (p = 0.003 for 1.5 mg vs. control, <0.001 for 3 mg vs. control).

Based on coronary artery intravascular ultrasound data obtained from a subset of the study population, both Certican doses were statistically significantly more effective than AZA in preventing allograft vasculopathy (defined as an increase in maximum intimal thickness from baseline ≥0.5 mm in at least one matched slice of an automated pullback sequence), an important risk factor for long-term graft loss.

Elevated serum creatinine was observed more frequently among subjects using Certican in combination with full-dose ciclosporin for microemulsion than in AZA patients. These results indicated that Certican increases ciclosporin-induced nephrotoxicity.

Study A2411 was a randomised, 12-month, open-label study comparing Certican in combination with reduced doses of ciclosporin microemulsion and corticosteroids to mycophenolic mofetil (MMF) and standard doses of ciclosporin microemulsion and corticosteroids in de novo cardiac transplant patients.
Certican was initiated at 1.5 mg/day and the dose was adjusted to maintain target blood everolimus trough concentrations of 3-8 ng/ml. MMF dosage was initiated at 1500 mg b.i.d. Ciclosporin microemulsion doses were adjusted to the following target trough concentrations (ng/ml): 
Table 12    Target ciclosporin trough concentrations by month

Target ciclosporin
Mo 1          Mo 2         Mo 3-4        Mo 5-6       Mo 7-12
C0
Certican group          200-350        150-250       100-200       75-150       50-100 MMF group               200-350        200-350       200-300       150-250      100-250 
Actual blood concentrations measured are shown in Table 13.


Table 13 Study A2411: Summary statistics for CsA blood concentrations* (mean ± SD) 
Certican group                         MMF group
(N=91)                              (N=83)
Visit                             C0                                  C0 Day 4                          154 ± 71                            155 ± 96 n=79                                n=74
Mo 1                           245 ± 99                            308 ± 96 n=76                                n=71
Mo 3                           199 ± 96                            256 ± 73 n=70                                n=70
Mo 6                           157 ± 61                            219 ± 83 n=73                                n=67
Mo 9                           133 ± 67                            187 ± 58 n=72                                n=64
Mo 12                          110 ± 50                            180 ± 55 n=68                                n=64
*:whole blood trough concentrations (C0)

Changes in renal function are shown in Table 14. Efficacy outcome is shown in Table 15.

Table 14    Study A2411: Changes in creatinine clearance during study (patients with paired values)

Estimated creatinine clearance (Cockcroft-Gault)* ml/mn
Value at    Difference between
Baseline timepoint          groups
Mean (± SD)
Mean (± SD)    Mean (95% CI)
Certican (n=87)        73.8 (± 27.8)      68.5 (± 31.5)         -7.3 Month 1
MMF (n=78)            77.4 (± 32.6)      79.4 (± 36.0)     (-18.1, 3.4) Certican (n=83)        74.4 (± 28.2)      65.4 (± 24.7)         -5.0 Month 6
MMF (n=72)            76.0 (± 31.8)      72.4 (± 26.4)     (-13.6, 2.9) Certican (n=71)        74.8 (± 28.3)      68.7 (± 27.7)         -1.8 Month 12
MMF (n=71)            76.2 (± 32.1)      71.9 (± 30.0)     (-11.2, 7.5) * includes patients with value at both baseline and visit


Table 15    Study A2411: Efficacy event rates (incidence in ITT population) 
Efficacy endpoint            Certican               MMF              Difference in event rates n=92                  n=84                 Mean (95% CI)
At 6 months
Biopsy-proven acute rejection ≥ ISHLT          18 (19.6%)             23 (27.4%)              -7.8 (-20.3, 4.7) grade 3A
Composite efficacy
26 (28.3%)             31 (36.9%)              -8.6 (-22.5, 5.2) failure *
At 12 months
Biopsy-proven acute rejection ≥ ISHLT          21 (22.8%)             25 (29.8%)              -6.9 (-19.9, 6.1) grade 3A
Composite efficacy
30 (32.6%)             35 (41.7%)              -9.1 (-23.3, 5.2) failure*
Death or graft
10 (10.9%)             10 (11.9%)                      - loss/re-transplant
* Composite efficacy failure: any of the following – acute rejection ≥ grade 3A, acute rejection with haemodynamic compromise, graft loss, death or loss to follow-up.

Study A2310 is a Phase III, multicentre, randomised, open-label study comparing two Certican/reduced-dose ciclosporin regimens against a standard mycophenolate mofetil (MMF)/ciclosporin regimen over 24 months. The use of induction therapy was centre-specific (no- induction or basiliximab or thymoglobulin). All patients received corticosteroids.

Starting doses in the Certican groups were 1.5 mg/day and 3 mg/day, and were adjusted to target blood trough everolimus concentrations of 3-8 ng/ml and 6-12 ng/ml, respectively. The MMF dose was 3 g/day. Ciclosporin dosages targeted the same blood trough concentrations as in study A2411. Blood concentrations of everolimus and ciclosporin are shown in Table 16.

Recruitment to the experimental, higher-dosage Certican treatment arm was prematurely discontinued because of an increased rate of fatalities, due to infection and cardiovascular disorders, occurring within the first 90 days post-randomisation.

Table 16    Study A2310: Measured trough blood concentrations of ciclosporin (CsA) and everolimus

Visit window   Certican 1.5 mg/reduced-dose CsA                 MMF 3 g/std-dose CsA N=279                                            N=268 everolimus (C0 ng/ml) ciclosporin (C0 ng/ml) ciclosporin (C0 ng/ml)
Day 4          5.7 (4.6)               153 (103)                151 (101) Month 1        5.2 (2.4)               247 (91)                 269 (99) Month 3        5.4 (2.6)               209 (86)                 245 (90) Month 6        5.7 (2.3)               151 (76)                 202 (72) Month 9        5.5 (2.2)               117 (77)                 176 (64) Month 12       5.4 (2.0)               102 (48)                 167 (66) Numbers are the mean (standard deviation) of measured values of C0=trough concentration 

Efficacy outcome at 12 months is shown in Table 17.

Table 17     Study A2310: Incidence rates of efficacy endpoints by treatment group (ITT population – 12-month analysis)

Certican 1.5 mg            MMF
N=279                N=271
Efficacy endpoints                                          n (%)                n (%) Primary: Composite efficacy failure                       99 (35.1)            91 (33.6) - AR associated with HDC                                   11 (3.9)              7 (2.6) - BPAR of ISHLT grade ≥ 3A                                63 (22.3)            67 (24.7) - Death                                                    22 (7.8)             13 (4.8) - Graft loss/re-transplant                                  4 (1.4)              5 (1.8) - Loss to follow-up                                         9 (3.2)             10 (3.7) Composite efficacy failure: biopsy-proven acute rejection (BPAR) episodes of ISHLT grade ≥ 3A, acute rejection (AR) associated with haemodynamic compromise (HDC), graft loss/re- transplant, death, or loss to follow-up.

The higher fatality rate in the Certican arm relative to the MMF arm was mainly the result of an increased rate of fatalities from infection in the first three months among Certican patients receiving thymoglobulin induction therapy. The imbalance in fatalities within the thymoglobulin subgroup was particularly evident among patients hospitalised prior to transplantation and with L-ventricular assistance devices (see section 4.4).

Renal function over the course of study A2310, assessed by calculated glomerular filtration rate (GFR) using the MDRD formula, was 5.5 ml/min/1.73 m2 (97.5% CI -10.9, -0.2) lower for the everolimus 1.5 mg group at Month 12.

This difference was mainly observed in centres where the mean ciclosporin concentrations were similar throughout the study period in patients receiving Certican and in patients randomised to the control arm. This finding underlines the importance of reducing the ciclosporin concentrations when combined with everolimus as indicated in Table 18 (see also section 4.2): 
Table 18     Target ciclosporin trough concentrations per month

Target ciclosporin C0       Mo 1          Mo 2          Mo 3-4       Mo 5-6       Mo7-12 Certican group             200-350       150-250        100-200       75-150       50-100 MMF group                  200-350       200-350        200-300      150-250      100-250 
Additionally, the difference was mainly driven by a difference developed during the first month post- transplantation when patients are still in an unstable haemodynamic situation, possibly confounding the analysis of renal function. Thereafter, the decrease in mean GFR from Month 1 to Month 12 was significantly smaller in the everolimus group than in the control group (-6.4 vs. -13.7 ml/min, p=0.002).

Proteinuria, expressed as urinary protein: creatinine levels measured in spot urine samples, tended to be higher in the Certican-treated patients. Sub-nephrotic values were observed in 22% of the patients receiving Certican compared to MMF patients (8.6%). Nephrotic levels were also reported (0.8%), representing 2 patients in each treatment group (see section 4.4).

The adverse reactions for the everolimus 1.5 mg group in Study A2310 are consistent with the adverse drug reactions presented in Table 4. A lower rate of viral infections was reported for Certican-treated patients, resulting principally from a lower reporting rate for CMV infection compared to MMF (7.2% vs. 19.4%).


Hepatic transplantation
In the Phase III adult hepatic transplant study (H2304), reduced exposure tacrolimus and Certican 1.0 mg twice daily was administered to patients, with the initial Certican dose 4 weeks after transplantation, and was investigated versus standard exposure tacrolimus. Certican was dose adjusted to maintain target blood everolimus trough concentrations between 3-8 ng/ml for the Certican + reduced tacrolimus arm. Tacrolimus doses were subsequently adjusted to achieve target trough concentrations between 3-5 ng/ml during 12 months in the Certican + reduced tacrolimus arm.

Only 2.6% of study participants in H2304 were black so this study provides only limited efficacy and safety data on this population (see section 4.2)

Overall, in the 12-month analysis, the incidence of the composite endpoint (tBPAR, graft loss or death) was lower in the Certican + reduced tacrolimus arm (6.7%) compared to the tacrolimus control arm (9.7%) and consistent results were observed at 24 months (see Table 19).

The results of individual components of the composite endpoint are shown in Table 20.

Table 19     Study H2304: Comparison between treatment groups for Kaplan-Meier incidence rates of primary efficacy endpoints (ITT population – 12 and 24-month analysis) 
EVR+Reduced TAC            TAC control
N=245                   N=243
Statistic
12-month                   12-
24-month               24-month month
Number of composite efficacy failures
(tBPAR, graft loss or death) from                        16           24          23          29 randomisation till Month 24/12
KM estimate of incidence rate of composite efficacy failure (tBPAR*, graft loss or death) at       6.7%        10.3%       9.7%        12.5% Month 24/12
Difference in KM estimates (vs. control)               -3.0%         2.2% (-8.8%,
97.5% CI for difference                             (-8.7%, 2.6%)
4.4%)
P-value Z-test (EVR+Reduced TAC - Control
= 0)                                                   0.230        0.452 (No difference test)
P-value* Z-test (EVR+Reduced TAC - Control
≥0.12)                                                 <0.001       <0.001 (Non-inferiority test)
*tBPAR = treated biopsy-proven acute rejection


Table 20     Study H2304: Comparison between treatment groups for incidence rates of secondary efficacy endpoints (ITT population – 12 and 24-month analysis) 
Efficacy                 EVR/Reduced         TAC         Risk diff. (95% CI)       P-value* endpoints                   TAC             control
N=245            N=243 n (%)            n (%)
Graft loss
12-month                    6 (2.4)         3 (1.2)        1.2 (-7.8, 10.2)         0.5038 24-month                    9 (3.9)         7 (3.2)        0.8% (-3.2, 4.7)          0.661
Death
12-month                    9 (3.7)         6 (2.5)        1.2 (-7.8, 10.1)         0.6015 24-month                   12 (5.2)        10 (4.4)        0.8% (-3.7, 5.2)          0.701
BPAR1
12-month                   10 (4.1)        26 (10.7)      -6.6 (-11.2, -2.0)        0.0052 24-month                   14 (6.1)        30 (13.3)     -7.2% (-13.5, -0.9)         0.010 tBPAR2
12-month                    7 (2.9)        17 (7.0)         -4.1 (-8.0, -0.3)       0.0345 24-month                   11 (4.8)        18 (7.7)        -2.9% (-7.9, 2.2)         0.203

1. BPAR = biopsy-proven acute rejection; 2. tBPAR = treated biopsy-proven acute rejection *All p-values are for two-sided test and were compared to 0.05 significance level.

Comparison between treatment groups for change in eGFR (MDRD4) [ml/min/1.73 m2] from time of randomisation (day 30) to Month 12 and 24 demonstrated superior renal function for the Certican + reduced tacrolimus arm (see Table 21).

Table 21     Study H2304: Comparison between treatment groups for eGFR (MDRD 4) at Month 12 (ITT population – 12 and 24-month analysis)

Difference vs. control
LS mean          LSM                          P-
Treatment            N             (SE)       mean (SE)     97.5% CI      value(1) P-value(2) EVR+Reduced
TAC
12-month            244        -2.23 (1.54)   8.50 (2.12) (3.74, 13.27)    <0.001       <0.001 24-month            245        -7.94 (1.53)   6.66 (2.12) (1.9, 11.42)     <0.0001      0.0018
TAC control
12-month            243       -10.73 (1.54)
24-month            243       -14.60 (1.54)
Least squares means, 97.5% confidence intervals and p-values are from an ANCOVA model containing treatment and HCV status as factors, and baseline eGFR as a covariate.
P-value (1): Non-inferiority test with NI margin = -6 ml/min/1.73m2, at one-sided 0.0125 level.
P-value (2): Superiority test at two-sided 0.025 levels.

A 24-month, multicenter, open-label, randomised, controlled study (H2307), was conducted in adult living donor liver transplant (LDLT) recipients with everolimus in combination with reduced tacrolimus (EVR+rTAC) compared to standard exposure tacrolimus (sTAC) to demonstrate comparable efficacy as measured by the composite efficacy failure (tBPAR, graft loss or death) and at least comparable eGFR. The recommended whole blood concentration before morning dose (C-0h) trough exposure (3 to 8 ng/mL) for the EVR+rTAC arm was maintained during the study. The target tacrolimus range of 3 to 5 ng/mL in combination with everolimus was chosen for the sTAC arm. This approach was supported by the 12 month data from Study H2304. In this study, the majority (N=223, 78.5%) of patients were of Asian origin. 284 patients were randomised to the EVR+rTAC group (N = 142) or sTAC group (N = 142). KM estimates for incidence of the primary composite efficacy failure events (tBPAR, graft loss or death) at month 12 and month 24 were comparable for EVR+rTAC and sTAC control arms. The eGFR was improved at month 12 and consistently maintained up to month 24. The adverse effects in the EVR+rTAC group in Study H2307 are consistent with the safety results from the pivotal studies presented in the "Undesirable effects" section.

Paediatric population
Certican is not indicated for children and adolescents under 18 years old.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
After oral administration, peak everolimus concentrations occur 1 to 2 hours post-dose. Everolimus blood concentrations are dose proportional over the dose range of 0.25 to 15 mg in transplant patients.
Food effect
Everolimus Cmax and AUC are reduced by 60% and 16% when the tablet formulation is given with a high-fat meal. To minimise variability, Certican should be taken consistently with or without food.

Distribution
The blood-to-plasma ratio of everolimus is concentration-dependent, ranging from 17% to 73% over the range of 5 to 5,000 ng/ml. Plasma protein binding is approximately 74% in healthy subjects and patients with moderate hepatic impairment. The distribution volume associated with the terminal phase (Vz/F) in maintenance renal transplant patients is 342 ± 107 litres.

Biotransformation
Everolimus is a substrate of CYP3A4 and P-glycoprotein. Following oral administration, it is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100 times less activity than everolimus itself. Hence, the parent substance is considered to contribute the majority of the overall pharmacological activity of everolimus.
Elimination
After a single dose of radiolabelled everolimus to transplant patients receiving ciclosporin, the majority (80%) of radioactivity was recovered from the faeces, and only a minor amount (5%) was excreted in urine. Parent drug was not detected in urine and faeces.

Steady-state pharmacokinetics
Pharmacokinetics were comparable for kidney and heart transplant patients receiving everolimus twice daily simultaneously with ciclosporin for microemulsion. Steady-state is reached by day 4 with an accumulation in blood concentrations of 2 to 3-fold compared with exposure after the first dose. Tmax occurs at 1 to 2 hours post-dose. Cmax averages 11.1 ± 4.6 and 20.3 ± 8.0 ng/ml and AUC averages 75 ± 31 and 131 ± 59 ng.h/ml at 0.75 and 1.5 mg b.i.d., respectively. Pre-dose trough blood concentrations (Cmin) average 4.1 ± 2.1 and 7.1 ± 4.6 ng/ml at 0.75 and 1.5 mg b.i.d., respectively.
Everolimus exposure remains stable over time in the first post-transplant year. Cmin is significantly correlated with AUC, yielding a correlation coefficient between 0.86 and 0.94. Based on a population pharmacokinetic analysis, oral clearance (CL/F) is 8.8 litres/hour (27% interpatient variation) and the central distribution volume (Vc/F) is 110 litres (36% interpatient variation). Residual variability in blood concentrations is 31%. The elimination half-life is 28 ± 7 hours.

Special populations
Hepatic impairment
Relative to the AUC of everolimus in subjects with normal hepatic function, the average AUC in 6 patients with mild hepatic impairment (Child-Pugh Class A) was 1.6-fold higher; in two independently studied groups of 8 and 9 patients with moderate hepatic impairment (Child-Pugh Class B), the average AUC was 2.1-fold and 3.3-fold higher, respectively; and in 6 patients with severe hepatic impairment (Child-Pugh Class C), the average AUC was 3.6-fold higher. Mean half-lives were 52, 59 and 78 hours in mild, moderate and severe hepatic impairment. The prolonged half-lives delay the time to reach steady-state everolimus blood concentrations.

Renal impairment
Post-transplant renal impairment (CCr range 11-107 ml/min) did not affect the pharmacokinetics of everolimus.

Paediatric population
Fourteen paediatric de novo renal transplant patients (2 to 16 years) received Certican dispersible tablets at a starting dose of 0.8 mg/m2 (maximum 1.5 mg) twice daily with ciclosporin for microemulsion. Their doses were subsequently individualised based on therapeutic drug monitoring to maintain everolimus pre-dose trough concentrations ≥3 ng/ml. At steady state, the everolimus trough level was 6.2 ± 2.4 ng/ml, Cmax was 18.2 ± 5.5 ng/ml, and AUC was 118 ± 28 ng.h/ml, which are comparable to adults receiving Certican targeted to similar pre-dose trough concentrations. The steady-state CL/F was 7.1 ± 1.7 l/h/m2 and the elimination half-life was 30 ± 11 h in paediatric patients.

Elderly patients
A limited reduction in everolimus oral clearance by 0.33% per year was estimated in adults (age range studied was 16-70 years). No dose adjustment is considered necessary.

Ethnicity
Based on a population pharmacokinetic analysis, oral clearance (CL/F) is, on average, 20% higher in black transplant patients. See section 4.2.

Exposure-response relationships
The average everolimus trough concentration over the first 6 months post-transplant was related to the incidence of biopsy-confirmed acute rejection and of thrombocytopenia in renal and cardiac transplant patients (see Table 22). In hepatic transplant patients, the relationship between average everolimus trough concentrations and the incidence of biopsy-proven acute rejection is less well defined. No correlation between higher everolimus exposure and adverse events such as thrombocytopenia has been observed (see Table22).

Table 22    Exposure-response relationships for everolimus in transplant patients 
Renal transplantation:
Trough concentration (ng/ml)      ≤3.4 3.5 - 4.5     4.6 - 5.7       5.8 - 7.7     7.8 - 15.0 Freedom from rejection            68%      81%         86%             81%            91% Thrombocytopenia                  10%       9%          7%             14%            17% (<100 x 109/l)
Cardiac transplantation:
Trough concentration (ng/ml)      ≤3.5 3.6 - 5.3    5.4 - 7.3       7.4 - 10.2    10.3 - 21.8 Freedom from rejection           65%       69%        80%              85%           85% Thrombocytopenia                  5%        5%         6%               8%            9% (<75 x 109/l)
Hepatic transplantation:
Trough concentration (ng/ml)      ≤3                    3-8                           ≥8 Freedom from treated BPAR        88%                   98%                           92% Thrombocytopenia                 35%                   13%                           18% (≤75 x 109/l)