Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, , protein kinase inhibitors, ATC code: L01EG02 
Mechanism of action

Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a key serine-threonine kinase, the activity of which is known to be upregulated in a number of human cancers. Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits mTOR complex-1 (mTORC1) activity. Inhibition of the mTORC1 signalling pathway interferes with the translation and synthesis of proteins by reducing the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4EBP-1) that regulate proteins involved in the cell cycle, angiogenesis and glycolysis. Everolimus can reduce levels of vascular endothelial growth factor (VEGF). In patients with TSC, treatment with everolimus increases VEGF-A and decreases VEGF-D levels. Everolimus is a potent inhibitor of the growth and proliferation of tumour cells, endothelial cells, fibroblasts and blood-vessel-associated smooth muscle cells and has been shown to reduce glycolysis in solid tumours in vitro and in vivo.

Two primary regulators of mTORC1 signalling are the oncogene suppressors tuberin-sclerosis complexes 1 & 2 (TSC1, TSC2). Loss of either TSC1 or TSC2 leads to elevated rheb-GTP levels, a ras family GTPase, which interacts with the mTORC1 complex to cause its activation. mTORC1 activation leads to a downstream kinase signalling cascade, including activation of the S6 kinases. In tuberous sclerosis complex syndrome, inactivating mutations in the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body. Besides pathological changes in brain tissue (such as cortical tubers) which may cause seizures, the mTOR pathway is also implicated in the pathogenesis of epilepsy in TSC. The mTOR regulates protein synthesis and multiple downstream cellular functions that may influence neuronal excitability and epileptogenesis. Overactivation of mTOR results in neuronal dysplasia, aberrant axonogenesis and dendrite formation, increased excitatory synaptic currents, reduced myelination, and disruption of the cortical laminar structure causing abnormalities in neuronal development and function. Preclinical studies in models of mTOR dysregulation in the brain demonstrated that treatment with an mTOR inhibitor such as everolimus could prolong survival, suppress seizures, prevent the development of new-onset seizures and prevent premature death. In summary, everolimus is highly active in this neuronal model of TSC, with benefit apparently attributable to effects on mTORC1 inhibition. However, the exact mechanism of action in the reduction of seizures associated with TSC is not fully elucidated.

Clinical efficacy and safety

Phase III study in patients with TSC and refractory seizures
EXIST-3 (Study CRAD001M2304), a randomised, double-blind, multicentre, three-arm, parallel-group phase III study of Votubia versus placebo as adjunctive therapy was conducted in TSC patients with refractory partial-onset seizures. In the study, partial-onset seizures were defined as all electroencephalogram (EEG)-confirmed sensory seizures or motor seizures in which a generalised onset had not been demonstrated on a past EEG. Patients were treated with concomitant and stable dose of 1 to 3 antiepileptics prior to study entry. The study consisted of three phases: an 8-week baseline observation phase; an 18-week double-blind, placebo-controlled core treatment phase (composed of titration and maintenance periods), an extension phase of ≥48 weeks in which all patients received Votubia and a post-extension phase of ≤48 weeks in which all patients received Votubia.

The study independently tested two different primary endpoints: 1) response rate defined as at least a 50% reduction from baseline in frequency of partial-onset seizures during the maintenance period of the core phase; and 2) percentage reduction from baseline in frequency of partial-onset seizures during the maintenance period of the core phase.

Secondary endpoints included seizure freedom, proportion of patients with >25% seizure frequency reduction from baseline, distribution of reduction from baseline in seizure frequency (≤-25%, >-25% to <25%; ≥25% to <50%; ≥50% to <75%; ≥75% to <100%; 100%), long-term evaluation of seizure frequency and overall quality of life.

A total of 366 patients were randomised in a 1:1.09:1 ratio to Votubia (n=117) low trough (LT) range (3 to 7 ng/ml), Votubia (n=130) high trough (HT) range (9 to 15 ng/ml) or placebo (n=119). The median age for the total population was 10.1 years (range: 2.2-56.3; 28.4% <6 years, 30.9% 6 to <12 years, 22.4% 12 to <18 years and 18.3% >18 years). Median duration of treatment was 18 weeks for all three arms in the core phase and 90 weeks (21 months) when considering both the core and extension phases.

At baseline, 19.4% of patients had focal seizures with retained awareness (sensory previously confirmed on EEG or motor), 45.1% had focal seizures with impaired awareness (predominantly non- motor), 69.1% had focal motor seizures (i.e. focal motor seizures with impaired awareness and/or secondary generalised seizures), and 1.6% had generalised onset seizures (previously confirmed by EEG). The median baseline seizure frequency across the treatment arms was 35, 38, and 42 seizures per 28 days for the Votubia LT, Votubia HT, and placebo groups, respectively. The majority of patients (67%) failed 5 or more antiepileptics prior to the study and 41.0% and 47.8% of patients were taking 2 and ≥3 antiepileptics during the study. The baseline data indicated mild to moderate mental retardation in patients 6-18 years of age (scores of 60-70 on the Adaptive Behavior Composite and Communication, Daily Living Skills, and Socialization Domain Scores).

The efficacy results for the primary endpoint are summarised in Table 5.



Table 5     EXIST-3 – Seizure frequency response rate (primary endpoint) 
Votubia                    Placebo
LT target of    HT target of
3-7 ng/ml       9-15 ng/ml
Statistic                                             N=117            N=130                N=119 Responders – n (%)                                   33 (28.2)        52 (40.0)           18 (15.1) Response rate 95% CI a                           20.3, 37.3       31.5, 49.0           9.2, 22.8 Odds ratio (versus placebo)      b
2.21             3.93
95% CI                                           1.16, 4.20       2.10, 7.32 p-value (versus placebo) c                         0.008           <0.001 Statistically significant per Bonferroni-Holm       Yes              Yes procedure d
Non-responders – n (%)                                84 (71.8)           78 (60.0)      101 (84.9) a
Exact 95% CI obtained using Clopper-Pearson method b
Odds ratio and its 95% CI obtained using logistic regression stratified by age subgroup. Odds ratio >1 favours everolimus arm.
c p-values computed from the Cochran-Mantel-Haenszel test stratified by age subgroup d
Family-wise error rate of 2.5% one-sided

Consistent results were found for the supportive analysis of the median percentage reduction from baseline in seizure frequency (other primary endpoint): 29.3% (95% CI: 18.8, 41.9) in the Votubia LT arm, 39.6% (95% CI: 35.0, 48.7) in the Votubia HT arm and 14.9% (95% CI: 0.1, 21.7) in the placebo arm. The p-values for superiority versus placebo were 0.003 (LT) and <0.001 (HT).

The seizure-free rate (the proportion of patients who became seizure-free during the maintenance period of the core phase) was 5.1% (95% CI: 1.9, 10.8) and 3.8% (95% CI: 1.3, 8.7) in the Votubia LT and HT arms, respectively, versus 0.8% (95% CI: 0.0, 4.6) of patients in the placebo arm.

Higher proportions of responders were evident for all response categories in the Votubia LT and HT arms relative to placebo (Figure 1). Furthermore, almost twice as many patients in the placebo arm experienced seizure exacerbation relative to the Votubia LT and HT arms.



Figure 1             EXIST-3 – Distribution of reduction from baseline in seizure frequency 
Votubia 3-7 ng/ml
50                                                                                                Votubia 9-15 ng/ml Placebo
41.2
40
Proportion of patients (%)



35.0

30.0
30
23.9
22.7
20.2                                                    20.8
20                                18.5
17.1
15.4
12.8
11.5
10                                                                                 9.2 6.0          5.0   5.1
3.8
0.8       0.8
0
Exacerbation          No change            25% resp.            50% resp.           75% resp.          Seizure-free         Missing ≤-25               >-25 to <25          25 to <50            50 to <75           75 to <100             100 Reduction from baseline in seizure frequency (%)

A homogeneous and consistent everolimus effect was observed across all subgroups evaluated for the primary efficacy endpoints by: age categories (Table 6), gender, race and ethnicity, seizure types, seizure frequency at baseline, number and name of concomitant antiepileptics, and TSC features (angiomyolipoma, SEGA, cortical tuber status). The effect of everolimus on infantile/epileptic spasms or on seizures associated with Lennox-Gastaut syndrome has not been studied and is not established for generalised-onset seizures and subjects without cortical tubers.

Table 6              EXIST-3 – Seizure frequency response rate by age 
Votubia                                                                      Placebo LT target of         HT target of
3-7 ng/ml           9-15 ng/ml
Age category                                      N=117                N=130                                                            N=119 <6 years                                           n=33                 n=37                                                             n=34 Response rate (95% CI) a                  30.3 (15.6, 48.7)    59.5 (42.1, 75.2)                                                 17.6 (6.8, 34.5) 6 to <12 years                                     n=37                 n=39                                                             n=37 Response rate (95% CI) a                  29.7 (15.9, 47.0)    28.2 (15.0, 44.9)                                                 10.8 (3.0, 25.4) 12 to <18 years                                    n=26                 n=31                                                             n=25 Response rate (95% CI) a                   23.1 (9.0, 43.6)    32.3 (16.7, 51.4)                                                 16.0 (4.5, 36.1) ≥18 years b                                        n=21                 n=23                                                             n=23 Response rate (95% CI) a                  28.6 (11.3, 52.2)    39.1 (19.7, 61.5)                                                 17.4 (5.0, 38.8) a
Exact 95% CI obtained using Clopper-Pearson method b
No efficacy data available in elderly patients

At the end of the core phase, overall quality of life in patients aged 2 to <11 years (as measured by the mean change from baseline in overall Quality Of Life score [total score] in the Childhood Epilepsy Questionnaire [QOLCE]) was maintained in each Votubia treatment arm as well as in the placebo arm.

Reduction in seizure frequency was sustained over an evaluation period of approximately 2 years.
Based on a sensitivity analysis considering patients who prematurely discontinued everolimus as non- responders, response rates of 38.4% (95% CI: 33.4, 43.7) and 44.4% (95% CI: 38.2, 50.7) were observed after 1 and 2 years of exposure to everolimus, respectively.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Absorption

In patients with advanced solid tumours, peak everolimus concentrations (Cmax) are reached at a median time of 1 hour after daily administration of 5 and 10 mg everolimus under fasting conditions or with a light fat-free snack. Cmax is dose-proportional between 5 and 10 mg. Everolimus is a substrate and moderate inhibitor of PgP.

Food effect
In healthy subjects, high fat meals reduced systemic exposure to Votubia 10 mg tablets (as measured by AUC) by 22% and the peak blood concentration Cmax by 54%. Light fat meals reduced AUC by 32% and Cmax by 42%.

In healthy subjects taking a single 9 mg dose (3 x 3 mg) of Votubia dispersible tablets in suspension, high fat meals reduced AUC by 11.7% and the peak blood concentration Cmax by 59.8%. Light fat meals reduced AUC by 29.5% and Cmax by 50.2%.

Food, however, had no apparent effect on the post absorption phase concentration-time profile 24 hours post-dose of either dosage form.

Relative bioavailability/bioequivalence
In a relative bioavailability study, AUC0-inf of 5 x 1 mg everolimus tablets when administered as suspension in water was equivalent to 5 x 1 mg everolimus tablets administered as intact tablets, and Cmax of 5 x 1 mg everolimus tablets in suspension was 72% of 5 x 1 mg intact everolimus tablets.

In a bioequivalence study, AUC0-inf of the 5 mg dispersible tablet when administered as suspension in water was equivalent to 5 x 1 mg intact everolimus tablets, and Cmax of the 5 mg dispersible tablet in suspension was 64% of 5 x 1 mg intact everolimus tablets.

Distribution

The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5,000 ng/ml, is 17% to 73%. Approximately 20% of the everolimus concentration in whole blood is confined to plasma of cancer patients given Votubia 10 mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment. In patients with advanced solid tumours, Vd was 191 l for the apparent central compartment and 517 l for the apparent peripheral compartment.

Nonclinical studies in rats indicate:
•    A rapid uptake of everolimus in the brain followed by a slow efflux.
•    The radioactive metabolites of [3H] everolimus do not significantly cross the blood-brain barrier.
•    A dose-dependent brain penetration of everolimus, which is consistent with the hypothesis of saturation of an efflux pump present in the brain capillary endothelial cells.
•    The co-administration of the PgP inhibitor, cyclosporine, enhances the exposure of everolimus in the brain cortex, which is consistent with the inhibition of PgP at the blood-brain barrier.

There are no clinical data on the distribution of everolimus in the human brain. Non-clinical studies in rats demonstrated distribution into the brain following administration by both the intravenous and oral routes.


Biotransformation
Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus 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, everolimus is considered to contribute the majority of the overall pharmacological activity.

Elimination

Mean CL/F of everolimus after 10 mg daily dose in patients with advanced solid tumours was 24.5 l/h.
The mean elimination half-life of everolimus is approximately 30 hours.
No specific excretion studies have been undertaken in cancer patients; however, data are available from the studies in transplant patients. Following the administration of a single dose of radiolabelled everolimus in conjunction with ciclosporin, 80% of the radioactivity was recovered from the faeces, while 5% was excreted in the urine. The parent substance was not detected in urine or faeces.

Steady-state pharmacokinetics

After administration of everolimus in patients with advanced solid tumours, steady-state AUC0-τ was dose-proportional over the range of 5 to 10 mg daily dose. Steady-state was achieved within 2 weeks.
Cmax is dose-proportional between 5 and 10 mg. tmax occurs at 1 to 2 hours post-dose. There was a significant correlation between AUC0-τ and pre-dose trough concentration at steady-state.

Special populations

Hepatic impairment
The safety, tolerability and pharmacokinetics of Votubia were evaluated in two single oral dose studies of Votubia tablets in 8 and 34 adult subjects with impaired hepatic function relative to subjects with normal hepatic function.

In the first study, the average AUC of everolimus in 8 subjects with moderate hepatic impairment (Child-Pugh B) was twice that found in 8 subjects with normal hepatic function.

In the second study of 34 subjects with different impaired hepatic function compared to normal subjects, there was a 1.6-fold, 3.3-fold and 3.6-fold increase in exposure (i.e. AUC0-inf) for subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively.

Simulations of multiple dose pharmacokinetics support the dosing recommendations in subjects with hepatic impairment based on their Child-Pugh status.

Based on the results of the two studies, dose adjustment is recommended for patients with hepatic impairment (see sections 4.2 and 4.4).

Renal impairment
In a population pharmacokinetic analysis of 170 patients with advanced solid tumours, no significant influence of creatinine clearance (25-178 ml/min) was detected on CL/F of everolimus. Post-transplant renal impairment (creatinine clearance range 11-107 ml/min) did not affect the pharmacokinetics of everolimus in transplant patients.

Paediatric population


In patients with TSC and refractory seizures receiving Votubia dispersible tablets, a trend was observed toward lower Cmin normalised to dose (as mg/m2) in younger patients. Median Cmin normalised to mg/m2 dose was lower for the younger age groups, indicating that everolimus clearance (normalised to body surface area) was higher in younger patients.

Elderly
In a population pharmacokinetic evaluation in cancer patients, no significant influence of age (27-85 years) on oral clearance of everolimus was detected.

Ethnicity
Oral clearance (CL/F) is similar in Japanese and Caucasian cancer patients with similar liver functions. Based on analysis of population pharmacokinetics, oral clearance (CL/F) is on average 20% higher in black transplant patients.

Pharmacokinetic/pharmacodynamic relationship(s)

In patients with TSC and refractory seizures, a conditional logistic regression analysis based on the core phase of Study CRAD001M2304 to estimate the probability of seizure response versus Time Normalized(TN)-Cmin stratified by age sub-group, indicated that a 2-fold increase in TN-Cmin was associated with a 2.172-fold increase (95% CI: 1.339, 3.524) in the odds for a seizure response over the observed TN-Cmin ranges of 0.97 ng/ml to 16.40 ng/ml. Baseline seizure frequency was a significant factor in the seizure response (with an odds ratio of 0.978 [95% CI: 0.959, 0.998]). This outcome was consistent with the results of a linear regression model predicting the log of absolute seizure frequency during the maintenance period of the core phase, which indicated that for a 2-fold increase in TN-Cmin there was a statistically significant 28% reduction (95% CI: 12%, 42%) in absolute seizure frequency. Baseline seizure frequency and TN-Cmin were both significant factors (α=0.05) in predicting the absolute seizure frequency in the linear regression model.