Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Anti-Parkinson-Drugs, monoamine oxidase -B inhibitors, ATC code: N04BD03.

Mechanism of action
Safinamide acts through both dopaminergic and non-dopaminergic mechanisms of action.
Safinamide is a highly selective and reversible MAO-B inhibitor causing an increase in extracellular levels of dopamine in the striatum. Safinamide is associated with state-dependent inhibition of voltage-gated sodium (Na+) channels, and modulation of stimulated release of glutamate. To what extent the non-dopaminergic effects contribute to the overall effect has not been established.

Pharmacodynamic effects
Population PK models developed from studies in patients with Parkinson’s disease indicate that the pharmacokinetic and pharmacodynamics effects of safinamide were not dependent on age, gender, weight, renal function and exposure to levodopa, indicating that dose adjustments will not be required based on these variables.

Pooled analyses of adverse event data from placebo controlled studies in Parkinson’s disease patients indicate that the concomitant administration of safinamide together with a broad category of commonly used medicinal products in this patient population (antihypertensive, beta-blockers cholesterol lowering, non-steroidal anti-inflammatory medicinal products, proton pump inhibitors, antidepressants, etc.) was not associated with an increased risk for adverse events. Studies were not stratified for co-medication, and no randomized interaction studies were performed for these medicinal products.

Clinical efficacy
Studies in mid- to late-stage PD patients

The efficacy of Xadago as add-on treatment in mid-to late-stage PD (LSPD) patients with motor fluctuations, currently receiving L-dopa alone or in combination with other PD medicinal products, was evaluated in two double-blind, placebo-controlled studies: Study SETTLE (Study 27919; 50-100 mg/day; 24 weeks), and Study 016/018 (50 and 100 mg/day; 2-year, double-blind, placebo-controlled study).

The primary efficacy parameter was the change from baseline to endpoint in ‘ON Time without troublesome dyskinesia’.

Secondary efficacy parameters included OFF Time, UPDRS II and III (Unified Parkinson’s Disease Rating Scale – sections II and III), and CGI-C (Clinical Global Impression of Change) 
Both the SETTLE and 016/018 studies indicated significant superiority of safinamide, compared to placebo, at the target doses of 50 and 100 mg/day for the primary, and selected secondary, efficacy variables, as summarized in the table below. The effect on ON Time was maintained at the end of the 24-month double-blind treatment period for both safinamide doses as compared to placebo.
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Study                                  016                          016/018              27919 (SETTLE) (24 weeks)                       (2 years)               (24 weeks)
Dose (mg/day) (a)                                                                                 Safin- Safinamide                      Safinamide amide
Placebo                          Placebo                       Placebo 50-100
50        100                    50       100
(d)
Randomized                 222         223    224           222        223       224       275      274 Age (years) (b)           59.4        60.1   60.1          59.4       60.1      60.1      62.1     61.7 (9.5)       (9.7)  (9.2)         (9.5)      (9.7)     (9.2)     (9.0)    (9.0) PD Duration (years) (b)                       8.2                      7.9       8.2                8.9 8.4 (3.8) 7.9 (3.9)               8.4 (3.8)                     9.0 (4.9) (3.8)                    (3.9)     (3.8)              (4.4)
ON time without troublesome dyskinesia (hrs) (c)
Baseline (b)                                  9.6                      9.4       9.6       9.3 9.3 (2.2) 9.4 (2.2)               9.3 (2.2)                     9.1 (2.5) (2.5)                    (2.2)     (2.5)     (2.4)
Change LSM (SE)                               1.2                      1.4       1.5       1.4 0.5 (0.2) 1.0 (0.2)            0.8 (0.2)               0.6 (0.1)
(0.2)                    (0.2)     (0.2)     (0.1)
LS Diff vs Placebo                   0.5      0.7                      0.6       0.7       0.9 [0.3,                    [0.1,     [0.2,     [0.6,
[0.1, 0.9]
95% CI                                       1.0]                     1.0]      1.1]      1.2] <0.000
0.0054     0.0002           0.0110 0.0028 p-value                                                                                     1 OFF time (hrs) (c)
Baseline (b)                                      5.2                    5.2      5.2                  5.3 5.3 (2.1) 5.2 (2.0)              5.3 (2.1)                    5.4 (2.0) (2.2)                 (2.2)     (2.1)               (2.0)
Change LSM (SE)            -0.8       -1.4       -1.5       -1.0        -1.5     -1.6    -0.5         -1.5 (0.20)     (0.20)     (0.20)     (0.20)     (0.19)    (0.19) (0.10)       (0.10) LS Diff vs Placebo                     -0.6      -0.7                   -0.5      -0.6                -1.0 [-0.9,     [-1.0,                [-0.8,    [-0.9,               [-1.3, 95% CI                                -0.3]      -0.4]                 -0.2]     -0.3]               -0.7] <0.000
0.0002 <0.0001                   0.0028 0.0003 p-value                                                                                                 1 UPDRS III (c)
Baseline (b)               28.6        27.3       28.4      28.6        27.3   28.4       23.0        22.3 (12.0)     (12.8)     (13.5)     (12.0)     (12.8) (13.5)      (12.8)     (11.8) Change LSM (SE)            -4.5        -6.1       -6.8      -4.4        -5.6   -6.5       -2.6        -3.5 (0.83)     (0.82)     (0.82)     (0.85)     (0.84) (0.84)      (0.34)     (0.34) LS Diff vs Placebo                     -1.6       -2.3                  -1.2   -2.1                   -0.9 [-3.0,     [-3.7,                [-2.6, [-3.5,                 [-1.8, 95% CI                                -0.2]      -0.9]                  0.2]  -0.6]                   0.0] p-value                              0.0207     0.0010                0.0939 0.0047                 0.0514 UPDRS II (c)
Baseline (b)              12.2        11.8   12.1          12.2         11.8   12.1      10.4         10.0 (5.9)       (5.7) (5.9)          (5.9)       (5.7)  (5.9)      (6.3)       (5.6) Change LSM (SE)           -1.2               -2.3          -1.4         -2.0   -2.5      -0.8         -1.2 -1.9 (0.4)
(0.4)             (0.4)          (0.3)       (0.3)  (0.3)      (0.2)       (0.2) LS Diff vs Placebo                   -0.7    -1.1                       -0.6   -1.1                   -0.4 [-1.3,   [-1.7,                     [-1.3, [-1.8,                 [-0.9, 95% CI                              -0.0]   -0.5]                       0.0]  -0.4]                   0.0] p-value                           0.0367 0.0007                       0.0676 0.0010                 0.0564 Responder analyses (post-hoc) (e) n(%)
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Study                                   016                     016/018      27919 (SETTLE) (24 weeks)                  (2 years)      (24 weeks)
Dose (mg/day) (a)                                                                     Safin- Safinamide              Safinamide amide
Placebo                     Placebo               Placebo
50-100
50      100             50     100
(d)
ON time increase ≥60         93        119      121     100    125     117    116      152 minutes                    (43.9)     (54.8)   (56.0)  (47.2) (57.6) (54.2) (42.5)    (56.3) p-value                               0.0233 0.0122           0.0308 0.1481          0.0013 ≥60 minutes increase
ON time and decrease
32                    56               43        42                  49 in OFF time and ≥ 30%                52 (24.0)          28 (13.2)                    24 (8.8) (15.1)                (25.9)           (19.8)    (19.4)              (18.1) improvement UPDRS
III p-value                               0.0216     0.0061           0.0671 0.0827                 0.0017 CGI-C: patients who
42                    78               62        64                  66 were much/very much                  72 (33.2)          46 (21.7)                    26 (9.5) (19.8)                (36.1)           (28.6)    (29.6)              (24.4) improved
<0.000
0.0017 0.0002                 0.0962 0.0575 p-value (f)                                                                                       1 (a) Daily targeted dose, (b) Mean (SD), (c) analysis population (mITT); MMRM model for change from Baseline to Endpoint includes treatment, region, and visit as fixed effects, and baseline value as a covariate; (d) target dose of 100 mg/day; (e) analysis population (mITT); data are presented as the number (percentage) of patients in each group meeting the responder definition (f) chi-square test of the odds ratio of the treatment groups compared to placebo using a logistic regression model, with fixed effects for treatment and country.
SE Standard Error, SD Standard deviation, LSM Least Square Mean, LS Diff. Least Square Difference vs Placebo mITT Population: Study 016/018 - Placebo (n=212), safinamide 50 mg/day (n=217) and 100 mg/day (n=216), and SETTLE - Placebo (n=270), safinamide 50-100 mg/day (n=273).

Paediatric population
The pharmacodynamic effects of safinamide have not been assessed in children and adolescents.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Absorption
Safinamide absorption is rapid after single and multiple oral dosing, reaching Tmax in the time range 1.8-2.8 h after dosing under fasting conditions. Absolute bioavailability is high (95%), showing that safinamide is almost completely absorbed after oral administration and first pass metabolism is negligible. The high absorption classifies safinamide as a highly permeable substance.

Distribution
The volume of distribution (Vss) is approximately 165 L which is 2.5-fold of body volume indicating extensive extravascular distribution of safinamide. Total clearance was determined to be 4.6 L/h classifying safinamide as a low clearance substance.

Plasma protein binding of safinamide is 88-90%.

Biotransformation
In humans, safinamide is almost exclusively eliminated via metabolism (urinary excretion of unchanged safinamide was <10%) mediated principally through high capacity amidases, that have XADAGO-SPC-0820-V1                               Page 11 of 14
not yet been characterized. In vitro experiments indicated that inhibition of amidases in human hepatocytes led to complete suppression of the NW-1153 formation. Amidase present in blood, plasma, serum, simulated gastric fluid and simulated intestinal fluid as well as human carboxylesterases hCE-1 and hCE-2 are not responsible for the biotransformation of safinamide to NW-1153. The amidase FAAH was able to catalyse the formation of NW-1153 at low rates only.
Therefore, other amidases are likely to be involved in the conversion to NW-1153. Safinamide’s metabolism is not dependent on Cytochrome P450 (CYP) based enzymes.

Metabolite structure elucidation revealed three metabolic pathways of safinamide. The principal pathway involves hydrolytic oxidation of the amide moiety leading to the primary metabolite ‘safinamide acid’ (NW-1153). Another pathway involves oxidative cleavage of the ether bond forming ‘O-debenzylated safinamide’ (NW-1199). Finally the ‘N-dealkylated acid’ (NW-1689) is formed by oxidative cleavage of the amine bond of either safinamide (minor) or the primary safinamide acid metabolite (NW-1153) (major). The ‘N-dealkylated acid’ (NW-1689) undergoes conjugation with glucuronic acid yielding its acyl glucuronide. None of these metabolites are pharmacologically active.

Safinamide does not appear to significantly induce or inhibit enzymes at clinically relevant systemic concentrations. In vitro metabolism studies have indicated that there is no meaningful induction or inhibition of cytochrome P450, CYP2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A3/5 at concentrations which are relevant (Cmax of free safinamide 0.4 µM at 100 mg/day) in man. Dedicated drug-drug interaction studies performed with ketoconazole, L-dopa and CYP1A2 and CYP3A4 substrates (caffeine and midazolam), did not detect any clinically significant effects on the pharmacokinetics of safinamide, or L-dopa, caffeine and midazolam.

A mass balance study showed that the plasma AUC0-24h of the unchanged 14C-safinamide accounted for approximately 30% of the total radioactivity AUC0-24h, indicative of an extensive metabolism.

Transporters
Preliminary in vitro studies have shown that safinamide is not a substrate for the transporters P-gp, BCRP, OAT1B1, OAT1B3, OATP1A2 or OAT2P1. Metabolite NW-1153 is not a substrate for OCT2, or OAT1, but it is substrate for OAT3. This interaction has the potential to reduce the clearance of NW- 1153 and increase its exposure; however the systemic exposure of NW-1153 is low (1/10 of parent safinamide), and as it is metabolised to secondary and tertiary metabolites, it is unlikely to be of any clinical relevance.

Safinamide transiently inhibits BCRP in the small intestine (see section 4.5). At concentrations of 50µM, safinamide inhibited OATP1A2 and OATP2P1. The relevant plasma concentrations of safinamide are substantially lower, therefore a clinically relevant interaction with co-administered substrates of these transporters is unlikely. NW-1153 is not an inhibitor of OCT2, MATE1, or MATE2-K up to concentrations of 5µM.

Linearity/non-linearity
The pharmacokinetics of safinamide are linear after single and repeated doses. No time-dependency was observed.

Elimination
Safinamide undergoes almost complete metabolic transformation (<10% of the administered dose was found unchanged in urine). Substance-related radioactivity was largely excreted in urine (76%) and only to a low extent in faeces (1.5%) after 192 hours. The terminal elimination half-life of total radioactivity was approximately 80 hours.

The elimination half-life of safinamide is 20-30 hours. Steady-state is reached within one week.
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Patients with hepatic impairment
Safinamide exposure in patients with mild hepatic disease increased marginally (30% in AUC), while in patients with moderate hepatic impairment exposure increased by approximately 80% (see section 4.2).

Patients with renal impairment
Moderate or severe renal impairment did not alter the exposure to safinamide, compared to healthy subjects (see section 4.2).