Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Other nervous system drugs, ATC code: N07XX07.

Pharmacodynamic effects
Fampyra is a potassium channel blocker. By blocking potassium channels, Fampyra reduces the leakage of ionic current through these channels, thereby prolonging repolarization and thus enhancing action potential formation in demyelinated axons and neurological function.
Presumably, by enhancing action potential formation, more impulses might be conducted in the central nervous system.
Clinical efficacy and safety

Three phase III, randomised, double-blind, placebo controlled confirmatory studies, (MS-F203 and MS-F204 and 218MS305) have been performed. The proportion of responders was independent of concomitant immunomodulatory therapy (including interferons, glatiramer acetate, fingolimod and natalizumab). The Fampyra dose was 10 mg BID.

Studies MS-F203 and MS-F204

The primary endpoint in studies MS-F203 and MS-F204 was the responder rate in walking speed as measured by the Timed 25-foot Walk (T25FW). A responder was defined as a patient who consistently had a faster walking speed for at least three visits out of a possible four during the double blind period as compared to the maximum value among five off-treatment visits.

A significantly greater proportion of Fampyra treated patients were responders as compared to placebo (MS-F203: 34.8% vs. 8.3%, p<0.001; MS-F204: 42.9% vs. 9.3%, p<0.001).

Patients who responded to Fampyra increased their walking speed on average by 26.3% vs 5.3% on placebo (p<0.001) (MS-F203) and 25.3% vs 7.8% (p< 0.001) (MS-F204). The improvement appeared rapidly (within weeks) after starting Fampyra.
Statistically and clinically meaningful improvements in walking were seen, as measured by the 12- item Multiple Sclerosis Walking Scale.

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Table 1: Studies MS-F203 and MS-F204

STUDY *                                  MS-F203                              MS-F204 
Placebo               Fampyra        Placebo              Fampyra
10 mg BID                           10 mg BID n of subjects           72                   224            118                  119 
Consistent                       8.3%                 34.8%          9.3%                 42.9% improvement
Difference                               26.5%                               33.5% CI95%                            17.6%, 35.4%                        23.2%, 43.9% P-value                               < 0.001                             < 0.001 
≥20% improvement                11.1%                31.7%           15.3%                 34.5% Difference                                20.6%                                 19.2% CI95%                             11.1%,30.1%                           8.5%,29.9% P-value                                <0.001                                <0.001 Walking speed                  Ft per sec           Ft per sec     Ft per sec            Ft per sec Feet/sec
Baseline             2.04                 2.02            2.21                 2.12 Endpoint             2.15                 2.32            2.39                 2.43 Change             0.11                 0.30            0.18                 0.31 Difference                        0.19                                 0.12 p-value                       0.010                               0.038 Average % Change              5.24                 13.88           7.74                14.36 Difference                         8.65                                6.62 p-value                       < 0.001                             0.007 STUDY *                                MS-F203                                MS-F204 
Placebo               Fampyra          Placebo                Fampyra 10 mg BID                               10 mg BID
MSWS-12-score
(mean, sem)
Baseline     69.27 (2.22)            71.06 (1.34)   67.03 (1.90)            73.81 (1.87) Average change      -0.01 (1.46)           -2.84 (0.878)    0.87 (1.22)            -2.77 (1.20) Difference                    2.83                                     3.65 p-value                    0.084                                   0.021 LEMMT (mean, sem)
(Lower Extremity
Manual Muscle Test)
Baseline     3.92 (0.070)           4.01 (0.042)    4.01 (0.054)            3.95 (0.053) Average change      0.05 (0.024)           0.13 (0.014)    0.05 (0.024)            0.10 (0.024) Difference                    0.08                                     0.05 p-value                    0.003                                   0.106 Ashworth Score
(A test for muscle spasticity)
Baseline     0.98 (0.078)            0.95 (0.047)   0.79 (0.058)             0.87 (0.057) Average change     -0.09 (0.037)           -0.18 (0.022)   -0.07 (0.033)           -0.17 (0.032) Difference                    0.10                                     0.10 p-value                    0.021                                   0.015 

Study 218MS305

Study 218MS305 was conducted in 636 subjects with multiple sclerosis and walking disability.
Duration of double-blind treatment was 24 weeks with a 2 week post–treatment follow-up. The primary endpoint was improvement in walking ability, measured as the proportion of patients achieving a mean improvement of ≥ 8 points from baseline MSWS-12 score over 24 weeks. In this study there was a statistically significant treatment difference, with a greater proportion of Fampyra treated patients demonstrating an improvement in walking ability, compared to placebo- controlled patients (relative risk of 1.38 (95% CI: [1.06, 1.70]). Improvements generally appeared within 2 to 4 weeks of initiation of treatment, and disappeared within 2 weeks of treatment cessation.

Fampyra treated patients also demonstrated a statistically significant improvement in the Timed Up and Go (TUG) test, a measure of static and dynamic balance and physical mobility. In this secondary endpoint, a greater proportion of Fampyra treated patients achieved ≥ 15% mean improvement from baseline TUG speed over a 24 week period, compared to placebo. The difference in the Berg Balance Scale (BBS; a measure of static balance), was not statistically significant.

In addition, patients treated with Fampyra demonstrated a statistically significant mean improvement from baseline compared to placebo in the Multiple Sclerosis Impact Scale (MSIS-  29) physical score (LSM difference -3.31, p<0.001).

Table 2: Study 218MS305

Over 24 weeks                     Placebo              Fampyra 10 mg      Difference (95% CI) N = 318*                 BID                  p - value
N = 315*
Proportion of patients with          34%                  43%             Risk difference: 10.4% mean improvement of ≥ 8                                                       (3% ; 17.8%) points from baseline                                                               0.006 MSWS-12 score

MSWS-12 score                                                                   LSM: -4.14 Baseline                        65.4                63.6                 (-6.22 ; -2.06) Improvement from               -2.59                -6.73                    <0.001 baseline
TUG                                  35%                  43%              Risk difference: 9.2% Proportion of patients with                                                   (0.9% ; 17.5%) mean improvement of ≥ 15%                                                           0.03 in TUG speed

TUG                                                                             LSM: -1.36 Baseline                        27.1             24.9                    (-2.85 ; 0.12) Improvement from               -1.94              -3.3                        0.07 baseline (sec)
MSIS-29 physical score                55.3             52.4                     LSM: -3.31 Baseline                       -4.68             -8.00                   (-5.13 ; -1.50) Improvement from                                                             <0.001 baseline
BBS score                                                                       LSM: 0.41 Baseline                        40.2             40.6                    (-0.13 ; 0.95) Improvement from                1.34             1.75                        0.141 baseline
*Intent to treat population = 633; LSM = Least square mean

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption:

Orally administered fampridine is rapidly and completely absorbed from the gastrointestinal tract.
Fampridine has a narrow therapeutic index. Absolute bioavailability of Fampyra prolonged-release tablets has not been assessed, but relative bioavailability (as compared to an aqueous oral solution) is 95%. The Fampyra prolonged-release tablet has a delay in the absorption of fampridine manifested by slower rise to a lower peak concentration, without any effect on the extent of absorption.

When Fampyra tablets are taken with food, the reduction in the area under the plasma concentration- time curve (AUC0-∞) of fampridine is approximately 2-7% (10 mg dose). The small reduction in AUC is not expected to cause a reduction in the therapeutic efficacy. However, Cmax increases by 15-23%. Since there is a clear relationship between Cmax and dose related adverse reactions, it is recommended to take Fampyra without food (see section 4.2).

Distribution:

Fampridine is a lipid-soluble medicinal product which readily crosses the blood-brain barrier.
Fampridine is largely unbound to plasma proteins (bound fraction varied between 3-7% in human plasma). Fampridine has a volume of distribution of approximately 2.6 l/kg.
Fampridine is not a substrate for P-glycoprotein.

Biotransformation:
Fampridine is metabolised in humans by oxidation to 3-hydroxy-4-aminopyridine and further conjugated to the 3-hydroxy-4-aminopyridine sulfate. No pharmacological activity was found for the fampridine metabolites against selected potassium channels in vitro.

The 3-hydroxylation of fampridine to 3-hydroxy-4-aminopyridine by human liver microsomes appeared to be catalyzed by Cytochrome P450 2E1 (CYP2E1).

There was evidence of direct inhibition of CYP2E1 by fampridine at 30 μM (approximately 12% inhibition) which is approximately 100 times the average plasma fampridine concentration measured for the 10 mg tablet.

Treatment of cultured human hepatocytes with fampridine had little or no effect on induction of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2E1 or CYP3A4/5 enzyme activities.

Elimination:

The major route of elimination for fampridine is renal excretion, with approximately 90% of the dose recovered in urine as parent medicinal product within 24 hours. Renal clearance (CLR 370 ml/min) is substantially greater than glomerular filtration rate due to combined glomerular filtration and active excretion by the renal OCT2 transporter. Faecal excretion accounts for less than 1% of the administered dose.

Fampyra is characterized by linear (dose-proportional) pharmacokinetics with a terminal elimination half-life of approximately 6 hours. The maximum plasma concentration (Cmax) and, to a smaller extent, area under the plasma concentration-time curve (AUC) increase proportionately with dose.
There is no evidence of clinically relevant accumulation of fampridine taken at the recommended dose in patients with full renal function. In patients with renal impairment, accumulation occurs relative to the degree of impairment.

Special Populations

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Elderly:
Fampyra is primarily excreted unchanged by the kidneys, and with creatinine clearance known to decrease with age, monitoring of renal function in elderlypatients is recommended (see section 4.2).

Paediatric Population:

No data are available.
Patients with renal impairment:

Fampridine is eliminated primarily by the kidneys as unchanged medicinal product and therefore renal function should be checked in patients where renal function might be compromised. Patients with mild renal impairment can be expected to have approximately 1.7 to 1.9 times the fampridine concentrations achieved by patients with normal renal function. Fampyra must not be administered to patients with, moderate and severe renal impairment (see sections 4.3 and 4.4).