Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Anti-Parkinson drugs, foslevodopa and decarboxylase inhibitor ATC code: N04BA07

Mechanism of action

Produodopa (foslevodopa/foscarbidopa) 240 mg/12 mg per ml solution for infusion is a prodrug combination of levodopa monophosphate and carbidopa monophosphate (ratio 20:1) in a solution for 24 hour/day continuous subcutaneous infusion in advanced Parkinson’s disease patients who are not adequately controlled with current medical therapy. Foslevodopa and foscarbidopa are converted in-vivo to levodopa and carbidopa. Levodopa relieves symptoms of Parkinson’s disease following decarboxylation to dopamine in the brain. Carbidopa, which does not cross the blood-brain barrier, inhibits the extracerebral decarboxylation of levodopa to dopamine, which means that a larger amount of levodopa becomes available for transportation to the brain and transformation into dopamine.

Pharmacodynamic effects

Produodopa subcutaneous administration and Duodopa intestinal administration were shown to have comparable levodopa Cmax, AUC, and degree of fluctuation, which supports a comparable efficacy 
profile. By achieving same concentrations of levodopa as Duodopa, Produodopa reduces the motor fluctuations and increases the “On”-time in levodopa-responsive patients with advanced Parkinson’s disease. The motor fluctuations and hyperkinesia or dyskinesia are reduced because the plasma concentrations of levodopa are being kept at a steady level within the individual therapeutic window.
Therapeutic effect on motor symptoms (“On” state) is achieved on the first treatment day.

Clinical efficacy and safety

Studies with Duodopa intestinal gel formulation
The efficacy of Duodopa intestinal gel was confirmed in two identically-designed Phase 3, 12-week, randomised, double-blind, double-dummy, active-controlled, parallel group, multicentre studies to evaluate the efficacy, safety, and tolerability of the Duodopa intestinal gel system against levodopa/carbidopa 100/25 mg tablets. The studies were conducted with patients with advanced Parkinson's disease who were levodopa-responsive and had persistent motor fluctuations despite optimised treatment with oral levodopa/carbidopa and other available anti-Parkinson's disease medications and enrolled a total of 71 patients. The results of the two studies were combined and a single analysis was conducted.

The primary efficacy endpoint, change in normalised "Off" time (baseline to endpoint) based on Parkinson's Disease Diary (PD Diary) data using last observation carried forward demonstrated a statistically significant least square (LS) mean difference in favour of the Duodopa treatment group (Table 6).

The primary end point results were supported by a Mixed Model Repeated Measures (MMRM) analysis which examined the change from baseline to each post-baseline study visit. This analysis of “Off” time demonstrated a statistically significant greater improvement of the Duodopa group over the Active control group at Week 4, and that improvement was shown to be statistically significant at Weeks 8, 10, and 12.

This change in “Off” time was associated with a statistically significant LS mean difference from baseline in the average daily normalised "On" time without troublesome dyskinesia between the Duodopa intestinal gel treatment group and the active control group based on PD Diary data. The baseline values were collected three days prior to randomisation and after 28 days of oral therapy standardisation.

Table 6. Change from baseline to endpoint in "off" time and in "on" time without troublesome dyskinesia

Baseline       Endpoint       LS mean         LS mean mean            Mean            (SE)            (SE)       P
Treatment Group                N
(SD)            (SD)         of change     of difference value
(hours)         (hours)        (hours)         (hours)
Primary measure: “Off” time a
Active control                         31     6.90 (2.06)    4.95 (2.04)    -2.14 (0.66) Duodopa intestinal gel                 35     6.32 (1.72)    3.05 (2.52)    -4.04 (0.65)   -1.91 (0.57) 0.0015 Key secondary measure: "On" time without troublesome dyskinesia
Active control                         31     8.04 (2.09)    9.92 (2.62)     2.24 (0.76) Duodopa intestinal gel                 35     8.70 (2.01)    11.95 (2.67)    4.11 (0.75)    1.86 (0.65) 0.0059 SD = standard deviation; SE = standard error a.
Active control, oral levodopa/carbidopa 100/25 mg tablets (Sinemet tablets over-encapsulated) 

Analyses of other secondary efficacy endpoints, in order of the hierarchical testing procedure, demonstrated statistically significant results for Duodopa intestinal gel compared to oral levodopa/carbidopa for the Parkinson's Disease Questionnaire (PDQ-39) Summary Index (an index Parkinson’s disease-related quality of life), Clinical Global Impression-Improvement (CGI-I) score, and Unified Parkinson's Disease Rating Scale (UPDRS) Part II score (Activities of Daily Living). The PDQ-39 Summary Index showed a decrease from baseline of 10.9 points at week 12 for Duodopa intestinal gel group. Other secondary endpoints UPDRS Part III score, EuroQol 5-dimensions Questionnaire (EQ-5D) Summary Index, and Zarit Burden Interview (ZBI) total score, did not meet statistical significance based on the hierarchical testing procedure.

A Phase 3, open-label, single-arm, multicentre study was conducted to assess the long-term safety and tolerability of Duodopa over 12 months in 354 patients. The study population was levodopa- responsive patients with advanced Parkinson's disease and motor fluctuations despite optimised treatment with available Parkinson's disease medications. The average daily normalised "Off" time changed by – 4.44 hours from Baseline to Endpoint (6.77 hours at Baseline and 2.32 hours at Endpoint) with a corresponding 4.8-hour increase in “On” time without troublesome dyskinesia.

A Phase 3, open-label, randomised, multicentre study was conducted to assess the effect of Duodopa intestinal gel on dyskinesia compared with optimised medical treatment (OMT) over 12 weeks in 61 patients. The study population was levodopa-responsive patients with advanced PD and motor fluctuations inadequately controlled with OMT and with a baseline Unified Dyskinesia Rating Scale (UDysRS) Total Score ≥30. The change from baseline to Week 12 in UDysRS total score (primary efficacy endpoint) demonstrated a statistically significant LS Mean difference (-15.05; P < 0.0001) in favour of the Duodopa treatment group compared with OMT group. Analysis of secondary efficacy endpoints using a fixed sequence testing procedure, demonstrated statistically significant results in favour of Duodopa compared with OMT for “On” time without troublesome dyskinesia as measured by PD Diary, for Parkinson's Disease Questionnaire-8 (PDQ-8) summary index, Clinical Global Impression Change (CGI-C) score, UPDRS Part II score, and for “Off” time as measured by PD Diary. The UPDRS Part III score did not meet statistical significance.

Studies with Produodopa

Produodopa is a prodrug combination of levodopa monophosphate and carbidopa monophosphate (ratio 20:1) in a solution intended for 24-hour/day continuous subcutaneous infusion. Subcutaneous Produodopa administration and Duodopa intestinal administration were shown to have comparable levodopa Cmax and AUC parameters, which supports a comparable efficacy profile. The study showed stable levodopa exposure with fluctuation values of 0.262 and 0.404 for Produodopa and Duodopa, respectively.

Following Produodopa administration in healthy volunteers, levodopa steady state is achieved rapidly, generally within 2 hours and maintained during the infusion period. Figure 1 below shows levodopa exposure following 24-hour Produodopa administration.

Figure 1. Mean Levodopa exposure following 24-hour Produodopa infusion 


700                                Produodopa
Mean Levodopa Plasma Concentration (ng/ml)


600

500
400

300

200
100

0

0   4   8   12   16     20   24   28      32   36
Time (h)

Results from an additional PK comparability study demonstrated that levodopa exposure was comparable between Produodopa and Duodopa when both were delivered over a 24-hour period.

A Phase 3, double-blind, double-dummy, randomised, active-controlled, multicentre study was conducted to assess the effect of Produodopa in patients with advanced PD over 12 weeks. A total of 145 patients were randomised in 1:1 ratio and 141 patients received either 24-hour/day continuous subcutaneous administration of Produodopa plus oral placebo capsules (N=74) or 24-hour/day continuous subcutaneous administration of placebo solution plus oral encapsulated carbidopa- levodopa IR tablets (N=67).

The study population was patients with levodopa-responsive PD whose motor fluctuations were inadequately controlled by their current medications and who experienced a minimum of 2.5 hours of “Off” time/day as assessed by PD diaries.

Produodopa demonstrated statistically significant improvements from baseline to Week 12 in "On" time without troublesome dyskinesia and “Off” time compared with the oral IR carbidopa-levodopa group (Table 7). Other secondary endpoints, motor experiences of daily living, morning akinesia, sleep, and quality of life indicators did not meet statistical significance based on the hierarchical testing procedure.



Table 7. Change from Baseline to Endpoint in Primary and Key Secondary Measures 
Change from                                   P value
Baseline                 LS Mean LS Mean
Baseline to                               (95%
Treatment Group           N      Mean                       of      of Endpoint                               Confidence
(SD)                    Change Difference
Mean                                  Interval)
(SD)


Primary Measure
“On” time without troublesome dyskinesia (hours)a
Oral IR carbidopa-
67 9.49 (2.62) 0.85 (3.46)             0.97 levodopab
0.0083
Produodopa                73    9.20 (2.42)   3.36 (3.62)      2.72       1.75 (0.46, 3.05)
Secondary Measure
“Off” time (hours)  a

Oral IR carbidopa-
67    5.91 (1.88) -0.93 (3.31)      -0.96 levodopab
0.0054
“Produodopa               73    6.34 (2.27) -3.41 (3.76)      -2.75       -1.79 (-3.03, -0.54)
SD = standard deviation;.
a
Derived from Parkinson’s Disease (PD) diary.
b
Oral immediate release carbidopa-levodopa tablets.

A total of 110 patients completed the study. During the double-blind treatment period, 7.5 % (N=5) of patients in the oral IR carbidopa-levodopa group and 35.1% (N=26) in the Produodopa group prematurely discontinued. The most common reason for discontinuation in the Produodopa group was adverse events 18.9% (N=14). One of the 74 patients in the Produodopa group was excluded from the analysis because the subject did not have valid baseline data for the efficacy model (N=73 in table 7) A J2R sensitivity analysis was also performed to evaluate the analysis results under a more conservative assumption. The results of the J2R sensitivity analysis were consistent with the results of the primary analysis.

A Phase 3, open-label, single-arm study was conducted to evaluate the safety and tolerability of 24-hour daily exposure of continuous subcutaneous infusion of Produodopa over 52 weeks in
244 patients. The study population was levodopa-responsive patients with Parkinson’s disease whose motor symptoms that were inadequately controlled with current treatment who experienced a minimum of 2.5 hours of "Off" time per day as assessed by Parkinson’s disease (PD) diaries.

A total of 137 patients completed the study. The most common reasons for discontinuation were adverse events (26%) and withdrawal of consent (16%). Adverse events reported for ≥ 10% of subjects were infusion site events, hallucination, fall, anxiety and dizziness. The most common adverse events related to Produodopa were infusion site events, which were nonserious, mild or moderate in severity and resolved. The summary of the safety profile of Produodopa from this study are provided in section 4.8 (see section 4.8 Undesirable effects).

Paediatric

The safety of Produodopa in patients under 18 years of age has not been established and its use in patients below the age of 18 is not recommended.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption

Produodopa is administered directly into the subcutaneous space and is quickly absorbed and converted to levodopa and carbidopa. In a phase 1 study in healthy volunteers, levodopa and carbidopa were detectable in plasma within 30 minutes at the first pharmacokinetic collection point. In most subjects the steady state was achieved within 2 hours when Produodopa dosing was delivered as loading dose followed by continuous infusion.

In order to determine absorption of Produodopa at different subcutaneous sites, healthy volunteers were administered Produodopa to the abdomen, arm and thigh using a 3-way crossover design.
Pharmacokinetic analysis from this study showed that the 3 sites have nearly identical levodopa and carbidopa exposure suggesting Produodopa absorption is similar at the different subcutaneous sites.

Produodopa bypasses the gut, so food does not change absorption or exposure of levodopa/carbidopa.

Distribution
The volume of distribution of levodopa is moderately small. The partitioning ratio for levodopa between erythrocytes and plasma is approximately 1. Levodopa has negligible binding to plasma proteins (< 10%). Levodopa is transported into the brain by the carrier mechanism for large neutral amino acids.

Carbidopa is approximately 36% bound to plasma protein. Carbidopa does not cross the blood-brain barrier.
Both foslevodopa and foscarbidopa have low binding to plasma proteins (24%-26%).

Biotransformation and elimination

Foslevodopa and foscarbidopa prodrugs are rapidly converted by alkaline phosphatases into levodopa and carbidopa. Levodopa is mainly metabolised by the aromatic amino acid decarboxylase (AAAD) and the COMT enzymes. Other routes of metabolism are transamination and oxidation. The decarboxylation of levodopa to dopamine by AAAD is the major enzymatic pathway when no enzyme inhibitor is co-administered. O-methylation of levodopa by COMT forms 3-O-methyldopa. When administered with carbidopa, the elimination half-life of levodopa is approximately 1.5 hours.

Carbidopa is metabolised to two main metabolites (α-methyl-3-methoxy-4-hydroxyphenylpropionic acid and α-methyl-3,4-dihydroxyphenylpropionic acid). These 2 metabolites are primarily eliminated in the urine unchanged or as glucuronide conjugates. Unchanged carbidopa accounts for 30% of the total urinary excretion. The elimination half-life of carbidopa is approximately 2 hours.

Special Populations

Produodopa is intended for use in Parkinson’s disease patients who are already on a stable dose of oral levodopa and Produodopa dose is optimised once patients begin therapy.

Elderly

The impact of age on the levodopa pharmacokinetics following Produodopa infusion was not specifically evaluated. Studies with levodopa suggest a modest reduction of levodopa clearance with increasing age.

Renal or hepatic impairment

The pharmacokinetics of Produodopa in subjects with renal and/or hepatic impairment has not been established.

The anticipated daily phosphorus load from the highest proposed clinical dose of foslevodopa/foscarbidopa (6000/300 mg/day of foslevodopa/foscarbidopa) is approximately 700 mg, which is considerably less than the United States National Academy of Sciences dietary reference intake upper limit of 3000 mg/day; however, there are no pharmacokinetic or safety data with Produodopa in patients with End Stage Renal Disease requiring dialysis. Therefore, caution should be exercised in patients with End Stage Renal Disease on dialysis requiring treatment with Produodopa because of diminished ability of the kidneys to eliminate phosphate.

Body weight

The impact of body weight on the levodopa pharmacokinetics following Produodopa infusion was not specifically evaluated. Previous studies of levodopa have shown that weight increases volume of distribution and can lower levodopa exposure.

Gender or race

Following Produodopa administration, carbidopa and levodopa exposures in both Japanese subjects and Han Chinese subjects were comparable to those in Caucasian subjects.

The impact of gender on the pharmacokinetics following Produodopa infusion was not specifically evaluated. The effect of gender on the pharmacokinetics of levodopa has been evaluated and studies suggested there is no clinically meaningful gender related difference in levodopa exposure. Following Produodopa dosing, levodopa exposure was higher in females once weight was considered by approximately 18% based on AUC.