Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1      Pharmacodynamic properties
Pharmacotherapeutic group: Anti-Parkinson drugs, levodopa and decarboxylase inhibitor ATC code: N04BA02.

      Mechanism of action
Duodopa is a combination of levodopa and carbidopa (ratio 4:1) in a gel for continuous intestinal infusion in advanced Parkinson’s disease with severe motor fluctuations and hyper- /dyskinesia.
Levodopa is a metabolic precursor of dopamine that 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, which means that a larger amount of levodopa becomes available for transportation to the brain and transformation into dopamine. Without the simultaneous administration of carbidopa much larger amounts of levodopa would be required to achieve the desired effect. Intestinal infusion of individualized doses of Duodopa maintains plasma concentrations of levodopa at steady levels within the individual therapeutic windows.

Pharmacodynamic effects
Intestinal therapy with Duodopa reduces the motor fluctuations and decreases the “Off” time for patients with advanced Parkinson’s disease who have received tablet treatment with levodopa/decarboxylase inhibitor for many years. The motor fluctuations and hyper-/dyskinesias are reduced due to less variable plasma concentrations than oral carbidopa/levodopa which allows treatment in a narrow therapeutic window. Therapeutic effects on motor fluctuations and hyper-/dyskinesias are often achieved during the first treatment day.

Clinical efficacy and safety
The efficacy of Duodopa was confirmed in two identically-designed Phase 3, 12-week, randomized, double-blind, double-dummy, active-controlled, parallel group, multicenter studies to evaluate the efficacy, safety, and tolerability of Duodopa 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 optimized 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 normalized "Off" time (baseline to endpoint) based on Parkinson's Disease Diary© data using last observation carried forward demonstrated a statistically significant least square (LS) mean difference in favor of the Duodopa treatment group (Table 3).

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 LC-oral 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 normalized "On" time without troublesome dyskinesia between the Duodopa treatment group and the active control group based on Parkinson's Disease Diary© data. The baseline values were collected three days prior to randomization and after 28 days of oral therapy standardization.

Table 3 Change from Baseline to Endpoint in "Off" Time and in "On" Time Without Troublesome Dyskinesia

Treatment Group        N    Baseline         Endpoint      LS Mean (SE) LS Mean P value Mean (SD)           (SD)        of Change    (SE) of
(hours)           (hours)         (hours)   Difference
(hours)
Primary Measure
"Off" time
Active Controla       31     6.90 (2.06)   4.95 (2.04)      –2.14 (0.66) 
Duodopa               35     6.32 (1.72)   3.05 (2.52)      –4.04 (0.65)    –1.91 (0.57) 0.0015 

Secondary Measure
"On" time without troublesome dyskinesia
Active Control    31         8.04 (2.09)   9.92 (2.62)      2.24 (0.76) 

Duodopa               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


Analyses of other secondary efficacy endpoints, in order of the hierarchical testing procedure, demonstrated statistically significant results for Duodopa 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 (CGI-I) score, and Unified Parkinson's Disease Rating Scale (UPDRS) Part II score (Activities of Daily Living (ADL)). The PDQ-39 Summary Index showed a decrease from baseline of 10.9 points at week 12. Other secondary endpoints, UPDRS Part III score, EQ-5D Summary Index, and ZBI total score, did not meet statistical significance based on the hierarchical testing procedure.

A Phase 3, open-label, single-arm, multicenter study was conducted to assess the long-term safety and tolerability of Duodopa over 12 months in 354 patients. The target population was levodopa-responsive patients with advanced Parkinson's disease and motor fluctuations despite optimized treatment with available Parkinson's disease medications. The average daily normalized "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 dyskinesia.
A Phase 3, open-label, randomized, multicenter study was conducted to assess the effect of Duodopa on dyskinesia compared with optimized medical treatment (OMT) over 12 weeks in 61 patients. The target 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.
Pediatric population
The safety of Duodopa 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
Duodopa is administered via an inserted tube directly into the duodenum or jejunum. Levodopa is absorbed quickly and effectively from the intestine through a high capacity transport system for amino acids. The absolute bioavailability of levodopa from oral levodopa/carbidopa immediate release tablets is reported to be 84-99%. A cross-study population pharmacokinetic analysis suggested that Duodopa has comparable levodopa bioavailability to the oral levodopa/carbidopa (100/25 mg) tablets.

In a Phase 1 study, intrajejunal administration of Duodopa rapidly achieved therapeutic plasma levels of levodopa and maintained consistent levodopa levels over the course of infusion.
Following termination of infusion, levodopa levels declined rapidly (Figure 1). The intra-subject variability in levodopa plasma concentrations starting from hour 2 to hour 16 following initiation of infusion was low (13%).

Figure 1. Plasma Concentrations (mean ± standard deviation) versus Time Profile of Levodopa with Duodopa 16-Hour Infusion



In a Duodopa double-blind, active-controlled, Phase 3 Study, the intra-subject variability in levodopa plasma concentrations was lower for patients treated with Duodopa (21%) than in patients treated with oral levodopa/carbidopa 100/25 mg over-encapsulated tablets (67%).

Distribution
Levodopa is co-administered with carbidopa, a decarboxylase inhibitor, which increases the bioavailability and decreases clearance for levodopa. Clearance and volume of distribution for levodopa is 0.3 l/hour/kg and 0.9-1.6 l/kg, respectively, when given together with a decarboxylase inhibitor. The partitioning ratio for levodopa between erythrocytes and plasma is 
approximately 1. The protein binding of levodopa in plasma is negligible (about 10%-30%).
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.

Biotransformation and elimination
When administered with carbidopa, the elimination half-life for levodopa is approximately 1.5 hours. Levodopa is eliminated completely through metabolism and the metabolites formed are excreted mainly in the urine. Four metabolic pathways are known, but levodopa is mainly eliminated via metabolism by the aromatic amino acid decarboxylase (AAAD) and the catechol- O-methyl-transferase (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. When levodopa is co-administered with carbidopa, the decarboxylase enzyme is inhibited, so that metabolism via catechol-O-methyl- transferase (COMT) becomes the dominant metabolic pathway. O-methylation of levodopa by COMT forms 3-O-methyldopa.

Carbidopa is metabolized 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.

Pharmacokinetic-pharmacodynamic relationship
The reduced fluctuations in the plasma concentration of levodopa reduce fluctuations in the treatment response. The levodopa dose needed varies considerably in advanced Parkinson’s disease and it is important that the dose is individually adjusted based on the clinical response.
Development of tolerance over time has not been observed with Duodopa.