Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Merz Therapeutics GmbH, Eckenheimer Landstraße 100, 60318 Frankfurt am Main, Germany
Pharmacotherapeutic group: Anti-Parkinson drugs, dopaminergic agents
ATC code: N04BA01
Levodopa is a precursor of dopamine, and is given as dopamine replacement therapy in Parkinson's disease.
The effectiveness of Inbrija for the treatment of OFF episodes in patients with Parkinson's disease given on top of background dopaminergic treatment was evaluated in a 12-week, randomised, placebo-controlled, double-blind study. Subjects had to be able to recognise OFF periods and to handle the device.
A total of 114 patients were randomised and treated with Inbrija 66 mg (two 33 mg capsules) and 112 patients received placebo. When experiencing an OFF period, subjects could use inhaled levodopa on demand up to five times a day. Apomorphine was not allowed as background medicinal product. At baseline, patients had at least 2 hours of OFF time per day, and the levodopa/dopa-decarboxylase inhibitor medicines did not exceed 1,600 mg levodopa per day.
The primary efficacy endpoint was the mean change from baseline in Unified Parkinson's Disease Rating Scale (UPDRS) part III score 30 minutes post dose at week 12. The UPDRS part III is designed to assess the severity of the cardinal motor findings (e.g. tremor, rigidity, bradykinesia, postural instability) in patients with Parkinson's disease. This endpoint was assessed in a clinical setting, i.e. patients had to take their regular morning oral levodopa/dopa-decarboxylase inhibitor dose and then visit the clinic 2-5 hours post dose. If an OFF period emerged subjects received placebo or inhaled levodopa. UPDRS-III was assessed before and 30 minutes post dose administration. Reduction in mean daily OFF time and improvement on the Patient Global Impression of Change (PGI-C) scale, a patient reported outcome of the overall improvement and satisfaction with Inbrija treatment, and Responders ON were the main secondary endpoints. Results are presented in Table 2.
Table 2. Baseline features and results of the efficacy endpoints:
| Parameters | Placebo n=112 | Inbrija 66 mg n=114 |
|---|---|---|
| Subject features | ||
| Age | 63 years | 64 years |
| Duration PD | 97 months | 96 months |
| Baseline Levodopa dose | 841 mg | 819 mg |
| UPDRS-III score during OFF period | n=95a | n=94a |
| Pre-dose score | 32.1 | 29.0 |
| Change at 30 min | -5.91 | -9.83 |
| Diff. (95% CI) | - | -3.92 (-6.84; -1.00) |
| p-value | - | 0.009 |
| Responders ONb | n=97a | n=97a |
| % (n) | 36.1% (35) | 57.7% (56) |
| Diff. | - | 21.6% |
| p-value | - | 0.003 |
| PGI-C | n=97a | n=98a |
| Much improved % (n) | 7.2% (7) | 11.2% (11) |
| Improved % (n) | 7.2% (7) | 26.5% (26) |
| Little improved % (n) | 32.0% (31) | 33.7% (33) |
| Not improved % (n) | 53.6% (52) | 28.6% (28) |
| p-value | - | <0.001c |
| Daily OFF-time (h) | n=97a | n=95a |
| Baseline mean (SD) | 5.59 (2.25) | 5.35 (2.26) |
| LS mean change Mean diff. (95% CI) p-value | -0.48 | -0.47 -0.01 (-0.55; 0.56) 0.975 |
| Daily doses (median) | 2 doses | 2 doses |
a Observed cases.
b A responder was defined as a subject that changed from OFF to ON within 60 minutes post dose and who remained ON at 60 minutes post dose.
c p-value for PGI-C is nominal.
In a subpopulation of the 12-week study, serial spirometry measurements were performed at 15, 30 and 60 minutes following the first dose of Inbrija 66 mg or placebo. No notable differences between placebo and Inbrija were observed in forced expiratory volume in 1 second (FEV1) following the first dose.
The effect of Inbrija on pulmonary function was also evaluated in patients with Parkinson's disease treated with an oral levodopa/dopa-decarboxylase inhibitor in a 12-month, randomised, controlled, open-labeled study. A total of 271 patients were treated with Inbrija 66 mg (two 33 mg capsules), and 127 patients in an observational control group were observed on their regular oral medication regimen for the treatment of Parkinson's disease. Pulmonary function was assessed by spirometry and carbon monoxide diffusing capacity (DLCO) every 3 months in both groups. After 12 months, the average reduction in FEV1 from baseline was the same in both groups (-0.1 L). The change from baseline for DLCO was compared between the Inbrija treatment group and the observational cohort; at the end of 12 months, there was no significant difference in the change from baseline between Inbrija group and the observational cohort in DLCO.
The European Medicines Agency has waived the obligation to submit the results of studies with Inbrija in all subsets of the paediatric population in the treatment of idiopathic Parkinson's disease (see section 4.2 for information on paediatric use).
The pharmacokinetics of Inbrija 66 mg (2 x 33 mg capsules) and carbidopa/levodopa 25 mg/100 mg immediate release tablets was evaluated in 24 healthy volunteers in a fasted state receiving a total of 50 mg carbidopa every 8 hours.
The median time to maximal plasma concentration of levodopa was 30 minutes after a dose of Inbrija 66 mg (2 x 33 mg capsules) compared to 45 minutes after a dose of carbidopa/levodopa 25 mg/100 mg immediate release tablets. The dose-normalised relative bioavailability of a single 66 mg emitted dose of Inbrija was 88.0% (90% CI: 80.3, 96.4) when compared to a single oral carbidopa/levodopa 25 mg/100 mg dose.
The mean maximal plasma concentration at 10 minutes (C10min) and at peak concentration (Cmax) of levodopa following administration of Inbrija 66 mg (2 x 33 mg capsules) was 418 ng/mL and 696 ng/mL, respectively, with exposure over 4 hours (AUC0-4h) of 1,280 ng●h/mL.
Apparent volume of distribution (Vz/F) was 168 L for Inbrija 66 mg (2 x 33 mg capsules).
Levodopa is extensively metabolised to various metabolites. The two major metabolic pathways are decarboxylation by L-aromatic amino acid decarboxylase and O-methylation by catechol-O-methyltransferase (COMT).
The pharmacokinetics of the major levodopa metabolites 3-O-methyldopa (3-OMD), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were studied following administration of a single inhaled dose of Inbrija and a single oral carbidopa/levodopa 25 mg/100 mg immediate release tablet. The metabolite profile following Inbrija inhalation was not substantially different than that observed following oral carbidopa/levodopa administration. The peak metabolite concentrations and total exposure achieved after Inbrija administration did not exceed those observed following an oral carbidopa/levodopa dose.
The impact of the amount of circulating dopa-decarboxylase at the end of an oral carbidopa/levodopa dosing interval on the efficacy of Inbrija was not studied.
In the presence of carbidopa, the apparent terminal elimination half-life (t1/2) of levodopa following a single administration of Inbrija 66 mg (2 x 33 mg capsules) was 2.3 hours and comparable to that following an oral dose of carbidopa/levodopa 25 mg/100 mg immediate release tablets of 1.9 hours.
Inbrija shows dose proportional pharmacokinetics of levodopa from 13 mg to 122 mg.
Inbrija has not specifically been studied in patients with renal impairment. It is recommended to administer this medicinal product cautiously to patients with severe renal disease (see section 4.2).
Inbrija has not specifically been studied in patients with hepatic impairment. It is recommended to administer this medicinal product cautiously to patients with severe hepatic impairment (see section 4.2).
A clinical study was performed with Inbrija 66 mg (2 x 33 mg capsules) in 24 healthy subjects (13 men and 11 women). After administration of Inbrija the Cmax and AUC0-24h for women were 42.2% higher and 48.8% higher than for men, respectively. After correcting the parameters for body weight, the gender difference after each treatment was no longer significant: the body-weight adjusted Cmax and AUC0-24h after a dose of Inbrija in women were 9.7% and 15.1% higher than men. Most of the gender difference is accounted for by differences in body weight. No dose adjustment is required based on gender.
A clinical study was performed with Inbrija 66 mg (2 x 33 mg capsules) administered to 56 healthy subjects (31 non-smokers and 25 smokers). After administration of Inbrija the Cmax and AUC0-24h was 11% to 12% higher for smokers than for non-smokers. No dose adjustment is required based on smoking status.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
Levodopa has caused visceral and skeletal malformations in rabbits. No effects were seen on male or female reproductive organs in repeat dose toxicology studies in mice, rats or monkeys with levodopa alone.
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