nal in healthysubjects taking up to 84 mg of INBRIJA. In the presence of carbidopa, the terminal eliminationhalf-life (t1/2) of levodopa following a single administration of INBRIJA 84 mg was 2.3 hours.
Absorption
After a single dose of INBRIJA 84 mg (two 42 mg capsules), the median Tmax for plasmalevodopa was approximately 0.5 hours (range 0.17–2.00 hours). In fasted healthy volunteers thebioavailability of levodopa from INBRIJA was approximately 70% relative to immediate-releaseoral levodopa tablets. The dose-normalized Cmax of levodopa from INBRIJA is approximately50% of that following immediate-release oral tablets.
Distribution
Apparent volume of distribution (Vz/F) was 168 L for INBRIJA 84 mg.
Metabolism and Elimination
Levodopa is extensively metabolized, and the two major metabolic pathways are decarboxylationby dopa decarboxylase and O-methylation by catechol-O-methyltransferase (COMT).
Specific Populations
Geriatric Population
Clinical studies specifically designed to analyze the effects of age on the pharmacokinetics of
levodopa were not conducted with INBRIJA.
Male and Female Patients
After a single dose administration of INBRIJA 84 mg, the body-weight adjusted Cmax and AUC0-
24 were similar between women and men. No adjustment in dosage is required based on sex.
Hepatic/ Renal Impairment
INBRIJA has not been studied in patients with hepatic or renal impairment.
Smokers
In a pharmacokinetic study following a single administration of INBRIJA 84 mg dose in thepresence of carbidopa, levodopa exposure (AUC and Cmax) in smokers (N=25) and non-smokers(N=31) were similar.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
In rats, oral administration of carbidopa/levodopa for two years resulted in no evidence ofcarcinogenicity.
Mutagenesis
Studies to assess the potential mutagenic or clastogenic effects of levodopa have not beenconducted.
Impairment of Fertility
In reproduction studies in rats, oral administration of carbidopa/levodopa resulted in no effectson fertility.
14 CLINICAL STUDIES
The efficacy and safety of INBRIJA for the treatment of OFF episodes in patients withParkinson’s disease treated with oral carbidopa/levodopa was eva luated in a 12-week,randomized, placebo-controlled, double-blind study (Study 1; NCT02240030).
Study 1:
In Study 1, a total of 114 patients were treated with INBRIJA 84 mg (two 42 mg capsules), and112 patients received placebo. Study medication could be administered up to five times a day. Atbaseline, patients had at least 2 hours per day of OFF time per day, and carbidopa/levodopamedication did not exceed 1600 mg levodopa per day. The mean UPDRS Part III scores atscreening in the ON state were 14.9 for patients randomized to INBRIJA 84 mg and 16.1 forpatients randomized to placebo. The UPDRS part III is designed to assess the severity of thecardinal motor findings (e.g., tremor, rigidity, bradykinesia, postural instability) in patients with
Parkinson’s disease.
The primary endpoint was the change in Unified Parkinson’s Disease Rating Scale (UPDRS)Part III motor score from pre-dose OFF state to 30 minutes post-dose, measured at Week 12. Theaverage use of INBRIJA 84 mg or placebo was approximately 2 doses per day. At Week 12, thereduction in UPDRS Part III motor score for INBRIJA 84 mg, compared to placebo at 30minutes post-dose, were -9.8 and -5.9, respectively ( |
