Abstract:
Objective This study aims to evaluate the bioequivalence of 2
formulations of rasagiline tablet (1mg) in Chinese healthy subjects.Methods An open, randomized, single-dose, double-cycle,
two-sequence, self-crossover pharmacokinetic study in healthy Chinese
subjects under fasting and high-fat postprandial conditions was
performed. A total of 108 healthy subjects (36 in the fasting group and
72 in the postprandial group) were recruited. In each of the two study
periods under both conditions, subjects received a single oral dose of 1
mg test or a reference rasagiline (1 mg each). There was a 3-day washout
period. Blood samples were obtained up to 10 hours post-intake. Several
pharmacokinetic parameters were estimated based on the concentrations of
rasagiline measured in plasma by means of LC-MS/MS. Results The
geometric mean ratio (90% CI) of the test drug versus reference drug
for rasagiline was 94.16% to 105.35% for AUC0-t under
fasting conditions and 99.88% to 107.07% under postprandial
conditions. The AUC0-∞s were 93.55% to 105.01% and
99.59% to 107.05% under fasting and postprandial conditions,
respectively. The Cmax values were 88.26% to 108.46%
and 89.54% to 118.23% under two conditions, respectively. The 90% CIs
for test/reference AUC ratio and Cmax ratio were within
the acceptable range (0.80–1.25) for BE. There were no serious adverse
events (AEs) encountered during this BE study. ConclusionBioequivalence between the test and the reference products was
established in both fasting and postprandial conditions. The two types
of rasagiline showed good tolerability and a similar safety profile.
Key words: bioequivalence, rasagiline, monoamine oxidase type B
inhibitor, pharmacokinetic
Parkinson’s disease (PD) is a progressively disabling neurodegenerative
disorder caused by the loss of dopaminergic neurons in the substantia
nigra pars compacta. The clinical symptoms of PD patients include
bradykinesia, muscle rigidity, resting tremor, and postural instability,
which lead to gait disturbances and falls [1,2].
Second only to Alzheimer’s disease (AD), PD is among the most common
neurodegenerative diseases in the world, which affects around 0.3% of
the general population and increases to 1-3% of people above 65 years
of age. The number of people who suffer from PD is predicted to climb
from 8.7 to 9.3 million by 2030[3]. A more recent
meta-analysis estimated the overall prevalence and annual incidence on
PD in China to be 16–440 per 100,000 and 1.5–8.7 per 100,000 people,
respectively[4]. Currently, PD affects millions of
people globally and has severe social and economic impacts.
Therapeutic agents to control the symptoms of PD include levodopa (a
precursor in dopamine synthesis), dopamine agonists and monoamine
oxidase type B (MAO-B) inhibitor, the major enzyme responsible for the
oxidative metabolism of dopamine in the human brain. The first (MAO-B)
inhibitor was selegiline, with a major drawback of metabolism to
(–)-amphetamine and (–)-methamphetamine. These metabolites play an
“anti-tyramine” role by inhibiting the uptake of dopamine by neurons,
resulting in neurotoxicity and cardiovascular adverse
effects[5-8]. Rasagiline mesylate is a potent,
highly selective, and irreversible second-generation MAO-B inhibitor and
has neuroprotective activity[8-9]. Its major
metabolite is 1(R)-aminoindan differentiated by distinctly
non-amphetamine structural features [7].
Rasagiline mesylate (AZILECT®), developed jointly by Israel’s Teva and
Denmark’s Lundbeck, was first approved by the European Medicines Agency
(EMA) in February 2005 and approved by the United States FDA in 2006 as
monotherapy in PD patients not treated with levodopa and as adjunct
therapy to levodopa in levodopa-treated patients. In June 2017,
rasagiline was approved by CFDA to be listed in China and is currently
used by PD patients in over 50 countries taking doses ranging between
0.5 mg and 1 mg daily.
According to recent surveys conducted with healthy individuals and PD
patients in China and Japan, rasagiline can safely and effectively treat
Parkinson’s disease symptoms by blocking the decomposition of the
neurotransmitter dopamine, with good drug tolerance and long-lasting
effects[10-13]. As a whole, it is a novel , safe
and effective drug to manage Parkingson’s disease.
From 2006 to 2016, there were only two MAO-B inhibitors (rasagiline and
safinamide) successfuly been commercialized. Consequently, PD patients
have limited choices of these drugs[6]. Although
antiparkinsonian medications are not considered to be the most expensive
pharmacological agents, lifelong treatment and often complex drug
regimens impose a high economic burden on both patients and the
healthcare system [14]. Accordingly, the
development and application of generic drugs as substitutes for the
branded ones is a clear and economic choice.
Rasagiline mesylate tablets produced by Changzhou Siyao Pharmaceuticals
Co., Ltd. is the first generic drug of its type in China. Taking a test
preparation and using AZILECT® as reference, this
study investigates the pharmacokinetic (PK) properties of rasagiline
mesylate in healthy Chinese volunteers with single-dose administration
under fasting or postprandial conditions and to assess the BE of the 2
rasagiline mesylate tablets. After the administration of a single 1 mg
oral dose on healthy Chinese volunteers, we applied a 2-sequence and
2-period crossover (2 × 2) study design. This study was registered and
approved by the China Food and Drug Administration.