Discussion
In addition to a BE study under fasting conditions, the US. FDA and
National Medical Products Administration (NMPA) currently recommends a
BE study under fed conditions should be conducted for all orally
administered drug products submitted as an ANDA, with only a few
specific exceptions: when the drug substance is considered a BCS class 1
drug, and dissolution, solubility, and permeability data support a
biowaiver of in vivo BE testing, or When the DOSAGE AND ADMINISTRATION
section of the reference listed drug (RLD) label states that the product
should be taken only on an empty stomach, or When the RLD label does not
make any statements about the effect of food on absorption or
administration [15-16]. Rasagiline is a highly
solube low permeable drug and therefore classifies as a BCS class III
product. According to the drug label of RLD, rasagiline can be
administered with or without food, because AUC is not signifcantly
affected by food[9]. Therefore, this BE study for
rasagiline was conducted under both fasting and postprandial conditions.
The main PK parameters (Tmax and AUC) of the test drug
and the reference rasagiline had similar performances under both fasting
and postprandial conditions. The 90% CIs of the GMRs for AUC and
Cmax of the two tablets were within the BE range.
As shown above, rasagiline was rapidly absorbed by the gastrointestinal
tract, with Tmax occurring between 0.17 and 0.75 hours
after a single 1 mg dose under fasting conditions. After a high-fat
meal, Tmax of rasagiline is delayed from 0.33 hours
under fasting conditions to 1 hour under postprandial conditions. This
shows some difference from previous studies which demonstrated that food
did not affect Tmax of rasagiline, although
Cmax and exposure (AUC) were decreased by approximately
60% and 20%, respectively, when the drug was taken with a high-fat
meal[8-9]. In our study, we also found that while
a high-fat meal has significant effects on the absorption rate of
rasagiline,but minor effects on the absorption amount. Compared with
fasting conditions, the Cmax of rasagiline measured
after high-fat meal decreased significantly (4.36±2.98 vs 8.87±4.13 ),
and the AUC decreased slightly (4.89±1.40 vs 6.10±1.90) , which was
consistent with prior literature.
Study shows that in most cases, increased bioavailability with food
resulted in decrease of intra-individual variation (IIV) of AUC. While
food has a negative effect on a drug’s bioavailability, administering
the drug with food resulted in greater IIV compared to administering it
without food[17]. In our study we found that, when
administered with a high-fat meal, corresponding to the decrease of
Cmax is a significant increase in CV (26.3% under
fasting conditions vs 52.89% under postprandial conditions).
As stated above, administration with food can influence the absorption
and systemic exposure of rasagiline. The effect of food on oral
bioavailability results from a complex interplay of drug, formulation,
food components, gastric and intestinal physiology (e.g.
gastrointestinal pH, gastric emptying, intestinal transit)[15,18,19]. The difference in PK parameters
obtained may have resulted from differences in subjects, sample sizes,
sample detectors, or other unknown factors. Additional considerations
such as interindividual variability may also have contribution to this
difference [11].
Results from previous studies suggested that rasagiline was a highly
variable drug (HVD), which was consistent with our study[17,20]. In 2016, a randomized, four-period,
two-sequence, single-dose, replicate-crossover bioequivalence study of
rasagiline was conducted in 30 healthy, adult male volunteers under
fasting conditions by Van Rijswick YGJ. In Van Rijswick YGJ’s studies,
the IIV for Cmax of the reference product was
34.71%[20]. In our study after co-administration
with food, rasagiline IIV for Cmax was up to 52.89%
under postprandial conditions, much higher than data from Van Rijswick
YGJ’s studies under fasting conditions. Traditionally statistical
analysis of BE study data is performed by obtaining the average
bioequivalence (ABE) approach via a two-way crossover design. Two
products are deemed bioequivalent when the 90% CIs of the GMRs for AUC
and Cmax fall within the limits of 80–125% by ABE.
Establishing BE for HVD is challenging as high IIV requires a
dramatically larger sample size. Since 2006, FDA has accepted a
reference-scaled average bioequivalence (RSABE) approach for HVDs. Using
the RSABE approach, the BE study can use either a partial replicate
(three-way crossover, RTR, RRT, or TRR) or full replicate (four-way
crossover, RTRT or TRTR) design, and the BE limits are broadened to
greater than 80–125 % [21-24]. This BE study
uses a two-way crossover design, meeting the ABE criteria which was also
required by the National Medical Products Administration (NMPA) for HVDs[25]. As an HVD, the bioequivalence between two
types of rasagiline was established by expanding the sample size of the
postprandial group to 72 cases.
In addition to PK bioequivalence, both types of rasagiline were well
tolerated with no significant differences between safety profiles. The
occurrence and severity of AEs in our study was similar to results from
previous studies and described under the the rasagiline label.