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.