Orodispersible Tablets Thesis Statement

The main objective of the present studies was to compare the bioavailability of ticagrelor following administration of either an OD tablet or an IR tablet. The pharmacokinetic findings for ticagrelor and AR-C124910XX demonstrated that most comparisons were within the acceptance interval for OD versus IR tablets, except for ticagrelor Cmax following administration of the OD tablet with water in Western subjects. The lower boundary of the 90% CI for this parameter was outside the acceptance range of 80%–125% [38, 39, 40]. The reason for the lower Cmax of ticagrelor following administration of the OD tablet with water in Western subjects is unknown. In response to a European Medicines Agency (EMA) request, key pharmacokinetic data from the Western and Japanese studies were pooled. Data pooling fulfils the EMA guideline recommendation to consider all the evidence as a whole if multiple studies have been conducted with a given formulation, and some results show bioequivalence, whereas other results do not [39]. As both the Western and Japanese studies had a crossover design, and, therefore, each subject was its own internal control, pooling data from both studies is considered appropriate. Additionally, due to the crossover design, any between-subject differences in age and body weight/BMI, for example, would have no impact on Cmax and AUC for tablet comparisons. Based on the pooled data (Supplementary Methods), the ticagrelor OD tablet given with or without water was bioequivalent to the IR tablet as the 90% CIs of the GMRs for AUC and Cmax of both ticagrelor and AR-C124910XX were within the acceptance range of 80%–125% (Supplementary Table S1). Thus, overall, the results from both the present studies, and the pooled data analyses, indicate that the OD ticagrelor tablet, with or without water, could be used in place of an IR tablet.

The validity of the present studies is confirmed since the current findings are in keeping with previously reported data. The pharmacokinetics and safety following a single dose of ticagrelor have been extensively studied, including studies using the same ticagrelor IR tablet employed in the present studies [41]. In the present Western study, the ticagrelor and AR-C124910XX pharmacokinetic parameters are generally comparable to previous studies in Caucasian subjects with a single 90-mg ticagrelor dose [12, 13]. Furthermore, the pharmacokinetic parameters in the current Japanese study are also generally similar to previous studies in Asian subjects, including Chinese [18] and Japanese [19] healthy subjects and in Japanese, Asian [20], and Chinese patients with coronary artery disease [21]. With regards to safety and tolerability, a single, 90-mg dose of ticagrelor was well tolerated in both studies. Moreover, the AE profile of ticagrelor in the present studies was consistent with previous studies in Caucasian subjects [5, 12, 13, 17], and Asian subjects [18, 19, 20, 21]. No new safety concerns with ticagrelor were identified with the OD tablet versus the IR tablet.

The present studies have some limitations. Only a single, 90-mg ticagrelor dose was evaluated, whereas, clinically, the ticagrelor dosing regimen is a 180-mg loading dose and 90 mg twice daily thereafter [7]. Furthermore, the current results in healthy subjects may not reflect those in populations of patients with ACS. In addition, the pharmacodynamic effects (i.e. platelet inhibition) were not evaluated in these studies.

The current pharmacokinetic results with the ticagrelor OD tablet, demonstrating bioequivalence with the IR tablet, are clinically important. OD tablets potentially address the medical needs of patients who are unable to take standard tablets [23, 34, 35]. Such patients include those who are unconscious, sedated, critically ill [24], elderly [25], or have dysphagia [26]. Moreover, all these scenarios are likely to be applicable to patients with cardiovascular disease [28, 29, 30, 31] who may require antiplatelet therapy. Based on the current results, the ticagrelor OD tablet is considered a suitable alternative formulation to the 90-mg ticagrelor IR tablet for patients who are unable to swallow whole tablets, for whom there is a preference for an OD formulation, or for those who require nasogastric administration. Easy dispersal of an OD tablet in water is simpler than crushing tablets for nasogastric tube administration. Other advantages of a ticagrelor OD tablet include convenience of dosing and use in situations when no water is available [34, 35].

Alternative methods of administering ticagrelor have also been studied, i.e. crushing or chewing the standard tablets. An ex vivo study demonstrated the feasibility of administering crushed ticagrelor tablets either orally or via a nasogastric tube [42]. Subsequently, a healthy subject study showed that crushed ticagrelor tablets were bioequivalent (i.e. pharmacokinetic parameters) to whole tablets [33]. Interestingly, higher ticagrelor and AR-C124910XX plasma levels occurred in the first hour post-dosing and tmax values were shorter for crushed versus whole tablets in healthy volunteers [33] and in patients with ST-elevation MI (STEMI) [43]. However, compared with the IR tablet, the ticagrelor OD tablet did not result in higher exposure to ticagrelor or AR-C124910XX at early time points post-dosing or a shorter tmax in either of the present studies. Three studies evaluated the effects of chewing ticagrelor tablets, the Chewing Versus Swallowing Ticagrelor to Accelerate Platelet Inhibition in ACS (CHEERS) study in patients with non-STEMI, the CHEERS-STEMI (similar study to CHEERS, but in patients with STEMI) and the Inhibition of Platelet Aggregation After Administration of Three Different Ticagrelor Formulations (IPAAD-Tica) study in patients with stable angina. All these studies showed that chewing two 90 mg ticagrelor tablets (180 mg loading dose) resulted in a faster onset of platelet inhibition versus a standard oral loading dose with whole tablets [44, 45, 46]. However, none of these studies reported ticagrelor or AR-C124910XX pharmacokinetic parameters. A faster onset of platelet inhibition in patients with STEMI has also been reported for crushed versus whole ticagrelor tablets [43, 47]. However, as platelet inhibition was not evaluated in the current studies, it is inappropriate to speculate on the possible pharmacodynamic effects of the ticagrelor OD tablet.

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