Pharmacokinetics of a 1,000 mg disintegrating Aspirin tablet formulation

The burden of migraine is considerable, as it affects 11% of people globally and significantly diminishes the quality of life and normal functioning of most sufferers [1]. The role of non-prescription medicinal product treatment options for acute migraine episodes is large, as a majority of patients opt for self-treatment over medical consultation with a physician [2]. Aspirin (acetylsalicylic acid, ASA) in doses of 1,000 mg has been proven to effectively relief migraine headache [3-13].


Introduction
A requirement for early onset of action includes tablet disintegration and consequent active ingredient dissolution and absorption. The bioavailability of a new quickly disintegrating 1,000 mg aspirin formulation has been investigated in a bioequivalence study versus a marketed Aspirin® formulation with clinically demonstrated early onset of action. The new formulation has a tablet strength (1,000 mg) and time to maximum plasma concentration (mean 21.6 minutes) providing upside for people requiring treatment of migraine headache.
Bayer previously developed a 500 mg quickly disintegrating aspirin coated tablet with microactive technology, which was proven to enhance bioavailability [19] and improve onset of action compared to regular aspirin tablets [20,21]. This enhanced speed can be attributed to two formulation enhancements: micronized aspirin particles that are smaller in size, providing a larger surface area for dissolution and absorption, and sodium carbonate which acts as a disintegrant and local buffer both resulting in improved pharmacokinetics [19,20,22].
The primary pharmacokinetic parameters evaluated were area under the plasma concentration-time curve from time zero to the time of last measurable concentration (AUC 0-t ), AUC from time zero extrapolated to infinity (AUC 0-inf ), and maximum plasma concentration (Cmax) for ASA. As secondary outcomes, the AUC 0-t , AUC 0-inf , and C max for the active metabolite salicylic acid (SA) were determined, as well as time to reach maximum plasma concentration (t max ), half-life (t 1/2 ), and apparent terminal rate constant (λ z ) for both analytes. Safety of the products was evaluated by subject`s self-reported adverse events and consequent assessment by the investigators and by clinical parameters (systolic/diastolic blood pressure, respiratory rate, pulse rate, physical examination, clinical and laboratory testing). Adverse events reports were collected throughout the trial, from screening through follow-up.
Under the assumption of μTest/μReference = 1.0, CV = 25.0%, acceptance range for equivalence: 0.8-1.25 it was determined that 30 subjects (15 per sequence group) would be adequate for the study to achieve 80% power and a significance level of 5%. To account for potential dropouts (which were not to be replaced unless the population dropped lower than 30), the study planned to enroll 38 subjects.
Pharmacokinetic analyses were performed on the pharmacokinetic (PK) Evaluable Population (all subjects having C max and AUC 0-t data for both treatments and no major protocol deviations). Supportive analyses were run using the PK Full Population (all subjects that were randomized and had plasma concentration data). Safety evaluations were based on the Safety Population (all subjects who received at least 1 dose of study drug). Plasma concentration-time data for both ASA and SA were summarized at each measured time point using descriptive statistics. PK parameters were calculated from the plasma concentration data using actual sample times and standard, non-compartmental methods of analysis (WinNonlin Professional version 6.3.1) and analyzed using analysis of variance (ANOVA).
The evaluation of bioequivalence for test versus reference products was based upon ASA data for C max , AUC 0-t , and AUC 0-inf . A 90% confidence interval (CI) for the difference between formulations was obtained. If the 90% CIs of the ratios for Cmax, AUC 0-t , and AUC 0-inf for test vs. reference treatment in the PK Evaluable Population were contained within 80-125%, then the formulations would be considered bioequivalent. As supportive analyses, the same test of bioequivalence was performed for SA in the PK Evaluable Population.
Thirty-eight subjects were randomized to receive treatment, of which 36 (94.7%) completed the trial and were included in the PK Evaluable Population. Two subjects discontinued prematurely (due to inadequate venous access and withdrawal of informed consent) and were only included in the PK Full and Safety Populations. Twenty-three (60.5%) subjects were male and 15 (39.5%) subjects were female, with ages ranging from 18 to 55 (mean (SD) = 37 (10.7)). A more complete list of study population demographics and baseline characteristics can be found in Table 1.

Results
Summary statistics for ASA and SA pharmacokinetic parameters are presented in Table 2. Plasma concentration vs. time curves for ASA and SA analytes are shown in Figures 1 and 2. The curves obtained for the 1 x 1,000 mg aspirin tablet (test) are consistent with those obtained for the 2 x 500 mg Aspirin® tablets (reference). This indicates that the formulations behaved similarly in terms of the speed of the ASA absorption (median t max (range): 0.38 h (0.25, 0.58) and 0.33 h (0.21, 0.67)) for test and reference, respectively). Mean peak plasma ASA level were also similar (geometric mean C max (SD): 22    and reference, respectively). Speed of SA absorption (median t max (range): 0.72 h (0.38, 2.00) and 0.80 h (0.29, 4.00) for test and reference, respectively) and SA mean peak plasma SA levels (geometric mean C max (SD): 74.39 µg/mL (1.197) and 73.09 µg/mL (1.206) for test and reference, respectively) further supports equivalence of the two formulations. Total exposure of drug measured as AUC 0-t and AUC 0-inf showed similar bioavailability of the two formulation regarding acetylsalicylic acid as well as salicylic acid. Results were consistent between formulations, with no sizable differences to note. This was confirmed by bioequivalence analysis presented in Table 3. The 90% CIs for the ratio of geometric means comparing test to reference formulation fell within the accepted range of 80 to 125% for each of the three primary PK parameters C max (102.1-119.8), AUC 0-t (98.29-105.8), and AUC 0-inf (98.28-105.8), confirming that 1 tablet of the 1,000 mg quickly disintegrating aspirin formulation is bioequivalent to 2 tablets of 500 mg quickly disintegrating Aspirin® formulation. A supportive analysis applying calculation of bioequivalence to the active metabolite SA also met criteria for bioequivalence (C max : 99.13-104.    Adverse events occurred in 3 subjects following test drug (7.9%) and 1 subject (2.8%) following reference drug administration, but overall the occurrence of events was low. The adverse events reported in the test group were considered to be drug related by the Investigator. One subject reported upper abdominal pain and 2 subjects increased alanine aminotransferase. None of the subjects discontinued treatment due to an adverse event. All events were considered mild to moderate in intensity, with no reports of serious adverse events during this trial. The one adverse event reported in the reference group was considered as not related (viral infection).

Safety
This study was conducted to compare the bioavailability of a single 1,000 mg quickly disintegrating acetylsalicylic acid tablet to two tablets of commercially available 500 mg quickly disintegrating Aspirin®. Both formulations apply small particle size active ingredients and sodium carbonate acting as a disintegrant. This microactive technology supports the pharmaceutical phase, i.e. quick disintegration and dissolution and consequent fast bioavailibilty resulting in early onset of action. This was demonstrated in in vitro dissolution and in vivo Phase I and Phase III studies for the 500 mg formulation [19][20][21]. The study presented demonstrated that both microactive technology formulations are bioequivalent and have similar small time to maximum plasma concentration. Therefore, the substantial improvement in speed of dissolution, absorption, and subsequent onset of action already demonstrated for the 500 mg quickly disintegrating tablet formulation, can also be assumed of this new higher dose formulation.

Discussion
In relation to speed, there are less obvious but important formulation driven benefits resulting from the microactive technology worthy of discussion. The first is the pharmaceutical behavior of quickly disintegrating aspirin tablets in the stomach. Acetylsalicylic The study was funded by Bayer AG, Leverkusen, Germany. Bayer is the originator and a major manufacturer of aspirin products. M.V. and S.F. are both employees of Bayer. The study was conducted by Frontage Clinical Services, Hackensack, New Jersey, United States.
acid from standard aspirin tablets is primarily absorbed in the small intestine [23], putting speed of absorption at the mercy of gastric emptying rate. In quickly disintegrating aspirin formulations, however, microactive technology, consisting of small active ingredient particles with a relatively large surface enabling easy dissolution and sodium carbonate supporting disintegration and providing a local pH supporting dissolution, enhances the rate of tablet disintegration and subsequent dissolution of active drug within the stomach, where it can be quickly absorbed into systemic circulation. The Biopharmaceutics Classification System (BCS) assigns aspirin to Class I (high solubility, high permeability) [24]. The quick disintegration and fast bioavailability of the new formulation supports the BCS properties of aspirin and provides pharmaceutical advantage for early onset of action.
Second, though this behavior is beneficial to any patient seeking for quick pain relief, it becomes especially critical in the context of acute migraine, which is often accompanied by impaired gastric motility. In this situation, transit of drug to the small intestine for absorption would be delayed, and onset of relief could be compromised if the drug administered is not optimized for gastric absorption. It can therefore be concluded that the pharmaceutical characteristics and the pharmacokinetic properties of the new 1,000 mg aspirin formulation would support its efficacy in the relief of headache caused by migraine attacks with or without aura.
Aspirin is approved for self-medication in single doses of up to 1,000 mg in many countries. The current study did not provide any signal for unexpected or unknown side effects or higher frequencies of known side effects. Doses of 1,000 mg of acetylsalicylic acid have generally been proven safe and tolerable in a variety of Phase III and IV studies including migraine studies [3][4][5][6][7][8][9][10][11][12][13]. The maximum plasma concentration is comparable to 2 tablets of a standard dose of 500 mg and also comparable to marketed effervescent tablet formulations [22] which are approved for the treatment of migraine headache.
The 1,000 mg quickly disintegrating aspirin tablet demonstrated bioequivalence compared to two tablets of commercially available 500 mg quickly disintegrating Aspirin®, when administered as a single dose to healthy, fasted adults. Both formulations were safe and well-tolerated under these conditions. The 1,000 mg aspirin formulation is appropriate for the treatment of migraine headache and provides requirements for fast onset of action.

Conclusions
Acknowledgement