Journal of Thrombosis and Thrombolysis

https://doi.org/10.1007/s11239-020-02051-5

Bioavailability of aspirin in fasted and fed states of a novel

pharmaceutical lipid aspirin complex formulation
Dominick J. Angiolillo1 · Deepak L. Bhatt2 · Frank Lanza3 · Efthymios N. Deliargyris4 · Jayne Prats5 · Weihong Fan4 ·
Upendra Marathi6

© The Author(s) 2020

Abstract
Dyspeptic symptoms are common with aspirin and clinicians frequently recommend that it be taken with food to reduce these
side effects. However, food can interfere with absorption, especially with enteric-coated aspirin formulations. We evaluated
whether food interferes with the bioavailability of a new, pharmaceutical lipid-aspirin complex (PL-ASA) liquid-filled capsule
formulation. In this randomized, open label, crossover study, 20 healthy volunteers fasted for ≥ 10 h and then randomized
as either “fasted”, receiving 650 mg of PL-ASA, or as “fed”, with a standard high-fat meal and 650 mg of PL-ASA 30 min
later. After a washout of 7 days, participants crossed over to the other arm. The primary outcome was comparison of PK
parameters of the stable aspirin metabolite salicylic acid (SA) between fasted and fed states. Mean age of participants was
36.8 years and 55% were male. The ratios for the fed to fasted states of the primary SA PK parameters of AUC​0−t and AUC​
0−∞ were 88.7% and 88.8% respectively, with 90% confidence intervals between 80 and 125%, which is consistent with FDA
bioequivalence guidance. Mean peak SA concentration was about 22% lower and occurred about 1.5 h later in the fed state.
Food had a modest effect on peak SA levels and the time required to reach them after PL-ASA administration, but did not
impact the extent of exposure (AUC) compared with intake in a fasted state. These data demonstrate that PL-ASA may be
co-administered with food without significant impact on aspirin bioavailability.
Clinical Trial Registration: http://www.clini​caltr​ials.gov Unique Identifier: NCT01244100

Keywords Aspirin · Pharmacokinetic · Platelet · Bioavailability · Fasted · Fed

Highlights

• Daily aspirin is frequently recommended to be taken with

food in an effort to minimize dyspeptic side effects.
Electronic supplementary material The online version of this
article (https​://doi.org/10.1007/s1123​9-020-02051​-5) contains • Enteric coated aspirin suffers from erratic absorption and
supplementary material, which is available to authorized users. bioavailability that is further exacerbated when taken
with food.
* Dominick J. Angiolillo • The novel pharmaceutical lipid-aspirin complex (PL-
[email protected]
ASA) liquid capsule formulation is an immediate release
1
Division of Cardiology, University of Florida College aspirin with predictable and consistent absorption and
of Medicine, Jacksonville, 655 West 8th Street, Jacksonville, bioavailability that has been specifically designed to
FL 32209, USA reduce aspirin’s GI toxicity.
2
Brigham and Women’s Hospital Heart & Vascular Center, • The results of the current study demonstrate that PL-
Harvard Medical School, Boston, MA, USA ASA can be taken with food with only minimal impact
3
Houston Institute for Clinical Research, Houston, TX, USA on overall drug exposure and bioavailability.
4
PLx Pharma, Sparta, NJ, USA
5
Elysis LLC, Carlisle, MA, USA
6
7 Hills Pharma, Houston, TX, USA

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Vol.:(0123456789)
 D. J. Angiolillo et al.

Introduction fasted pharmacokinetics (PK) of a single administration

of PL-ASA (650-mg aspirin, administered as two 325-mg
Aspirin, or acetylsalicylic acid, is an irreversible inhibi- capsules) in 20 healthy volunteers from October to Decem-
tor of the platelet cyclooxygenase (COX)-1 and COX-2 ber 2010 (Clinicaltrials.gov identifier: NCT01244100).
enzymes, causing a reduction in prostaglandin and direct We selected 650 mg as the appropriate dose to test the
prostaglandin derivatives such as thromboxane and pro- impact of food since most patients take two 325 mg tab-
ducing several important downstream clinical effects. lets when seeking acute pain relief or fever reduction. All
Aspirin is an effective antipyretic, analgesic and anti- subjects underwent screening procedures to determine eli-
inflammatory agent and has been clinically used for those gibility for the study. In brief, healthy volunteers between
conditions for over a century. However, the subsequent 21 and 65 years of age who had not been exposed to an
recognition that aspirin is also an effective inhibitor of antiplatelet, anticoagulant or non-steroidal inflammatory
platelet activation has resulted in its current use to be agent in the previous 14 days were considered eligible
primarily for the prevention of cardiovascular events [1]. for the study (See Online Supplement for specific study
Although the role of aspirin for primary prevention is sub- inclusion and exclusion criteria). Study subjects fasted
ject to controversy, aspirin is the cornerstone of treatment for ≥ 10 h and underwent baseline evaluations prior to
for secondary prevention in patients with atherosclerotic dosing. Eligible subjects were then randomized to 1 of
cardiovascular disease (ASCVD) [2–6]. The main side- the 2 treatment sequences, with ten subjects randomized
effect of aspirin is related to its associated gastrointesti- to each sequence: 650 mg PL-ASA [fasted] or to 650 mg
nal (GI) toxicity, which can manifest as bleeding of vary- PL-ASA [fed]. If randomized to the fasted arm, subjects
ing severity and dyspeptic symptoms [7, 8]. Importantly, immediately received the single 650 mg dose of PL-ASA.
such GI side-effects are key contributors to poor adher- If randomized to the fed arm, subjects first ate a standard
ence or discontinuation of aspirin therapy, which in turn high-fat, high-caloric meal and were dosed 30 min later.
can increase the risk of ischemic events in patients with Each dose of PL-ASA was administered with 240 mL of
ASCVD [9]. Clinicians frequently recommend that daily water. A standard meal was provided for all subjects (fed
doses of aspirin be taken with food as a way to reduce dys- or fasted) 4 h after administration of study drug and dinner
peptic symptoms [10]. However, food can interfere with was permitted immediately following the 10-h blood draw.
aspirin absorption, especially with enteric-coated aspirin After a washout period of 7 days each subject crossed over
formulations, which are the most commonly used tablets to the other arm and was again dosed with 650 mg of
in clinical practice [11]. Overall, these observations under- PL-ASA (i.e., subjects who received the first treatment
score the unmet need for aspirin formulations with a more in the fasted state, now received PL-ASA in the fed state
favorable safety profile while maintaining pharmacologic and vice versa). Subjects had 6-mL blood samples drawn
efficacy. for PK analysis at the following time points after each
A novel pharmaceutical lipid-aspirin complex (PL-ASA) study drug administration: within 1 h prior to administra-
liquid formulation was developed to mitigate disruption of tion, at 5, 10, 15, 20, 25, 30, 40, 50, 60, 75, and 90 min
the epithelial phospholipid layer of the gastric mucosa with- post administration; and at 2, 3, 4, 6, 8, 10, 12 and 24 h
out delaying absorption [12–14]. Studies have shown that post administration. Laboratory assessments (hematology,
PL-ASA has similar bioavailability to immediate-release blood chemistry) were performed at screening (Visit 1),
aspirin in fasted healthy volunteers and obese patients with prior to the second administration (Visit 3), and 24 h after
diabetes [14, 15]. Moreover, PL-ASA significantly reduces each administration (Visits 2 and 4). The study design is
the risk of acute gastric mucosal erosions and ulcers com- illustrated in Fig. 1.
pared with immediate release aspirin [16]. The present study The protocol was approved by IntegReview Ethical
evaluated whether co-administration with food would inter- Review Board (Number ORG0000689) and the study con-
fere with the bioavailability of PL-ASA. ducted at The Houston Institute for Clinical Research. Dr
Angiolillo prepared the first draft of this manuscript and had
full access to the analyzed data.

Methods PK analyses

Study design and study population Assessment of a food effect on PL-ASA bioavailability
was determined by comparing PK parameters of salicylic
This was a single-center, randomized, active-controlled, acid (SA) after drug administration in the presence and
open-label crossover study designed to assess fed vs. absence of food. SA is the metabolite that is responsible
for the analgesic and antipyretic effects of aspirin. SA is

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Bioavailability of aspirin in fasted and fed states of a novel pharmaceutical lipid aspirin…

Fast for 10 hours 20 Healthy Volunteers of SA and acetylsalicylic acid were determined from individ-
meet inclusion criteria ual plasma concentration data by non-compartmental analy-
Randomize sis using the actual, exact sampling time in relation to dos-
ing. PK parameters were summarized by the fed and fasted
Fasted Fed
High Fat Meal, then
states. Mean, SD, coefficient of variance (CV), median and
Immediately
650 mg PL-ASA 650 mg PL-ASA range were presented, and p-values were calculated based on
n=10 n=10
the Wilcoxon Rank-Sum test. The statistical significance was
PK sampling to 24h
assessed using a two-sided test at the 0.05 significance level.
7-day washout then crossover Log-transformed parameters for AUC​0−t, AUC​0−∞, and
­Cmax were calculated for each subject to determine the bio-
availability ratio between fed and fasted states. The least-
Fasted* Fed square means (LSM) of log-transformed PK parameter for
Immediately High Fat Meal, then
650 mg PL-ASA 650 mg PL-ASA both fed and fasted states were estimated by the use of a
n=10 n=10 mixed-effects repeated measures Analysis of Variance
(ANOVA) model. The model included sequence, period, fed/
* 10 hour fasting period before dosing
fasted state as fixed effects and subjects as a random effect.
The exponentiality of LSM was called geometric mean.
Fig. 1  Study design
The ratio for each parameter was determined by dividing
the geometric mean of fed state by the geometric mean of
a far more stable metabolite compared with acetylsalicylic fasted state. To determine whether a meaningful food effect
acid and is the analyte agreed upon by the Food and Drug exists with PL-ASA, we referenced the FDA bioequivalence
Administration (FDA) for PK assessments of aspirin in this guidelines that propose that 90% confidence intervals (CI) of
study. Specifically, acetylsalicylic acid is rapidly converted the ratio are between 80–125%.
to SA by hydrolysis and first-pass metabolism making peak
plasma acetylsalicylic acid concentrations extremely sen-
sitive to minor variations in solid dosage form dissolution Results
and disintegration. In contrast, plasma SA concentrations are
predictable and relatively stable making it a more reliable A total of 24 subjects were screened for this study, of whom
analyte for PK assessments [15]. four did not meet study entry criteria. Thus, 20 subjects
Accordingly, SA parameters were used for primary PK were enrolled, randomized, and treated with PL-ASA. All
endpoints; while acetylsalicylic acid parameters were tested 20 treated subjects were 100% compliant with study drug
for secondary PK analysis. The primary PK assessments administration and completed this study without protocol
were made on AUC​0−t, AUC​0−∞, ­Cmax, ­tmax, λz, ­t½, ­VD/F, deviations. The baseline characteristics of the study popula-
CL/F and ratios of the least square means (LSM) of the log- tion are summarized in Online Table 3. No adverse events
transformed PK parameters of AUC​0−t, AUC​0−∞, ­Cmax of SA were reported during the study. Vital signs and laboratory
in the presence or absence of food. Secondary PK assess- results were unremarkable.
ments included similar parameters for acetylsalicylic acid in Mean SA concentrations over time following a single
the presence and absence of food. A full list of PK param- 650 mg dose of PL-ASA in fed versus fasted states are
eters measured is provided in Online Table 2. Plasma sam- graphically displayed in Fig. 2. Overall, the curves in the
ples were collected into sodium fluoride/potassium oxalate, fasted and fed states were very similar, however, mean peak
frozen (− 80 °C) and analyzed by Medtox Laboratories (St. SA concentration was 28.1% higher in the fasted state and
Paul, MN). Plasma SA and acetylsalicylic acid levels were mean time to maximum SA concentration occurred about
determined by High Performance Liquid Chromatography 1.5 h later in the fed state. Detailed listings of all SA param-
with tandem Mass Spectrometry (LC- MS/MS) [15]. eters in both fed and fasted states are shown in Table 1.
Most PK parameters in fed and fasted states were similar
Statistical methods except for ­Cmax that was significantly higher in the fasted
state (p = 0.01), and t­ max that was significantly higher in the
Full details regarding statistical methods are provided in the fed state (p = 0.002).
Online Supplement. Demographic and baseline character- Log-transformed AUC​0−t, AUC​0-∞ and C ­ max were used
istics were summarized using descriptive statistics: mean, to calculate ratios of fed to fasted states as summarized in
standard deviation (SD), median, and range (minimum and Table 2. To quantitively evaluate whether a food effect was
maximum) for continuous variables and frequency and per- present we applied the FDA guidance and determined that
centage of subjects for categorical variables. PK parameters the 90% confidence intervals for the SA log-transformed

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 D. J. Angiolillo et al.

Fig. 2  Mean plasma salicylic 100000

acid concentration versus time.
Plasma concentrations (log-lin-

Plasma concentration (ng/mL)

ear scale) for salicylic acid are 10000
depicted after a single 650 mg
dose of PL-ASA in the presence
(fed, dotted line) and absence of 1000
food (fasting, solid line)
100

Fasting state Fed state

10

0
0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500

Time (minutes)

Table 1  Summary of fed and fasted salicylic acid PK parameters after a single dose of 650 mg PL-ASA
PK ­parametera Fed N = 20 Fasted N = 20 P-valueb
Mean (SD) CV (%) Median (range) Mean (SD) CV (%) Median (range)

AUC​0−t ([µg × min] /mL) 14,945.7 43.1 14,929.1 16,521.8 36.1 16,582.0 0.3
(6436.2) (7844.8–33,463.9) (5958.7) (7915.6–32,414.2)
AUC​0−∞ ([µg × min] /mL) 15,202.9 44.2 14,952.5 16,791.0 36.7 17,036.1 0.3
(6723.0) (8175.7–35,576.8) (6167.9) (8224.8–34,102.3)
Cmax (µg/mL) 29.9 28.9 29.7 38.3 25.8 38.9 0.01
(8.6) (17.9–55.3) (9.9) (22.2–57.8)
tmax (min) 283.5 33.9 360.0 180.0 28.1 180.0 0.002
(96.1) (90.0–360.0) (50.6) (90.0–240.0)
λZ (1/min) 0.0048 19.2 0.0050 0.0048 18.9 0.0050 0.8
(0.0009) (0.0023–0.0061) (0.0009) (0.0024–0.0060)
t½ (min) 152.9 28.4 137.5 152.9 28.2 139.2 0.8
(43.1) (113.0–296.8) (43.1) (115.9–292.8)
CL/F (mL/min) 50.1 38.4 43.5 44.0 37.9 38.2 0.3
(19.2) (18.3–79.5) (16.7) (19.1–79.0)
VD/F (mL) 10,400 30.1 9880 9148 27.3 8093 0.3
(3128) (6086–15,433) (2498) (5644–13,824)

AUC​0−t area-under-the-curve; AUC​0−∞ AUC​0−t extrapolated to infinity; Cmax maximum plasma concentration; CL/F apparent clearance; CV coef-
ficient of variation; λz terminal elimination rate constant; μg micrograms; mg milligrams; min minutes; mL milliliters; n number of subjects;
PK pharmacokinetic; PL-ASA pharmaceutical lipid-aspirin complex; SD standard deviation; tmax time of peak drug concentration; t½ first-order
elimination half-life; VD/F apparent volume of distribution
a
N = 20 for all PK parameters
b
P-value based on the Wilcoxon Rank-Sum test

AUC​0−t and AUC​0−∞ ratios were indeed within the 80% Online Table 4. The slope of the log-linear elimination
to 125% range (82.2–95.8% and 82.2–96%, respectively) phase was not estimable in 10 subjects in the fed state and
while the 90% CI for C ­ max was slightly outside that range 14 subjects in the fasting state (18 unique subjects) due to an
(72.3–83.6%). insufficient number of measurable ASA concentrations after
Mean plasma acetylsalicylic acid concentrations over the ­Cmax. While there were no significant differences noted
time in fed versus fasted states are graphically displayed in between fed and fasted states in AUC​0−t and AUC​0−∞ ace-
Fig. 3. Peak acetylsalicylic acid concentration was about tylsalicylic acid PK, there were significant differences noted
40% lower in the fed state and occurred about 1 h later com- in ­Cmax (p = 0.003) and ­tmax (p = 0.01) suggesting a limited
pared with the fasted state. The summary of acetylsalicylic food effect on acetylsalicylic acid bioavailability. In aggre-
acid PK parameters in fed and fasted states is provided in gate, assessments of fed to fasted ratios for log-transformed

13
Bioavailability of aspirin in fasted and fed states of a novel pharmaceutical lipid aspirin…

Table 2  Summary of ratios between fed and fasted states for log- transformed PK parameters of salicylic acid
PK parameter N LSM Geometric mean Ratioa (%) 90% ­CIb ANOVA p-valuec
Fed Fasted Fed Fasted

AUC​0−t (ng × min/mL) 20 9.53 9.65 13,772.6 15,521.3 88.7 (82.27, 95.8) 0.01
AUC​0−∞ (ng × min/mL) 20 9.55 9.66 14,000.7 15,767.0 88.8 (82.2, 96.0) 0.02
Cmax (ng/mL) 20 3.36 3.61 28.9 37.1 77.8 (72.3, 83.6) < 0.0001

ANOVA analysis of variance; AUC​0−t area-under-the-curve; AUC​0−∞ AUC​0−t extrapolated to infinity; Cmax maximum plasma concentration; CI
confidence interval; LSM least square mean; mL milliliters; min minutes; N number of subjects; ng nanograms; PK pharmacokinetic; SD stand-
ard deviation
a
Ratio = 100% × geometric mean (fed) / geometric mean (fasted)
b
90% Confidence interval on the ratio of fed and fasted
c
p-value for the difference in the treatment estimates. Significant difference was defined as p-value < 0.05

Fig. 3  Mean plasma acetylsali-

cylic acid concentration versus 100000
time. Plasma concentrations
Plasma concentration (ng/mL)

(log-linear scale) for acetylsali-

10000
cylic acid are depicted after a
single 650 mg dose of PL-ASA
in the presence (fed, dotted line) 1000
and absence of food (fasting,
solid line) Fasting state Fed state
100

10

0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500
Time (minutes)

acetylsalicylic acid parameters suggest a greater food effect be of clinical significance and are consistent with results in
compared to what was seen with SA. studies of uncoated aspirin [11, 18].
The differences in the median ­tmax values observed with
food are consistent with the published results of similar
Discussion analyses of immediate release and enteric-coated aspirin
formations [11, 18]. In particular, in studies using immedi-
The results of this study demonstrate that with food, even ate release aspirin tablets, acetylsalicylic acid levels were
though the time required to reach maximum SA concentra- higher and peaked earlier in fasted subjects compared with
tions ­(Tmax) was significantly delayed and peak levels ­(Cmax) fed subjects, indicating a decreased rate of absorption in the
were also lower, there was a minimal effect on the overall fed state [19]. However, overall bioavailability of the active
exposure to SA (AUC), the primary aspirin metabolite, fol- metabolite, SA, demonstrated no food effect, as reflected in
lowing PL-ASA administration. Since the efficacy of aspirin comparable salicylate levels in fed and fasted subjects [18].
is believed to be related to overall exposure but not peak Enteric-coated aspirin demonstrated a delayed and variable
dose [17] the effects of food on peak SA levels and the time absorption rate relative to that of immediate release aspirin,
required to achieve them observed in our study are not con- particularly when administered in the fed state [11, 19, 20].
sidered to have clinical significance. Furthermore, the lower Enteric-coated aspirin absorption rates were shown to be
­Cmax observed with food after a 650 mg PL-ASA dose is still significantly lowered by concurrent ingestion of food when
significantly higher than peak concentrations observed after compared to plain aspirin, with larger sized tablets being
325-mg PL-ASA in a prior investigation in fasted healthy affected more significantly [21]. Current practice patterns
volunteers [15]. Similarly, any observed food effects on ace- suggest that enteric-coated aspirin is the dominant formula-
tylsalicylic acid bioavailability are also not considered to tion in clinical practice and is frequently taken with food. It

13
 D. J. Angiolillo et al.

is therefore important to consider that enteric-coating itself, Conclusions

designed to hamper aspirin-induced gastrointestinal toxic-
ity and improve aspirin adherence, may be responsible for Food had a modest effect on peak SA levels and the time
delayed and impaired drug absorption, and hence contribute required to reach them after a single dose of 650 mg PL-
to variability in drug bioavailability. The implications are ASA, but did not impact the extent of exposure (area under
obvious since reduced aspirin bioavailability is associated the curve) compared with intake on an empty stomach.
with high rates of aspirin non-responsiveness that is linked These data demonstrate that PL-ASA may be taken with
to recurrent events among ASCVD patients [22]. food without significant variability in absorption. Future
Despite the available evidence of such food effects for investigations should focus on defining the impact of fasted
commercially available aspirin formulations, it is nota- vs fed states of PL-ASA compared with low dose enteric-
ble that labels for consumers do not describe a food effect coated aspirin, which is the current standard of care for sec-
nor do they provide guidance on dose administration with ondary prevention in ASCVD patients.
respect to food consumption. In the current study, SA lag
time (i.e., the time from dose administration to first appear- Acknowledgements We are grateful to Frank Lanza, the principal
ance of salicylate in the blood) reported for PL-ASA at a investigator, and to Francis Rack and the other clinical staff at Hou-
ston Institute for Clinical Research, a Phase I clinic where the current
650-mg dose was 20.3 min ± 3.8 min in the fasted state study was conducted.
and 65.3 min ± 39.4 min in the fed state. This is consider-
ably lower than the reported lag times for enteric-coated Funding PLx Pharma was the study sponsor.
aspirin at a dose of 648 mg of 162 min ± 48 min and
474 min ± 180 min for the fasted and fed states, respectively Compliance with ethical standards
[20]. This data confirms that PL-ASA behaves as an imme-
diate release formulation and that the food effect observed Conflict of Interest Dr Angiolillo declares that he has received con-
for PL-ASA is indeed less than that observed with enteric- sulting fees or honoraria from Amgen, Aralez, AstraZeneca, Bayer,
Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi,
coated aspirin. Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio,
PLx Pharma, Pfizer, Sanofi, and The Medicines Company and has re-
ceived payments for participation in review activities from CeloNova
Study limitations and St Jude Medical. D.J.A. also declares that his institution has re-
ceived research grants from Amgen, AstraZeneca, Bayer, Biosensors,
CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead,
The present study was conducted in healthy volunteers Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis,
who did not have an indication to be treated with aspirin. Osprey Medical, and Renal Guard Solutions. Dr. Deepak L. Bhatt dis-
Moreover, the study was conducted using a dosing regimen closes the following relationships—Advisory Board: Cardax, Cereno
Scientific, Elsevier Practice Update Cardiology, Medscape Cardiol-
of aspirin commonly used for anti-inflammatory effects. ogy, PhaseBio, Regado Biosciences; Board of Directors: Boston VA
This approach is consistent with standard FDA guidance Research Institute, Society of Cardiovascular Patient Care, TobeSoft;
for bioequivalence studies in order to allow for pure phar- Chair: American Heart Association Quality Oversight Committee;
macologic comparisons without the risk of interaction or Data Monitoring Committees: Baim Institute for Clinical Research
(formerly Harvard Clinical Research Institute, for the PORTICO trial,
interference by underlying clinical conditions (i.e. healthy funded by St. Jude Medical, now Abbott), Cleveland Clinic (includ-
volunteers) and with dosing consistent with the clinical use ing for the ExCEED trial, funded by Edwards), Duke Clinical Re-
on the proposed label which in the case of aspirin is for pain search Institute, Mayo Clinic, Mount Sinai School of Medicine (for
relief or fever reduction (i.e. 650 mg). The results from this the ENVISAGE trial, funded by Daiichi Sankyo), Population Health
Research Institute; Honoraria: American College of Cardiology (Sen-
study were included in the review and supported the sub- ior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair,
sequent FDA approval of the 325 mg dose [23]. The delay ACC Accreditation Committee), Baim Institute for Clinical Research
in reporting of these early data evaluating the food effect (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical
on the bioavailability of PL-ASA is the result of prioritiza- trial steering committee funded by Boehringer Ingelheim; AEGIS-II
executive committee funded by CSL Behring), Belvoir Publications
tion of studies focusing on antiplatelet activity (efficacy) and (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Insti-
gastrointestinal toxicity (safety) following FDA approval. tute (clinical trial steering committees), HMP Global (Editor in Chief,
However, in light of the upcoming commercial availability Journal of Invasive Cardiology), Journal of the American College of
of PL-ASA, investigators felt that publication of all prior Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD
(CME steering committees), Population Health Research Institute (for
data with PL-ASA, including information on fasted vs fed the COMPASS operations committee, publications committee, steer-
states on this novel, liquid-based formulation is important. ing committee, and USA national co-leader, funded by Bayer), Slack
Finally, since an 81 mg dose is also under development, it is Publications (Chief Medical Editor, Cardiology Today’s Intervention),
important to note that the findings of our study with 650 mg Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD
(CME steering committees); Other: Clinical Cardiology (Deputy
cannot be extrapolated to the PL-ASA 81 mg dose, which Editor), NCDR-ACTION Registry Steering Committee (Chair), VA
warrants dedicated investigations.

13
Bioavailability of aspirin in fasted and fed states of a novel pharmaceutical lipid aspirin…

CART Research and Publications Committee (Chair); Research Fund- nonsteroidal anti-inflammatory drugs, aspirin and combinations.
ing: Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingel- Gut 55:1731–1738
heim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, 9. Pratt S, Thompson VJ, Elkin EP, Næsdal J, Sörstadius E (2010)
Ferring Pharmaceuticals, Forest Laboratories, Idorsia, Ironwood, Is- The impact of upper gastrointestinal symptoms on nonadherence
chemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi to, and discontinuation of, low-dose acetylsalicylic acid in patients
Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Edi- with cardiovascular risk. Am J Cardiovasc Drugs 10:281–288
tor, Cardiovascular Intervention: A Companion to Braunwald’s Heart 10. Aspirin monograph. https​://www.drugs​.com/monog​raph/aspir​
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ology; Unfunded Research: FlowCo, Fractyl, Merck, Novo Nordisk, ence of food on the absorption of acetylsalicylic acid from enteric-
PLx Pharma, Takeda. Dr. Deliargyris, Ms. Fan are employees of PLx coated dosage forms. Eur J Clin Pharmacol 14:351–355
Pharma. Dr. Prats is a consultant to PLx Pharma. Dr. Marathi was an 12. Lichtenberger LM, Wang ZM, Romero JJ et al (1995) Non-ste-
employee of PLx Pharma at the time of the study, and is an investor, roidal anti-inflammatory drugs (NSAIDs) associate with zwitte-
option holder, and a co-inventor of the PL-ASA delivery technology. rionic phospholipids: Insight into the mechanism and reversal of
No other conflicts related to the current study are reported. NSAID-induced gastrointestinal injury. Nat Med 1:154–158
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otherwise in a credit line to the material. If material is not included in pharmacodynamic assessment of a novel, pharmaceutical lipid–
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