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Pharmacokinetics of naproxen and esomeprazole in PN400, a single-tablet, multilayer formulation
of enteric-coated naproxen coupled with immediate-release esomeprazole
Philip Miner, Jr., MD, FACG,1 John Plachetka, PharmD,2 Eric Orlemans, PhD,2 John G. Fort, MD,2 Mark Sostek, MD, AGAF, FACG3
1Oklahoma Foundation for Digestive Disease Research, Oklahoma City, OK, USA; 2POZEN Inc., Chapel Hill, NC, USA; 3AstraZeneca US, Wilmington, DE, USA.
ᮣ Following AM or PM doses on Day 1 and Day 9, plasma esomeprazole
ᮣ Esomeprazole concentrations were higher on Day 9 than Day 1 for each
Table 3. Summary of naproxen pharmacokinetic parameters. Values are Mean
ᮣ Eligible patients were healthy adults aged 18-55 years who tested negative
concentrations increased with the esomeprazole dose for all three PN400
for Helicobacter pylori
infection and had no history of peptic ulcer disease
treatments. On both days, the measurable plasma concentrations of
ᮣ Following treatment with naproxen + EC E20, C for esomeprazole plasma
esomeprazole were higher following the AM dose than the PM dose for
PN400 is a single-tablet formulation with an enteric-coated (EC) naproxen core
concentrations were observed at approximately 1.5 hours post-dose (1 hour
all three PN400 treatments (Figure 1a and 1b).
surrounded by an immediate-release (IR) esomeprazole mantle designed for initial and rapid
Patients with a history of hypersensitivity, allergy, or intolerance to any
release of esomeprazole in the stomach followed by release of EC naproxen after esomeprazole
NSAID or PPI were excluded from this study.
ᮣ Following naproxen + EC E20 treatment on Day 1 and Day 9, measurable
absorption. The aim of this study was to determine levels of exposure of esomeprazole and
plasma concentrations of esomeprazole were not available until 0.75-1.5
naproxen when used in combination in PN400 and with EC esomeprazole + naproxen 500 mg.
hours post-dose in the majority of subjects and were measurable for longer
ᮣ Pharmacokinetic parameters (C , T , and AUC
than concentrations following PN400 administration (Figure 1a and 1b).
This randomized, open-label, 9-day, four-way crossover, single-center study enrolled
esomeprazole and naproxen following the three PN400 treatments, and
The plasma esomeprazole profile exhibited was consistent with that of a
28 healthy H. pylori
-negative adults without a history of peptic ulcer/acid-related gastrointestinal
the naproxen + EC E20 treatment on Day 1 and Day 9.
– measurable plasma concentrations of naproxen were first detected at
symptoms. Subjects were randomized to different sequences of the following: A) PN400/E30
approximately 2 hours post-PN400 administration for all three PN400
[EC naproxen 500 mg/IR esomeprazole 30 mg] BID; B) PN400/E20 [EC naproxen 500 mg/IR
ᮣ Safety of each treatment group was assessed using clinical adverse events,
esomeprazole 20 mg] BID; C) PN400/E10 [EC naproxen 500 mg/IR esomeprazole 10 mg] BID;
as well as physical examination, vital signs, and clinical laboratory tests.
Figure 1. Mean plasma esomeprazole concentration vs time curves
and D) EC E20 [EC esomeprazole 20 mg] QD + non-EC naproxen 500 mg BID. Blood samples
Other end points included pharmacodynamics (primary end point was percent
were taken on Days 1 and 9 before dosing and at various times up to 24 hours afterwards for
of time on Day 9 in which intra-gastric pH was Ͼ4.0; secondary end point was
– pre-AM dose samples showed that naproxen concentrations were
pharmacokinetic assessments of esomeprazole and naproxen.
the percent of time on Day 1 in which intra-gastric pH was Ͼ4.0) and safety.
measurable in all subjects and were measurable throughout the entire
Esomeprazole was rapidly absorbed from all three doses of PN400 with measurable
(Pharmacodynamics are presented in Poster T1969).
plasma concentrations as early as 10 minutes after the AM dose and at 20-30 minutes after
ᮣ The mean plasma profiles of naproxen were comparable following the three
and AUCs for esomeprazole from PN400 were generally dose-
PN400 treatments, particularly on Day 9 (Figure 2a and 2b), demonstrating
ᮣ The primary analysis was performed using Analysis of Variance (ANOVA) to
for EC naproxen was delayed in relation to the T
delayed-release characteristics consistent with the formulation design of
determine the point estimate and 90% CI of the Day 9 to Day 1 ratios for
esomeprazole. Steady-state AUCs for naproxen monocomponent were comparable to all
PN400. The higher mean naproxen plasma concentrations observed at the
with non-EC naproxen occurred considerably earlier than with the EC
end of a 24-hour daily interval resulted from the delayed absorption of
naproxen component of the PN400 formulations. Esomeprazole and naproxen pharmacokinetic
ᮣ Adverse events were coded using the Medical Dictionary for Regulatory
naproxen from PN400 (Figure 2a and 2b).
parameters for the AM dose on Day 9 of BID dosing for PN400 are provided in the Table.
Activities (MedDRA, version 8.0) for system organ class and preferred term.
ᮣ The safety analysis was based on the safety population.
Figure 2. Mean plasma naproxen concentration vs time curves
Twenty-eight subjects were randomized to treatment and were included
in the safety, pharmacokinetics, and intent-to-treat (ITT) populations.
The study was completed by 27 subjects and 25 subjects were included
in the per-protocol (PP) population; the three patients excluded from the
Values are mean (% coefficient of variation) for C
– one who withdrew because of personal reasons
Table 4. Clinical adverse events reported by Ͼ1 subject (greater than 4%) on
PN400 produced dose-dependent increases in plasma esomeprazole
– one with invalid intra-gastric pH data.
concentrations and similar naproxen concentrations to dosing with EC E20 + naproxen.
The pharmacokinetics of esomeprazole administered as the PN400 formulation were consistent
for esomeprazole preceded that for EC naproxen.
Baseline characteristics of enrolled subjects are outlined in Table 1.
Table 1. Baseline demographics (ITT population)
The pharmacokinetic parameters of esomeprazole for all PN400 treatments
following administration of the AM and PM doses on Day 1 and Day 9 are
ᮣ The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated
Table 2. Summary of esomeprazole pharmacokinetic parameters. Values are
with a substantial risk of upper gastrointestinal (GI) adverse events ranging
from endoscopic erosions and ulcers to serious ulcer complications such
as perforation, obstruction, and bleeding.1
The efficacy of proton pump inhibitors (PPIs) (eg, esomeprazole) for the
prevention of NSAID-associated endoscopic injury and upper GI symptoms
ᮣ Mean plasma concentrations of naproxen were much higher on Day 9
Enteric-coated (EC) esomeprazole 20 mg QD has demonstrated clinical efficacy
in the prevention of gastroduodenal ulcers in at-risk patients using NSAIDs.4
PN400 is a single-tablet, fixed-dose formulation of an EC naproxen 500 mg
Following naproxen + EC E20 treatment on Day 1, plasma naproxen
core surrounded by an immediate-release (IR) esomeprazole mantle,
concentrations were measurable in all subjects at the 10-minute post-dose
Esomeprazole was rapidly absorbed following administration of the
designed to provide sequential delivery of gastroprotective esomeprazole
sample time and for up to 24 hours, consistent with a non-EC naproxen
three PN400 treatments—plasma concentrations were measurable
as early as 10 minutes after dose, consistent with an immediate-
release formulation; elimination of esomeprazole from plasma
This study evaluated the pharmacodynamics, pharmacokinetics, and
ᮣ Following AM and PM doses on Day 1 and Day 9, mean plasma naproxen
occurred between 6-8 hours post dose.
safety of three different dose formulations of PN400. Here we present the
concentrations were higher and occurred earlier following naproxen + EC
pharmacokinetic and safety findings of the study (the pharmacodynamic
E20 treatment than with any of the PN400 treatments (Figure 2a and 2b).
ᮣ Esomeprazole C
and AUC following administration of PN400
were dose-dependent; esomeprazole concentrations were higher
ᮣ The aim of this study was to determine levels of exposure of esomeprazole
ᮣ The pharmacokinetic parameters of naproxen for all PN400 treatments
on Day 9 than on Day 1 for each of the PN400 treatments.
and naproxen, and time to exposure to these drugs, when used in combination
following administration of the AM and PM doses on Day 1 and Day 9
in PN400 and with naproxen 500 mg + EC esomeprazole (20 mg).
ᮣ The naproxen plasma concentration vs time profiles were
comparable across all three PN400 treatments; higher
ᮣ C for naproxen plasma concentration occurred approximately 3-4 hours
concentrations were observed at the end of a 24-hour
post-AM dose, and between 10-14 hours post-PM dose on Day 1 and
daily interval, consistent with delayed-release characteristics.
Day 9 for all three PN400 treatments. The delay in naproxen absorption
was consistent with the EC naproxen in the PN400 formulations.
ᮣ Esomeprazole T for all three PN400 treatments occurred
approximately 1 hour earlier than that observed for naproxen + EC E20.
ᮣ Naproxen C and AUCs post- AM and PM doses on Day 1 and Day 9
– measurable plasma concentrations of esomeprazole were obtained
were comparable among all three PN400 treatments, consistent with
ᮣ PN400 was well tolerated with no serious adverse events.
ᮣ This was a prospective, randomized, Phase I, open-label, single-center,
rapidly with all three PN400 treatments—at 10 minutes after the AM
the same dose of naproxen in each formulation.
cross-over study comprising four treatment periods.
dose and at 20-30 minutes after administration of the PM dose.
ᮣ These finding support the ongoing evaluation of PN400 in
ᮣ Following treatment with EC E20 + naproxen, naproxen was quickly
– esomeprazole was rapidly eliminated from plasma in the majority of
patients at risk for developing NSAID-associated ulcers.
On Day 1 of the first treatment period, patients were randomized into one
subjects by 6-8 hours post-dose (AM and PM) for all three PN400
absorbed, with peak plasma concentrations observed at 1.5 hours
of four treatment sequences to receive each of the following treatments
for 9 days in a cross-over fashion, with a washout period of у14 daysbetween treatments:
– PN400/E30 (EC naproxen 500 mg/IR esomeprazole 30 mg) BID
– pre-AM dose samples showed that esomeprazole concentrations were
ᮣ Adverse events are summarized in Table 4.
1. Laine L. Gastroenterology 2001; 120: 594-606.
– PN400/E20 (EC naproxen 500 mg/IR esomeprazole 20 mg) BID
measurable in 19 subjects receiving PN400/E30 treatment, 13 receivingPN400/E20 treatment, and 6 receiving PN400/E10 treatment.
ᮣ C for esomeprazole plasma concentration occurred approximately 0.5 hours
2. Scheiman JM. Curr Treat Options Gastroenterol 2008; 11: 125-134.
ᮣ No serious adverse events were reported and no patients withdrew from
– PN400/E10 (EC naproxen 500 mg/IR esomeprazole 10 mg) BID
post-AM dose, and between 1.0-1.5 hours post-PM dose on Day 1 and Day 9
3. Hawkey CJ et al. N Engl J Med 1998; 338: 727-734.
– post- AM and PM dose samples showed that, in the PN400 treatments
– Naproxen + EC E20 (non-EC naproxen 500 mg BID and EC
containing higher esomeprazole doses (PN400/E30 and PN400/E20),
4. Scheiman JM et al. Am J Gastroenterol 2006; 101: 701-710.
ᮣ Most laboratory abnormalities were small deviations from the normal range.
plasma concentrations of esomeprazole were measurable at earlier
ᮣ Esomeprazole C and AUCs were higher following the AM dose than the
ᮣ Study medication was administered 60 minutes before meals in the
post-dose time points in a large number of subjects and for a longer
PM dose on Day 1 and Day 9 for all three PN400 treatments and were
ᮣ Vital sign measurements and physical examination findings were similar
Editorial support was provided by Complete Medical Communications and was funded by AstraZeneca.
Poster presented at Digestive Disease Week, Chicago, Illinois, 30 May – 4 June 2009
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