`
`
`
`
`
`
`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`APPLICATION NUMBER:
`22511Orig1s000
`
`
`PHARMACOLOGY REVIEW(S)
`
`

`

`
`
`
`MEMORANDUM DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`FROM: Sushanta Chakder, Ph.D., Supervisory Pharmacologist
`
`DATE: April 13, 2010
`
`Application number: NDA 22,511
`
`Date of submission: June 30, 2009
`
`Sponsor: POZEN Pharmaceutical Development Co.
`
`Drug Product: VIMOVO (Naproxen/Esomeprazole magnesium)
`
`Indication: Treatment of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis patients
`at risk of developing NSAID-associated gastric ulcer
`
`Comments:
`
`
`Under NDA 22511, the sponsor is seeking approval of a combination of naproxen and
`esomeprazole magnesium for the treatment of osteoarthritis, rheumatoid arthritis, and ankylosing
`spondylitis patients at risk of developing NSAID-associated gastric ulcer. The only nonclinical
`study submitted in this NDA application was a pharmacokinetic study in which the urinary and
`plasma metabolites of buffered and unbuffered omeprazole were determined in female Sprague
`Dawley rats following 14 days of oral dosing. The NDA was supported by reference to the
`Agency’s previous findings of safety and publicly available information on the toxicology of
`naproxen and esomeprazole (including omeprazole) to meet the nonclinical assessment
`requirements.
`The nonclinical safety of esomeprazole and naproxen has been established by the respective
`innovators. During approval of the espmeprazole (Nexium) application, its nonclinical safety was
`partially based on studies conducted with omeprazole. Following oral administration of
`omeprazole buffered and unbuffered formulation to female Sprague Dawley rats, the plasma and
`urinary metabolite profiles for omeprazole were similar. Thus, following oral administration of
`uncoated esomeprazole, present in VIMOVO, the patients are not expected to be exposed to any
`new metabolites. Since the mechanisms of action, and the microsomal enzyme systems involved
`in the metabolism the two components of VIMOVO are not similar, no significant drug-drug
`interactions between the two components are expected. The sponsor adopted the labeling of the
`nonclinical sections from the existing labeling of the individual components which is acceptable.
`
`
`Recommendations:
`
`1. I concur with Dr. Wu’s recommendation that there are no additional nonclinical safety
`concerns for the proposed combination of naproxen and esomeprazole, other than those
`expected from the individual components.
`
`
`
`
`1
`
`

`

`
`
`
`
`2. In the nonclinical sections of the labeling (Sections 8.1 and 13.1), the sponsor used
`headings for reproductive toxicology and carcinogenicity studies of individual
`components of VIMOVO. These headings should be removed form the labeling.
`
`3. From a nonclinical standpoint, the NDA application is approvable with the
`recommended changes in the labeling.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Sushanta Chakder, Ph. D. Date
`Supervisory Pharmacologist, HDF-180
`
`
`
`2
`
`

`

`Application
`Type/Number
`--------------------
`NDA-22511
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`POZEN INC
`
`------------------------------------------
`PN 400
`NAPROXEN/ESOMEPRAZOLE
`MAGNESIUM
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SUSHANTA K CHAKDER
`04/13/2010
`
`

`

`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`
`Applicant:
`Review Division:
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`
`22511
`1
`June 30, 2009
`July 1, 2009
`VIMOVO (naproxen/esomeprazole magnesium)
`Treatment of osteoarthritis, rheumatoid arthritis
`and ankylosing spondylitis patients at risk for
`developing NSAID-associated gastric ulcer
`POZEN Pharmaceutical Development Co.
`Gastroenterology Products
`Charles G. Wu, Ph.D.
`Sushanta Chakder, Ph.D.
`Donna Griebel, M.D.
`Anna Simon, MSN, CPNP
`
`
`Disclaimer
`
`
`Except as specifically identified, all data and information discussed below and necessary
`for approval of NDA 22511 are owned by POZEN Pharmaceutical Co. or are data for which
`POZEN Pharmaceutical Co. has obtained a written right of reference. Any information or data
`necessary for approval of NDA 22511 that POZEN Pharmaceutical Co. does not own or have a
`written right to reference constitutes one of the following: (1) published literature, or (2) a prior
`FDA finding of safety or effectiveness for a listed drug, as described in the drug’s approved
`labeling. Any data or information described or referenced below from a previously approved
`application that POZEN Pharmaceutical Co. does not own (or from FDA reviews or summaries
`of a previously approved application) is for descriptive purposes only and is not relied upon for
`approval of NDA 22511.
`
`1
`
`

`

`NDA 22511
`
`
`
`
`Charles Wu
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 3
`1.1 RECOMMENDATIONS............................................................................................ 3
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 3
`2 DRUG INFORMATION ............................................................................................ 5
`
`3 STUDIES SUBMITTED............................................................................................ 8
`
`4 PHARMACOLOGY.................................................................................................. 8
`4.1
`PRIMARY PHARMACOLOGY................................................................................... 8
`4.2
`SECONDARY PHARMACOLOGY............................................................................ 10
`SAFETY PHARMACOLOGY................................................................................... 10
`4.3
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 10
`5.1
`PK/ADME........................................................................................................ 10
`5.2
`TOXICOKINETICS ............................................................................................... 17
`6 GENERAL TOXICOLOGY..................................................................................... 17
`SINGLE-DOSE TOXICITY..................................................................................... 17
`6.1
`6.2 REPEAT-DOSE TOXICITY.................................................................................... 18
`7 GENETIC TOXICOLOGY ...................................................................................... 19
`
`8 CARCINOGENICITY ............................................................................................. 19
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ................................ 20
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT............................................... 20
`9.1
`9.2
`EMBRYONIC FETAL DEVELOPMENT ..................................................................... 20
`9.3
`PRENATAL AND POSTNATAL DEVELOPMENT......................................................... 21
`10
`SPECIAL TOXICOLOGY STUDIES................................................................... 21
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION................................. 21
`
`APPENDIX/ATTACHMENTS........................................................................... 213
`
`11
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`12
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`2
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`

`

`
`
`Charles Wu
`
`NDA 22511
`
`
`1
`
`Executive Summary
`
`1.1 Recommendations
`
`1.1.1 Approvability
`
`From a nonclinical standpoint, approval of the NDA application is recommended.
`
`1.1.2 Additional Non Clinical Recommendations
`
`None
`
`1.1.3
`
`Labeling
`
`In this 505(b)(2) NDA submission, the sponsor did not submit any new nonclinical studies on
`Naproxen, Esomeprazole or the combination. The nonclinical sections of the labeling are
`adopted from the innovator’s labeling of Naproxen and Esomeprazole. Therefore, no changes in
`the proposed labeling are recommended.
`
`
`
`1.2 Brief Discussion of Nonclinical Findings
`
`
`The sponsor did not submit any nonclinical study reports in this NDA except a PK study
`on determination of urinary and plasma metabolite profiles following 4 days oral administration
`of buffered- and unbuffered-omeprazole to female Sprague Dawley rats. In addition, the
`following statement was made: “This NDA is submitted under section 505(b) (2) of the Federal
`Food, Drug and Cosmetic Act and relies on studies that were not conducted by or for the
`applicant and for which this applicant does not have right of reference. Specifically, this NDA is
`supported by reference to the Agency’s previous findings of safety and publicly available
`information on the toxicology of naproxen and esomeprazole (including omeprazole) to meet the
`nonclinical assessment requirements as part of the PN 400 new drug application, by POZEN”. In
`addition to the above-mentioned PK study, the sponsor provided published studies to support the
`safety of the drug from a nonclinical standpoint. Pharmacologic, pharmacokinetic and
`toxicological properties of individual components of PN 400 (naproxen and esomeprazole,
`including omeprazole) are well-established.
`
`Like other non-steroidal anti-inflammatory drugs (NSAIDs), naproxen inhibits
`cyclooxygenase enzyme activity. This inhibition reduces prostaglandin synthesis and leukocyte
`activation resulting in anti-inflammatory, analgesic and anti-pyretic activity. Esomeprazole is a
`substituted benzimidazole that suppresses gastric acid secretion through specific inhibition of the
`
`3
`
`

`

`
`
`NDA 22511
`
`H+, K+-ATPase enzyme located in the secretory membrane of the gastric parietal cell. This
`enzyme is the acid (proton) pump within the gastric parietal cell. Hence, esomeprazole is a
`proton pump inhibitor (PPI). PPIs inhibit the final common pathway of acid production in the
`stomach and thus reducing both basal and stimulated gastric acid secretion.
`
`
`Charles Wu
`
`Following oral administration, naproxen is almost completely absorbed with a
`bioavailability of approximately 95 to 99% in dogs, minipigs and humans, but only about 50% in
`rats. Tmax values in animals range from 0.5 to 2 hours; similarly the Tmax in humans usually
`occurs 1 to 2 hours after dosing. The half-life of naproxen in man is 10 to 17 hours, while
`rodents have a short half-life of 1 to 3 hours or less, but in dog with a prolonged half-life (35 to
`74 hours). There are no consistent gender-related differences in naproxen pharmacokinetics and
`no apparent differences in exposure between pregnant and non-pregnant rats and rabbits. Tissue
`distribution studies in rats suggest that there is no preferential uptake of naproxen by any major
`organ system, which is consistent with its low volume of distribution (approximately 10% of
`body weight) and its high (98 to 99%) protein binding. Naproxen is extensively metabolized,
`with only 1% of the naproxen dose recovered in urine as the unchanged parent drug.
`Approximately 95% of an oral naproxen dose is recovered in urine, largely as the conjugated
`metabolites of naproxen and its O-demethylated metabolite (66 to 92% of the dose). Only 1 to
`2% of a radioactive dose of naproxen is recovered in feces following intravenous administration.
`In vitro studies have demonstrated that CYP2C9 and CYP1A2 are the two primary CYP450
`isoenzymes responsible for the oxidative metabolism of naproxen to form 6-O-
`desmethylnaproxen in humans and most animal species.
`After oral dosing, omeprazole was rapidly absorbed in mice, rats and dogs and was readily
`distributed into tissues. Tmax was 10, 15, 5 to 15 and 13.8 minutes in the mouse, rat, dog and
`human, respectively. The oral bioavailability was only about 5% in fed and 15 to 20% in starved
`rats of either sex. The Cmax and AUC values were similar after treatment with equivalent oral
`doses of esomeprazole or omeprazole, but higher plasma concentrations of both compounds were
`noted in females compared to males. In dogs, exposure (AUC) after oral administration of the
`same dose of omeprazole and esomeprazole was equivalent, but the Cmax value was somewhat
`higher after esomeprazole administration. There were no significant differences between single
`and repeated administration, or between males and females. Omeprazole was 87.5, 90 and 95.7%
`bound to plasma proteins in rat, dogs and humans, respectively. Both compounds were
`metabolized via the same biotransformation routes to the same primary metabolites. The in vitro
`metabolism studies by CYP enzyme system have shown that CYP2C19 is the key enzyme
`involved in the formation of the hydroxyl metabolite, a major metabolite of both esomeprazole
`and omeprazole. The formation of the achiral sulfone, another primary metabolite, is dependent
`on CYP3A4. The elimination half-lives in the rat, dog and man were approximately 60 minutes.
`The esomeprazole in PN 400 is immediate-release and therefore subject to acid degradation in
`the gastric lumen, which is different to the marketed delayed-release esomeprazole. In a study in
`rats (PN200-T1) submitted in this NDA, similar metabolite profiles were noted in rats given oral
`omeprazole either with or without buffer for 14 days. This indicates that there were no
`significant differences in the systemic exposure to any degradation products that may have been
`formed in the gastric lumen of rats given omeprazole with or without buffer.
`
`
`No new nonclinical toxicology studies have been conducted by POZEN with PN 400 or a
`naproxen/esomeprazole combination. The principal findings after single and repeat-dose oral
`
`4
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`

`

`
`
`Charles Wu
`
`NDA 22511
`
`naproxen administration in animals and humans are thought to be due to inhibition of
`prostaglandin synthesis; they include gastrointestinal irritation and renal injury. Regenerative
`anemia, increased extramedullary hematopoiesis, increased white blood cells (neutrophils) and
`decreased serum total protein and albumin occur secondary to the gastrointestinal erosions/ulcers
`and bleeding caused by naproxen. Increases in serum BUN and proteinuria also occur and
`correlate with naproxen-associated renal injury. Toxicology studies showed no genetic,
`reproductive, teratogenic or oncogenic adverse effects.
`The acute toxicity of esomeprazole was low after both oral and IV administration to rats, and
`was equivalent to that of omeprazole. Besides lethality, the main signs of acute toxicity were
`unspecific neurological effects, changes in respiratory frequency and abdominal respiration.
`Repeated oral treatment of rats with esomeprazole or omeprazole at oral doses of 14-280
`mg/kg/day for up to 3 months resulted in low systemic toxicity. In both rats and dogs,
`histopathological changes in the stomach, accompanied by a dose-dependent increase in stomach
`weight and serum gastrin levels, were noted at the higher dose levels of both compounds.
`Esomeprazole was not mutagenic in an Ames test, but was clastogenic in an in vitro human
`lymphocyte assay. Omeprazole, its R-enantiomer, also showed similar clastogenic activity under
`the same experimental conditions. In two 24-month carcinogenicity studies in rats, omeprazole at
`daily doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (about 2 to 175 times the human dose of
`40 mg per day, based on 50 kg body weight) produced gastric ECL cell carcinoids in a dose-
`related manner in both male and female rats; the incidence of this effect was higher in female
`rats, which show higher blood levels of omeprazole. Since no carcinoid-free dose was
`established for the female rats in this first study, a second 104-week carcinogenicity study was
`completed using female rats only. The second study also revealed a dose-related increase in the
`incidence of gastric carcinoids. Omeprazole at oral doses up to 138 mg/kg/day in rats was found
`to have no effect on fertility and reproductive performance and had no teratogenic potential. At
`the high dose level in rabbits, severe anorexia, reduced water consumption and reduced body
`weight was noted in the dams, but all animals survived, ate and gained weight as soon as dosing
`was stopped. Decreased litter size and increased fetal loss was noted in rabbits at both 69 and
`138 mg/kg, with some minor fetal effects at 138 mg/kg due to maternal toxicity. An extended
`peri- and post-natal study with omeprazole in rats demonstrated only slight reductions in food
`consumption and body weight gain and a slight decrease in the mean body weight gain of the
`pups.
`
`
`
`Drug Information
`
` 2
`
`2.1 Drug: VIMOVO (naproxen/esomeprazole magnesium) Tablets
`
`5
`
`

`

`NDA 22511
`
`2.1.1 CAS Registry Number: Naproxen 22204-53-1,
`
`
`
`Charles Wu
`
`
`
`
`
`
`
`
`
` Esomeprazole Magnesium 161973-10-0
`
`2.1.2 Generic Name: Naproxen and Esomeprazole
`
`2.1.3 Code Name: PN 400
`
`2.1.4 Chemical Name:
`
`Naproxen - (S)-6-methoxy-α-methyl-2-napthaleneacetic acid
`Esomeprazole magnesium - bis (5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)
`Methyl] sulfinyl]-lH- benzimidazole-l-yl) magnesium trihydrate
`
`
`2.1.5 Molecular Formula/Molecular Weight
`
`Naproxen: C14H14O3/MW 230.26;
`Esomeprazole: (C17H18N3O3S)2Mg x 3 H2O/MW 767.2
`
`2.1.6
`
`Structure
`
`
`
`
`
`6
`
`

`

`NDA 22511
`
`2.1.7
`
`Pharmacologic class
`
`
`
`Charles Wu
`
`Naproxen: NSAID (Non-Steroidal Anti-Inflammatory Drug)
`Esomeprazole: PPI (Proton Pump Inhibitor)
`
`2.2 Relevant IND/s, NDA/s, and DMF/s
`
`
`IND 76-301 for PN 400 (500 mg naproxen/ 20 mg esomeprazole magnesium)
` for the treatment of the signs and
`symptoms of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in patients at risk for
`developing NSAID-associated gastric ulcers.
`
`2.3 Clinical Formulation
`
`2.3.1 Drug Formulation
`
` of
` of Croscarmellose Sodium,
`500 mg of Naproxen with
`Povidone,
` of Colloidal Silicon Dioxide and 20 mg of Esomeprazole with
` of Methacrylic Acid Copolymer, film coated tablet.
`,
`
`2.3.2 Comments on Novel Excipients
`
`No novel excipients are present in VIMOVO. None of the excipients used in the manufacture of
`VIMOVO Tablets are of animal origin.
`
`2.3.3 Comments on Impurities/Degradants of Concern
`
`, and any individual impurity does not
`Total impurities in naproxen are not more than
`exceed
`. Total impurities in esomeprazole are not more than
`, and any individual
`impurity does not exceed
` for indentified or
` for any unidentified impurity. The
`individual impurities in both drugs are equal to the qualification thresholds as per ICH Q3B(R2),
`and are acceptable.
`
`
`2.4 Proposed Clinical Population and Dosing Regimen
`
`Proposed clinical population is patients with osteoarthritis, rheumatoid arthritis and
`ankylosing spondylitis at risk for developing NSAID-associated gastric ulcers. Risk factors
`include age, documented history of gastric ulcers, or concomitant therapy with low dose aspirin.
`
`2.5 Regulatory Background
`
`To identify and characterize any new degradants that may arise from the administration
`of immediate-release omeprazole, which is different from the marketed delayed-release
`omeprazole, the Division asked the sponsor to conduct a PK study on determination of urinary
`and plasma metabolite profiles following 14-day oral administration of buffered- and
`
`7
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 22511
`
`unbuffered-omeprazole, as support for a related product (PN200,
`mg/omeprazole 20 mg). The study was submitted and reviewed.
`
`
`
`Charles Wu
`
`: naproxen 500
`
`3
`
`Studies Submitted
`
`3.1 Studies Reviewed
`
`The Sponsor submitted a PK study on determination of urinary and plasma metabolite profiles
`following 14-day oral administration of buffered- and unbuffered-omeprazole to female Sprague
`Dawley rats. In addition, several published study reports were submitted in this submission and
`selected studies were reviewed.
`
`3.2 Studies Not Reviewed
`
`None
`
`3.3 Previous Reviews Referenced
`
`Summaries of nonclinical studies under IND 76-301 for PN 400 (20 mg Esomeprazole/500
`mg Naproxen) and
` for PN 200 (20 mg Omeprazole/500 mg Naproxen)
`(POZEN).
`
`4.1 Primary Pharmacology
`
`The following published pharmacology studies on naproxen and PPI were selectively reviewed:
`
`Mechanisms of Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Damage R. Schoen
`and R. Vender, the American J. of Medicine, 1989 86:449-458
`
`
`The molecular pharmacology of naproxen is similar to that of other non-steroidal anti-
`inflammatory drugs (NSAIDs); all are cyclo-oxygenase inhibitors. The naproxen anion inhibits
`prostaglandin synthesis. The physiological effects of naproxen, like other NSAIDs, include anti-
`inflammatory, analgesic and anti-pyretic activity. These 3 therapeutic effects are due both to a
`reduction in prostaglandin synthesis and an inhibition of leukocyte activation. Naproxen is
`known to produce ulcers and erosions in the digestive tract of animals and humans. Concepts
`regarding NSAID-induced gastroduodenal mucosal injury have evolved from a simple notion of
`topical injury to theories involving multiple mechanisms with both local and systemic effects.
`According to the dual-injury hypothesis, NSAIDs have direct toxic effects on the gastroduodenal
`mucosa and indirect effects through decreased protective mucosal prostaglandins.
`
`Nonsteridal anti-inflammatory drugs and gastropathy: The second hundred years. Wallace
`JL. (1997) Gastroenterology 112:1000-1016.
`
`
`8
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 22511
`
`
`
`
`Charles Wu
`
`Direct effects of therapeutic levels of NSAIDs on the gastric mucosa include ion trapping
`(resulting in high intracellular NSAID concentrations), gastric epithelial cell swelling and lysis,
`and an inhibition of adenosine triphosphate (ATP) production (leading to an inability to regulate
`intracellular pH or maintain the integrity of the gastric epithelial cell barrier). NSAIDs also
`directly interact with the surface phospholipids to reduce the hydrophobicity of the mucosal gel
`layer, exposing the gastric epithelium to the harsh acidic environment of the stomach. Through
`the inhibition of prostaglandin production, NSAIDs reduce the protective secretion of
`bicarbonate ion by the gastric mucosa, reduce gastric epithelial cell proliferation and migration
`(thus inhibiting gastric repair mechanisms), reduce mucosal blood flow (reducing the ability of
`the gastric mucosa to disperse H+ ion and therefore regulate pH), and reduce platelet aggregation
`(promoting the bleeding of pre-existing ulcers). Thus, NSAIDs inhibit the ability of the gastric
`mucosa to protect and repair itself from the effects of gastric acid. Among the most common of
`these are hemorrhagic gastric erosions, which are most often found in the corpus. These erosions
`usually heal within a few days and occur less frequently as NSAID use is continued due to
`phenomenon of gastric adaptation to NSAID ingestion. Duodenal ulcers can also be induced by
`NSAIDs.
`
`Antisecretory Effect of Leminoprazole on Histamine-Stimulated Gastric Acid Secretion in
`Dogs: Potent Local Effect. S. Okabe et al. Jpn. J. Pharmacol. 69: 91-100 (1995)
`
`
`Esomeprazole belongs to a class of anti-secretory compounds, the substituted
`benzimidazoles, that suppress gastric acid secretion through specific inhibition of the
`H+, K+-ATPase enzyme located in the secretory membrane of the gastric parietal cell. This
`enzyme is the acid (proton) pump within the gastric parietal cell. Hence, esomeprazole is
`characterized as a PPI. PPIs act to inhibit the final common pathway of acid production in the
`stomach and thus inhibit both basal and stimulated gastric acid secretion. Stimuli for gastric acid
`secretion include gastrin from the antral G cells, histamine from enterochromaffin-like cells in
`the gastric mucosa and acetylcholine via vagus nerve stimulation.
`
`
`To determine whether or not systemic or local administration of a PPI exerts an
`antisecretory effect, the following study was conducted in conscious dogs. The gastric acid
`secretion by dogs with a vagally denervated Heidenhain pouch was stimulated by intravenous
`histamine infusion. Leminoprazole, a novel acid pump inhibitor, and omeprazole (as a reference
`drug) were administered either intravenously or locally into the pouch before or after histamine
`infusion. A bolus intravenous administration of leminoprazole and omeprazole significantly and
`dose-relatedly inhibited the stimulated gastric acid secretion for >26 hr. Local application of
`leminoprazole, but not omeprazole, significantly inhibited the acid secretion when applied for 15
`to 30 min. The duration of the local antisecretory effect observed after 30 min application was
`around 8 - 10 hr. The acid-degraded products of leminoprazole had no effect when applied to the
`pouch. The blood concentration of leminoprazole was very low at 1 hr after local application.
`These results indicate that leminoprazole suppresses the secretory function of the parietal cells of
`dogs.
`
`
`No nonclinical pharmacology studies have been conducted by POZEN with PN 400 or a
`naproxen / esomeprazole combination.
`
`
`9
`
`

`

`Charles Wu
`
`NDA 22511
`
`4.2 Secondary Pharmacology
`
`
`
`No secondary pharmacology studies were submitted.
`
`4.3 Safety Pharmacology
`
`No studies were submitted.
`
`5
`
`Pharmacokinetics/ADME/Toxicokinetics
`
`5.1 PK/ADME
`
`No preclinical pharmacokinetic studies have been performed by POZEN with PN 400 or
`a naproxen / esomeprazole combination.
`
` POZEN completed study
`PN200-T1 in rats to identify and characterize any new degradants that may arise from the
`administration of immediate-release omeprazole. Qualitatively similar metabolite profiles in
`groups of animals treated with buffered or unbuffered omeprazole in this study indicated that
`there were no significant differences in the systemic exposure to any degradation products that
`may have been formed in the gastric lumen of rats given omeprazole with or without buffer.
`
`Title: Determination of urinary and plasma metabolite profiles following 14-day oral
`administration of [14C]omeprazole to female Sprague Dawley rats (Study # PN200-T1)
`
`Methods: This degradant study was conducted to compare urine and plasma metabolite profiles
`from rats treated with 14C-omeprazole ([14C]OMZ) in buffered vs. unbuffered solutions used
`radioactive [14C]-omeprazole. Groups of six female Sprague-Dawley (SD) rats each received 14
`successive daily oral doses of ~128 mg/kg OMZ (Target: 138 mg/kg) containing [14C]OMZ in
`buffered (5.1 mg/mL NaHCO3 in 0.5% HPMC [pH 9.0]) or non-buffered (0.5% HPMC [pH 7.0])
`suspensions. The radiochemical content of [14C]OMZ doses was ~38 µCi (Target: 50 µCi).
`On Study Days 1, 4, 7, and 14, blood was sampled at 45 and 120 min post dose and plasma
`prepared. These time points were chosen based on data from a pilot study; the Cmax for plasma
`radioactivity occurred at approximately 45 min and 120 min was the time when plasma
`metabolite recovery was highest. Daily urine and feces were collected separately at 0–8 and 8–24
`h (urine) and 0−24 h (feces) intervals post dose and total radiochemical content determined.
`Metabolite profiles of urine and plasma collected on Study Days 1, 4, 7, and 14 were determined
`using HPLC radiochromatographic methods optimized during pilot studies. Total daily
`radiochemical recovery was determined. New degradants were identified by their consistent
`appearance in plasma and/or urine from rats treated with OMZ in an unbuffered solution relative
`to their consistent absence in plasma and/or urine from rats treated with OMZ in a buffered
`solution.
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`Results: Overall mean daily recovery of OMZ derived radioactivity was 78.4 ± 21.1% in rats
`receiving unbuffered formulations (Group A) and 88.4 ± 20.6% in rats receiving buffered
`formulations (Group B). All animals from both formulation groups showed signs of struggling
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`against dosing by Day 7 and study animals continued to struggle against dosing for the
`remainder of the study. Overall, Urinary elimination of OMZ derived radioactivity in the urine
`was similar between rats in the unbuffered group (Group A) relative to those in the buffered
`group (Group B). Group A urinary elimination of OMZ equivalents was 39.4 ± 6.5% on Day 1 of
`dosing and 27.0 ± 3.6% by Day 14. Group B urinary elimination of OMZ equivalents was 54.3 ±
`2.0% on Day 1 of dosing and 35.9 ± 6.6% by Day 14. Fecal elimination of OMZ derived
`radioactivity was similar between rats in unbuffered group (Group A) relative to those in the
`buffered group (Group B). Group A mean fecal elimination of OMZ equivalents was 33.9 ±
`11.5% on Day 1 of dosing and 56.9 ± 13.1% by Day 14. Group B fecal elimination of OMZ
`equivalents was 38.9 ± 7.1% on Day 1 of dosing and 60.4 ± 9.3% by Day 14. Generally the
`concentration of [14C]OMZ derived equivalents in blood at 45 min and 2h post dose on Days 1,
`4, 7, and 14 was higher in rats receiving OMZ in the buffered formulation (Group B) relative to
`those receiving OMZ in the unbuffered formulations (Group A). By Day 14, blood
`concentrations of [14C]OMZ derived equivalents increased approximately 3 fold relative to those
`measured on Day 1 in both formulation groups. The concentrations of [14C]OMZ derived
`equivalents in plasma at 45 min and 2 h post dose on Day 1were higher in rats receiving OMZ in
`the buffered formulation (Group B) relative to those receiving OMZ in the unbuffered
`formulations (Group A). In both formulation groups, the concentration of [14C]OMZ derived
`equivalents in plasma was highest on Day 1, declined by ~40 − ~70% by Day 4, and then
`remained at those levels through Day 14. Plasma concentrations of [14C]OMZ derived
`equivalents were similar between both formulation groups from Day 4 through Day 14.
`Metabolite profiles of rat plasma collected at 45 and 120 min following oral
`administration of [14C]OMZ on Dose Days 1, 4, 7, and 14 consisted of several metabolites and
`parent OMZ. Representative HPLC radiochromatograms of plasma sampled from rats receiving
`either the unbuffered (Group A) or buffered (Group B) formulation of OMZ are displayed in
`Figures 1−2. Profiles of plasma metabolites varied between individual animals, but generally
`were qualitatively similar between rats receiving either the unbuffered (Group A) or buffered
`(Group B) formulation of OMZ on any given sampling time or day.
`
`Figure 1. Representative HPLC Radiochromatograms of [14C]OMZ-derived Metabolites in
`Plasma in Female SD Rats Receiving Unbuffered Formulations (Group A) and Buffered
`Formulations (Group B) of [14C]OMZ Via Oral Gavage for 14 days: Day 1, 45 Minutes
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`As shown in the Fig 1, there were four metabolites (Relative Mean Total Area of 1.27, 0.25, 0.95
`and 3.4 at Relative Retention Time of 0.17, 0.48, 0.68 and 1.00 respective) detected in plasma of
`individual rats receiving unbuffered formulation (Group A) on Day 1 which were also detected
`in the corresponding Day 1 Group B plasma samples with Relative Mean Total Area of 1.2, 0.36,
`2.08 and 4.64. Similarly, there were two metabolites (Relative Mean Total Area of 0.35 and
`0.349 at Relative Retention Time of 0.17 and 1.00 respective) detected in plasma of individual
`rats receiving unbuffered formulation (Group A) on Day 14 which were also detected in the
`corresponding Day 14 Group B plasma samples with Relative Mean Total Area of 0.39 and 0.57
`as shown in Fig. 2.
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`Figure 2. Representative HPLC Radiochromatograms of [14C]OMZ-derived Metabolites in
`Plasma in Female SD Rats Receiving Unbuffered Formulations (Group A) and Buffered
`Formulations (Group B) of [14C]OMZ Via Oral Gavage for 14 days: Day 14, 45 Minutes
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`Metabolite profiles of rat urine collected at 0−8 and 8−24 h following oral administration