In Vivo Dissolution and Systemic Absorption of Immediate Release

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In Vivo Dissolution and Systemic Absorption of Immediate Release Ibuprofen in Human Gastrointestinal Tract Under Fed and Fasted Conditions Duxin Sun, Jason R. Baker, Bo Wen, Ann Frances, Huixia Zhang, Alex Yu, Ting Zhao, Yasuhiro Tsume, Manjunath Pai, Barry Bleske, Xinyuan Zhang, R. Lionberger, Allen Lee, Gordon Amidon, William L. Hasler, and Mark Koenigsknecht Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.7b00425 • Publication Date (Web): 22 Sep 2017 Downloaded from http://pubs.acs.org on September 24, 2017

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Molecular Pharmaceutics

In Vivo Dissolution and Systemic Absorption of Immediate Release Ibuprofen in Human Gastrointestinal Tract Under Fed and Fasted Conditions Mark J. Koenigsknecht1, Jason R. Baker2, Bo Wen1, Ann Frances1, Huixia Zhang1, Alex Yu1, Ting Zhao1, Yasuhiro Tsume1, Manjunath P. Pai3, Barry E Bleske4, Xinyuan Zhang5§, Robert Lionberger5§, Allen Lee2, Gordon L. Amidon1, William L. Hasler2*, Duxin Sun1* Affiliations 1Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, USA 2Department

of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan 48109, USA

3Department

of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, USA

4 Department

of Pharmacy Practice and Administrative Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, 87120, USA

5Office

of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993, USA

§Disclaimer:

The views expressed in this article are those of the authors and not necessarily those of the Food and Drug Administration (FDA).

*Corresponding

authors:

Duxin Sun, Ph.D., Professor, Department of Pharmaceutical Sciences, College of Pharmacy. University of Michigan, Room 3353, Building 520,1600 Huron Parkway, Ann Arbor, Michigan 48105. Phone: 734-615-8740, Email: [email protected] William L. Hasler, M.D., Professor, Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan 48109. Phone: 734936-4780, Email: [email protected]

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Graphical Abstract:

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Abstract:

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Purpose: In vivo drug dissolution in the gastrointestinal (GI) tract is largely

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unmeasured. The purpose of this clinical study was to evaluate the in vivo drug

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dissolution and systemic absorption of the BCS Class IIa drug ibuprofen under fed

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and fasted conditions by direct sampling of stomach and small intestinal luminal

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content. Expanding current knowledge of drug dissolution in vivo will help to

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establish physiologically relevant in vitro models predictive of drug dissolution.

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Methods: A multi-lumen GI catheter was orally inserted into the GI tract of healthy

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human subjects. Subjects received a single oral dose of ibuprofen (800 mg tablet)

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with 250 mL of water under fasting and fed conditions. The GI catheter facilitated

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collection of GI fluid from the stomach, duodenum, and jejunum. Ibuprofen

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concentration in GI fluid supernatant and plasma was determined by LC-MS/MS.

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Results: A total of 23 subjects completed the study, with 11 subjects returning for

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an additional study visit (a total of 34 completed study visits). The subjects were


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primarily white (61%), male (65%) with an average age of mean of 30 years. The

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subjects had a median [minutes, max] weight of 79 [52, 123] kg and body mass

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index of 25.7 [19.4, 37.7] kg/m2. Ibuprofen plasma levels were higher under fasted

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conditions and remained detectable for 28 hours under both conditions. The AUC0-24

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and Cmax were lower in fed subjects vs. fasted subjects and Tmax was delayed in fed

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subjects vs. fasted subjects. Ibuprofen was detected immediately after ingestion in

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the stomach under fasting and fed conditions until 7 hours after dosing. Higher

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levels of ibuprofen were detected in the small intestine soon after dosing in fasted

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subjects compared to fed. In contrast to plasma drug concentration, overall gastric

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concentrations remained higher under fed conditions due to increased gastric pH vs.

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fasting condition. The gastric pH increased to near neutrality after feeding before

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decreasing to acidic levels after 7 hours.

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Conclusions: Induction of the fed state reduced systemic levels but increased

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gastric levels of ibuprofen, which suggest slow gastric emptying and transit

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dominate effect for plasma drug concentration. High levels of ibuprofen in stomach

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and small intestine 7 hours post dosing was an unexpected finding. Future work is

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needed to better understand the role of various GI parameters, such as motility and

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gastric emptying, on systemic ibuprofen levels in order to improve in vitro

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predictive models.

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Key Words:

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Ibuprofen; in vivo dissolution; pharmacokinetics; immediate release; local


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gastrointestinal concentration; clinical study

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List of abbreviations:

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Gastrointestinal (GI), biopharmaceutical classification system (BCS), nonsteroidal

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anti-inflammatory drug (NSAIDs), Food and Drug Administration (FDA).

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Introduction: Designing oral drug formulations with predictable gastrointestinal (GI)

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absorption profiles is a major objective during drug development. Understanding

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the dissolution properties of oral formulations using in vitro systems can support

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this endeavor. Current in vitro models are useful for in vivo prediction of absorption

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of high solubility drugs. In contrast the absorption of low solubility drugs with high

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GI permeability, referred to as biopharmaceutical classification system (BCS) II

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drugs, are especially difficult to predict1, 2. This prediction problem arises from the

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inability to optimally mimic the dynamic physiologic parameters such as pH,

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buffering conditions, and shifting GI volumes that impart changes dissolution and

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absorption of BCS II drugs in the GI tract. Designing a predictive model that is able

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to address this complex drug-GI behavior may play a major role in drug

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development. Importantly, such a system has the potential to help qualify waivers

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of bioavailability and bioequivalence studies for BCS II drugs during generic drug

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development.

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Currently there are very limited data available analyzing in vivo BCS II drug dissolution and dosage form performance in the GI tract, however recent studies by


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Hens et al. and Van Den Abeele et al. have begun to shed light on drug dissolution

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and absorption of weakly acidic BCS II drugs3-5. Drug absorption in the GI tract is a

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complex process that remains to be fully elucidated. Constructing a comprehensive

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translational model requires clinical measurement of GI variables such as pH, buffer

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capacity, motility, etc. in order to develop better in vitro models. The goal of this

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clinical study was to obtain in vivo drug dissolution of BCS Class IIa drug ibuprofen

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in the GI tract in fed and fasted conditions and correlate with systemic drug

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concentration. We chose to evaluate a model BCS IIa drug, ibuprofen, one of the

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most commonly used nonsteroidal anti-inflammatory drug (NSAIDs) to treat acute

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pain, fever, and inflammation6.

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The potential benefits of ibuprofen are hampered by side-effects7.

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Specifically, the chronic use of NSAIDs like ibuprofen is associated with GI adverse

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events such as gastroduodenal ulceration8. This adverse event occurs due to topical

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epithelial irritant effects, suppression of GI prostaglandin synthesis, alteration of

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local GI blood flow, and interference of injury repair mechanisms. To improve GI

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tolerability, ibuprofen is often taken with food9. Food can delay the rate of ibuprofen

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absorption and lower its pharmacological effects10. While we understand the effect

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food has on plasma levels we have yet to understand the effect of food on local GI

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ibuprofen concentrations.

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In this study a novel multi-lumen GI catheter was orally placed into the

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stomach and small intestine of healthy human volunteers to obtain in vivo samples

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of the GI tract after dosage of an ibuprofen tablet. This study was performed in

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volunteers under both fed and fasted conditions in order to characterize in vivo drug


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disintegration and dissolution under each condition. Corresponding plasma samples

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and GI fluid samples were collected for seven hours following study drug

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administration. The concentration of ibuprofen in plasma and GI fluid supernatant

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was determined via LC-MS/MS and correlated with the human physiology data

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(such as pH) to better understand the effect of food on drug absorption. Correlating

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in vivo drug concentrations with GI physiology data under fasting and fed conditions

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from healthy subjects will help support mechanistic absorption model development

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in the future. This information may also be helpful to improve our understanding of

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local ibuprofen concentrations that may influence gastroduodenal ulceration with

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NSAIDs use.

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Methods:

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Ethics Statement

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Samples collected in this study were part of clinical trial NCT02806869. The

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institutional review boards at the University of Michigan (IRBMED, protocol number

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HUM00085066) and the Department of Health and Human Services, Food and Drug

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Administration (Research Involving Human Subjects Committee/RIHSC, protocol

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number14-029D) both approved the study protocol. All subjects provided written

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informed consent in order to participate. The study was carried out accordance with

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the protocol, International Conference on Harmonization Good Clinical Practice

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guidelines, and applicable local regulatory requirements.

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Ibuprofen Formulation


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Ibuprofen tablets (800 mg) were purchased from Dr. Reddy’s Laboratories

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(Shreveport, LA). The ibuprofen tablet was administered with approximately 250

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mL of water, actual volumes of water consumed for each subject is listed in

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Supplemental Table 1. The study drug was dispensed by the Investigational Drug

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Service (IDS) at the University of Michigan.

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Catheter Design

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A customized multi-lumen catheter was manufactured by Mui Scientific.

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(Mississauga, ON, Canada). The catheter was 292 cm long and consisted of four

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independent aspiration ports located 30-20 cm apart and 16 manometry ports

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located proximal to the aspiration ports. The outer diameter of the catheter was 3.3

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mm while the single lumen tubes used for aspiration had an inner diameter of 1.2

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mm. Additionally, the catheter had a channel to fit a guidewire (0.035 in x 450 cm,

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Boston Scientific, Marlborough, MA) as well as a channel connected to a balloon that

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could be filled with 7 mL of water to assist in catheter placement. Finally, the end of

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the catheter was weighted with 7.75 grams of tungsten weights.

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Inclusion and Exclusion Criteria for the Study Male and female healthy human volunteers between the ages of 18 and 55

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were eligible for inclusion in the study. All subjects completed a physical exam and

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had their previous medical history reviewed by the study physician to confirm the

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subjects were healthy volunteers able to participate in the study. All subjects

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enrolled in the study had normal values for the following laboratory tests: vital


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signs, electrocardiogram (ECG), urine drug screen, serum pregnancy test (for

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women of child-bearing potential), comprehensive metabolic panel, complete blood

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count with platelet and differential, and lactate dehydrogenase. There were no

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exclusionary criteria in regards to BMI, however all tests listed above had to be in

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normal range and the subject had to overall be deemed healthy by the study

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physician.

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Exclusionary criteria for the study were as follows: Adults unable to consent

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for themselves or mentally incapacitated; prisoners; significant clinical illness

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within 3 weeks prior to screening; use of concomitant medications within 2 weeks

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prior to receiving study drug, including but not limited to prescription drugs, herbal

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and dietary supplements, over the counter medications, and vitamins (oral

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contraceptive was permitted); received an investigational drug within 60 days prior

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to receiving the study drug; history of gastrointestinal surgery; surgery within the

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past 3 months; history of allergy to ibuprofen or other non-steroidal anti-

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inflammatory drugs (NSAIDs); pregnant or lactating females; history of severe

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allergic diseases including drug allergies, with the exception of seasonal allergies;

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history of drug addiction or alcohol abuse within the past 12 months; any clinically

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significant abnormal lab values during screening’ any other factor, condition, or

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disease, including, but not limited to, cardiovascular, renal, hepatic, or

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gastrointestinal disorders that may, in the opinion of the investigator, jeopardize the

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safety of the patient or impact the validity of the study results.

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Study Procedure


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All clinical procedures were performed at the Michigan Clinical Research

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Unit (MCRU) or the Medical Procedures Unit (MPU) in the University of Michigan

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hospital. The subjects were instructed to fast beginning 13 hours prior to dosing and

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to avoid consuming water for 10 hours prior to dosing. Upon arrival a physical exam

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was performed by the study doctor to ensure the health of the subject prior to the GI

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catheter insertion procedure. The multi-lumen GI catheter was orally inserted into

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the GI tract of the subject under the supervision of the study doctor. Lubricating jelly

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was applied to the GI catheter prior to insertion. To lessen the gag reflex, subjects

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received a topical anesthetic (1 mL of 4% lidocaine) before the catheter insertion.

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Once the catheter was swallowed, catheter placement was continued under

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abdominal fluoroscopy to ensure proper positioning in the GI tract. When catheter

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placement was completed the GI catheter was secured to the cheek of the subject

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using medical tape. The subject remained in bed for one hour while the GI tube was

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equilibrated to the manometry instrument, then for 3-5 hours while baseline GI

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motility data was collected. Additionally, GI motility was measured continuously for

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7 hours following study drug administration. The rate of water perfused into the

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subject to measure motility was approximately 100 mL per hour for the 11-13 hours

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that motility was recorded.

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Prior to study drug administration, an intravenous (IV) catheter was placed

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and was kept open with saline solution throughout the study visit. A blood sample

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and GI sample was collected immediately prior to study drug administration and

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food consumption. The study subjects were randomized to one of two arms for this

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study: the study drug dosed in the fasting state or the study drug dosed immediately


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after consuming up to 710 calories (473 mL) of a 55% fat liquid meal to induce the

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fed state (Pulmocare (pH 6.6), Abbott Nutrition, Lake Forest, IL). Randomization

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was performed using Research Randomizer software version 4.0. The maximum

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time allowed to consume the liquid meal was 15 minutes and then the subjects were

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immediately dosed with ibuprofen.

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The subject was given an 800 mg tablet of ibuprofen to be swallowed with

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250 mL of water. After administration of the study drug the subjects did not

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consume any additional food or water. The study drug, water, and/or Pulmocare

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were swallowed by the subject and were not administered via the GI catheter. Blood

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samples were collected at 0 (immediately prior to food consumption and/or study

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drug administration), 10, 20, 30, and 45 minutes, then at 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8,

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11 or 12, and approximately 28 hours following study drug administration. Blood

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samples were added to venous blood collections tubes (K2 EDTA (spray-dried),

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7.2mg) and plasma was separated from blood samples by centrifugation and stored

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at -80⁰C.

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GI fluid samples were collected from available ports by aspiration from

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individual tubes within the GI catheter. Before collection the contents in the GI

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catheter remaining from the previous aspiration were collected and discarded. This

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volume ranged from 3.2 mL for the most distal (jejunal) tube to 1.7 mL for the most

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proximal (stomach) tube. If the tube was filled with air bubbles then at least 30 cc of

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the air/fluid mixture (containing no more than 3.2 mL of liquid) was collected and

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discarded. Collection times included 0 (immediately prior to study drug

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administration), 15, 30, and 45 minutes, then at 1, 1.5, 2, 2.5, 3, 4, 5, 6, and 7 hours


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following study drug administration. Immediately after collection the samples were

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pH using a calibrated micro pH electrode (Thermo Scientific Orion pH probe

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9810BN). Then the GI fluid samples were centrifuged at 21,000 x g for 5 minutes

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and the supernatant was collected and stored at -80⁰C.

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At 7 hours following study drug administration, the GI catheter was removed

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orally from the GI tract and the subject was served a meal. Following the 8 hour

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blood draw the IV catheter was removed and the remaining blood draws were

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performed with a butterfly needle and syringe. The subject then returned

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approximately 28 hours post dosing for the final blood draw.

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To gain an understanding of intrasubject variability, each subject was asked

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to complete two GI catheter insertion procedures under the same conditions, either

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fasting state or fed state. A minimum of 7 days separated each GI catheter insertion

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procedure. The screening visit was repeated prior to the second study visit if

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scheduled more than 4 weeks after the first study visit.

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LC-MS/MS Analysis of Ibuprofen in GI Fluid and Plasma All samples were analyzed by the Pharmacokinetics Core at the University of

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Michigan. LC-MS/MS analyses was performed using a Shimadzu HPLC system

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interfaced to an AB SCIEX QTRAP 5500 mass spectrometer by a TurboV

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electrospray ionization (ESI) source (Applied Biosystems/MDS Sciex, Toronto,

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Canada). Ibuprofen-D3 was used as an internal standard (IS) to normalize variation

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during sample preparation and LC-MS/MS analyses. Chromatographic separation

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was achieved using a 2.1 x 50 mm, 3.5 µm Agilent ZORBAX Extend-C18 column. The


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injection volume was 5 µL and the flow rate was kept constantly at 0.4 mL/minutes.

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Mobile phase A and B were water and acetonitrile, respectively. Both water and

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acetonitrile contained 0.1% acetic acid (v/v). The flow gradient was initially 98:2

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v/v of A:B for 0.5 minutes, linearly ramped to 5:95 A:B over 1 minute. To completely

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wash the column, the gradient was held at 5:95 A:B for 2 minutes and then returned

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to 98:2 over 0.5 minutes. This condition was held for 3 minutes prior to the injection

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of another sample. The mass spectrometer was operated at ESI negative ion mode

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and multiple reaction monitoring (MRM) was used for monitoring the transitions of

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m/z 205.1→159.1 and m/z 208.2→161.2 for ibuprofen and ibuprofen-D3 (IS),

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respectively.

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Protein precipitation with methanol was used to extract ibuprofen from the

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human plasma. 60 µL of each plasma sample was mixed with 180 µL of methanol

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containing 500 ng/mL ibuprofen-D3 in a 96-well plate. The mixture was vortexed

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for 60 seconds at a high speed. The 96-well plate was centrifuged at 3000 x g for 20

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minutes to precipitate proteins at 4 ⁰C. The clear supernatants were collected and 5

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µL of the supernatant was injected for LC-MS/MS analysis.

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Sample preparation of GI fluid was similar to the plasma samples. Due to the

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inadequate amount of blank GI fluid for preparation of calibration standards and QC

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samples, the plasma calibration curve was used to quantify ibuprofen in GI fluid. In

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order to reduce matrix effect, all of the GI fluid samples were diluted 10 fold with

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blank human plasma before protein precipitation in methanol containing 500

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ng/mL ibuprofen-D3.


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Stock solutions of ibuprofen (2 mg/mL) were prepared in methanol. An

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ibuprofen-D3 (IS) stock solution (5 mg/mL) was prepared in dimethyl sulfoxide. To

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prepare the calibration standards, the 2 mg/mL ibuprofen stock solution was

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diluted to 500 µg/mL using methanol, which was spiked with blank human plasma

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to provide a final ibuprofen plasma concentration of 10 µg/mL. Then serial dilution

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with the blank human plasma was carried out to provide a series of calibration

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standards from 2.5-10,000 ng/mL. Quality control (QC) plasma solutions at 5, 25,

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250, 5000, and 10000 ng/mL were prepared similarly using separately weighed

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methanol stock solutions of ibuprofen (2 mg/mL). Methanol was used to further

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dilute the stock ibuprofen-D3 solution to 500 ng/mL for protein precipitation

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during sample preparation, also to minimize the variation.

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According to Food and Drug Administration (FDA) guidelines, validation

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procedures were performed in human plasma and GI fluid diluted with human

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plasma. These procedures included: (A) specificity and selectivity; (B) recovery and

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matrix effects at low (0.015 µg/mL), medium (0.1 and 10 µg/mL), and high (35

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µg/mL) concentrations; (C) calibration curve with a correlation coefficient (r) of

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more than 0.98; (D) precision and accuracy, with the intra-day and inter-day assay

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precision and accuracy estimated by analyzing six replicates at three QC levels; (E)

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stability, with all stability studies conducted at three concentration levels in the

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biomatrix at room temperature, 4 °C, −20 °C, and −80 °C; and (F) dilution integrity,

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with experiments carried out with blank biomatrix.

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Pharmacokinetic Analysis and Data Presentation


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Given the intensive plasma sampling procedure (up to 17 samples/subject),

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plasma pharmacokinetics were characterized by non-compartmental analyses.

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These analyses included computation of the area under the curve from time zero to

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24 hours (AUC0-24) based on the linear-logarithm trapezoidal rule, maximum

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concentration (Cmax) and time to Cmax (Tmax). Statistical comparisons of these

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between group comparisons of pharmacokinetic parameters were performed using

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the Kruskal-Wallis test. Matched comparisons by subjects who had repeated

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measures was performed using the Wilcoxon-signed rank test. A p value of < 0.05

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was qualified as statistically significant. Pharmacokinetic and statistical analysis

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were performed using StataIC version 14.2 (StataCorp, College Station, TX) . All

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figures were generated with the R 3.2.3 software package utilizing ggplot2 or with

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Prism 6 (GraphPad Software, Inc.). Average values were shown with the standard

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error of the mean (SEM). Significance was determined using nonparametric

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statistical tests.

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Results:

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Study enrollment numbers and demographics

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To determine eligibility for this study, 65 subjects were screened and 46 met

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eligibility criteria. These 46 subjects participated in 60 GI catheter placement

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procedures. Of these 60 catheter placement studies, 24 were discontinued. There

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was 1 study visit that was discontinued after study drug administration due to

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discomfort from the GI catheter. There were 23 study visits that were discontinued

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prior to study drug administration due to the following reasons: inability to advance


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the GI catheter (n=1), vomiting (n=2), or discomfort caused by the GI catheter after

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insertion (n=20). One subject experienced an adverse event during the study visit.

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The subject became hypotensive and reported feeling hot and was clammy to the

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touch during the study procedures. The subject was immediately placed into the

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Trendelenburg position while cooling the forehead and neck with ice packs. The

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subject’s blood pressure returned to baseline after 8 minutes and remained at that

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level throughout the remainder of the study.

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The plasma concentration-time information from all 25 subjects that

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completed the study were reviewed individually and revealed two subjects as

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extreme values. One subject had a rising concentration time profile over the 8 to 28-

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hour period with concentrations at the last time-point that were two-fold higher

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than at the mid-point. Non-adherence with the study protocol such as self-

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administration of another dose of ibuprofen was assumed and as a precaution

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samples collected from this subject were not included in subsequent analysis. The

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second subject had plasma concentrations that were approximately ten-fold lower

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on two study visits (fed conditions) than values measured in comparable subjects

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with no reasonable explanation for these observations. Given the small sample size,

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inclusion of these extreme value data from this subject would contribute to a larger

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difference in the central tendency estimates of ibuprofen exposure in fed compared

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to fated subjects (detailed in next section). As a precaution we removed this subject

354

from subsequent data analyses to not skew the effects of food on ibuprofen

355

dissolution and absorption.


14


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356

Page 16 of 32

Details regarding study participants who completed the study procedure and

357

were included in our analysis are included in Table 1. There were a total of 23

358

subjects that completed the study, with 11 subjects returning for an additional study

359

visit (a total of 34 completed study visits) in our analysis. The subjects were

360

primarily white (61%), male (65%) with an average age of 30 years. The subjects

361

had a median [minutes, max] weight of 79 [52, 123] kg and body mass index of 25.7

362

[19.4, 37.7] kg/m2.

363

Table 1: Demographics of study subjects. Study Arm

Number of Subjects

Age (years)

N

Mean ± SD (MinutesMax) 30 ± 9 (18-54)

Total

23

Fed

10

32 ± 9 (22-49)

Fasted

13

29 ± 9 (18-54)

Body Mass Index (BMI) Mean ± SD (MinutesMax) 26.2 ± 4.6 (19.437.7) 27.0 ± 4.5 (21.635.9) 25.7 ± 4.7 (19.435.8)

Sex

Race

Ethnicity

Male

Female

Caucasian

AfricanAmerican

Asian

Hispanic or Latino

2

Not Hispanic or Latino 22

15

8

14

7

6

4

6

4

0

9

1

9

4

8

3

2

13

0

1

364 365 366

Plasma concentration after administration of ibuprofen The mean and standard deviation concentration time profiles from the 23

367

included subjects are displayed in Figure 1 as a semi-logarithm plot and as absolute

368

values by fasted and fed states. Individual concentration-time profiles of subjects by

369

fasted and fed conditions are shown in Figure 2. In both the fasted and fed

370

conditions ibuprofen was detected in the plasma 10 minutes after administration of

371

ibuprofen. As shown in Figures 1 and 2, the Cmax was lower and Tmax longer in the

372

fed versus fasted state.


15

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373

374 375

Figure 1. Average plasma concentration vs. time profiles of ibuprofen. Fasted

376

(n=20, green line) and fed (n=14, black line) conditions plotted in A) logarithmic

377

and B) linear scale. Error bars indicate the standard error of the mean (SEM). Data

378

from fasted subjects (n=20) and fed subjects (n=14) are shown.

379

380 381

Figure 2. Individual plasma concentration vs. time profiles of ibuprofen under

382

(A) fasted, and (B) fed conditions. Each line represents an individual subject.


16


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Page 18 of 32

383 384

Fed subjects had a significantly (p= 0.020) lower AUC0-24 value than those in

385

the fasted condition, though this difference was a mean of 5.42% lower. In contrast,

386

the difference in Cmax was 35.2% lower (p=0.025) in the fed versus fasted

387

conditions. This lower Cmax was also associated with a longer Tmax that was a mean

388

of 1.71 hours longer in the fed condition. The specific values and statistical

389

comparison of these parameters are provided in Table 2. To quantify intra-subject

390

variability, we analyzed the AUC0-24 from the 11 subjects that completed two

391

separate study visits under the same treatment conditions. The geometric mean

392

[90% confidence interval] plasma AUC0-24 ratio was 1.056 [0.929, 1.193].

393

Table 2. Plasma pharmacokinetic parameters of ibuprofen (mean +/-

394

standard deviation), including area under the curve from time zero to 24

395

hours (AUC0-24), maximum concentration (Cmax) and time to Cmax (Tmax). Study Arm

Number of Observations

Fasted

20

Fed

14

Statistical Significance

AUC0-24 (µg•hr/mL) 241.888 ± 88.907 229.452 ± 76.879 p = 0.020

Cmax (µg/mL) 58.247 ± 18.400 43.051 ± 14.312 p = 0.025

Tmax (hr) 2.980 ± 1.613 4.694 ± 1.994 p = 0.010

396

Significance was determined using the nonparametric Kruskal-Wallis equality-of-

397

populations rank test.

398 399 400 401

GI pH vales in the GI tract The average pH values in the GI tract are shown in Figure 3. Immediately after feeding the gastric pH increased from acidic values (2.3 ± 0.3) closer to


17

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402

neutrality (4.6 ± 0.58). The pH levels gradually decreased until the final

403

measurement 7 hours post dosing, returning to values seen prior to feeding (2.8 ±

404

0.64). After feeding, the pH of the small intestine increased from approximately 5 to

405

6. Fasted subjects had a relatively stable pH compared to the fed subjects

406

throughout the study. The pH values from each subject are shown in Figure 4.

407

Regardless of fed or fasted conditions, the pH in the jejunum showed much less

408

variability than the duodenum and stomach. Both of these regions exhibited large

409

variably between subjects.

410

411 412

Figure 3. Average pH values vs. time profiles throughout the GI tract. A) Fasted

413

and B) Fed study visits are shown. Mid jejunum (black line), Proximal jejunum (red

414

line), Duodenum (green line) and Stomach (blue line). Error bars indicate the

415

standard error of the mean (SEM). Data from fasted subjects (stomach: n=15,

416

duodenum: n=16, proximal jejunum: n=10, mid jejunum: n=12) and fed subjects

417

(stomach: n=13, duodenum: n=11, proximal jejunum: n=6, mid jejunum: n=7) are

418

shown.

419


18


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Page 20 of 32

420 421

Figure 4. Individual pH values vs. time profiles for each subject throughout the

422

GI tract. Each line represents an individual subject.

423 424

In vivo GI concentration of ibuprofen in the GI tract

425

The average concentration of ibuprofen detected in the GI tract is shown in

426

Figure 5 while the ibuprofen concentration in the GI tract for each individual study

427

visit is shown in Figure 6. GI fluid was aspirated 15 minutes post dosing and

428

continued at specified intervals until 7 hours post dosing. As shown in Figure 5,

429

initial samples had a higher concentration of ibuprofen in the stomach for fed

430

subjects while fasted subjects had a higher concentration of ibuprofen in the small

431

intestine. All subjects still had high levels of ibuprofen throughout the GI tract until

432

the last sampling time point, 7 hours post dosing.

433


19

Page 21 of 32

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434 435

Figure 5. Average concentration of ibuprofen in luminal GI fluid supernatant

436

throughout the GI tract. A) fasted and B) fed conditions. Mid jejunum (black line),

437

Proximal jejunum (red line), Duodenum (green line) and Stomach (blue line). Error

438

bars indicate the standard error of the mean (SEM). Data from fasted subjects

439

(stomach: n=15, duodenum: n=16, proximal jejunum: n=10, mid jejunum: n=12) and

440

fed subjects (stomach: n=13, duodenum: n=11, proximal jejunum: n=6, mid jejunum:

441

n=6) are shown.

442


20


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Page 22 of 32

443 444

Figure 6. Individual ibuprofen concentrations in plasma and luminal GI fluid

445

supernatant. Each line represents an individual subject.


21

Page 23 of 32

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446 447

Figure 7 shows the ibuprofen concentration profiles broken down into each

448

site of the stomach and small intestine. In the stomach under fasted condition, the

449

ibuprofen concentration (19,442 ng/ mL) was detected at 15 minutes post dosing.

450

Surprisingly, the high ibuprofen concentration in stomach remained for 7 hours

451

after dosing (20,055 ng/ mL). In the stomach under fed condition, the ibuprofen

452

concentration (90,637 ng/mL) was detected at 15 minutes post dosing. This was 4.7

453

fold higher than that of fasted condition and this increase of ibuprofen dissolution in

454

the stomach may be due to the higher pH under fed condition.

455


22


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456

Page 24 of 32

Figure 7. Site comparison of the average concentration of ibuprofen in

457

luminal GI fluid supernatant in fed and fasting conditions. A) Stomach, B)

458

Duodenum, C) Proximal Jejunum, and D) Mid Jejunum. Error bars indicate the

459

standard error of the mean (SEM). Data from fasted subjects (stomach: n=15,

460

duodenum: n=16, proximal jejunum: n=10, mid jejunum: n=12) and fed subjects

461

(stomach: n=13, duodenum: n=11, proximal jejunum: n=6, mid jejunum: n=6) are

462

shown.

463 464

It is worth noting that although ibuprofen has higher dissolution in the

465

stomach under fed condition (due to higher pH), the ibuprofen concentration in the

466

duodenum is delayed (due to slow gastric emptying and transit). This delay resulted

467

lower plasma ibuprofen concentration. These data strongly suggest the gastric

468

emptying and transit (at fed state) is dominant to determine the plasma drug

469

concentration.

470 471

Discussion:

472

The goal of this clinical study was to directly measure drug dissolution in the

473

stomach and small intestine of healthy humans in order to better understand the in

474

vivo conditions that affect drug disintegration and dissolution. We chose to evaluate

475

the in vivo drug dissolution and systemic absorption of the BCS Class IIa drug

476

ibuprofen by in vivo sampling of stomach and small intestinal luminal content of

477

fasted and fed subjects. In this study we were able to characterize in vivo the

478

dissolution pattern of ibuprofen through to the mid-jejunum. In addition, this study


23

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479

was to determine influence of gastric pH and a fed state on dissolution. These in vivo

480

findings improved our understanding of the luminal profile of this poorly soluble

481

drug and can help to support future models of agents within this class.

482

The effect of food on the pharmacokinetics of immediate release NSAIDs has

483

recently been reviewed10. Having increased plasma levels of ibuprofen results in

484

increased analgesic effect of the drug11, however consumption of food can decrease

485

plasma levels of ibuprofen10. Ibuprofen is generally taken with food to improve

486

tolerability therefore we sought to understand the effect of food on in vivo drug

487

disintegration and dissolution of ibuprofen. Our results were consistent with

488

previous studies10 showing an overall decrease in the Cmax, delay of the Tmax, and

489

overall decrease in the AUC0-24 in the plasma of fed subjects compared to fasted

490

subjects. By utilizing direct in vivo sampling of the GI tract we were able to detect

491

ibuprofen 15 minutes after dosing in both fed and fasted conditions. In fasted

492

subjects ibuprofen was readily detected in the small intestine, which reflected in

493

higher plasma concentrations compared to fed subjects. There were high

494

concentrations of ibuprofen in the stomachs of fed subjects compared to fasted

495

subjects. The increase in pH increased drug dissolution in the stomach, however,

496

that did not increase the rate of systemic drug absorption. Ibuprofen is thought to

497

be poorly absorbed in the stomach of humans, with the small intestine being the

498

main site of absorption12. Our data suggests that feeding increases the stomach pH

499

which in turn increases drug dissolution, however this does not result in higher

500

plasma concentrations. The fed condition likely delay of gastric emptying and transit

501

of drug from stomach to duodenum which correlated with lower Cmax, lower AUC0-24,


24


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Page 26 of 32

502

and longer Tmax. These data strongly suggest that the GI transit a major determinant

503

for lower plasma drug concentration under fed state.

504

Our results, as well as results from others13, 14, show that there is remarkable

505

intersubject variability in the pH of the gastrointestinal tract. The low pH in the

506

stomach below the pKa of 4.4 for ibuprofen15, 16 correlates with low measurable

507

concentrations in this part of the GI tract. Consumption of food that leads to an

508

initial increase in stomach pH also leads to measurable stomach concentrations of

509

ibuprofen. However, food slows the rate of absorption leading to a lower Cmax and

510

longer Tmax but marginally alters the extent of absorption (as indicated by a similar

511

AUC0-24). This alteration in the concentration-time profile relevant for ibuprofen

512

because the analgesic effects of this drug are related to increased plasma levels of

513

the drug11. The observed extension in the Tmax by approximately 1.7 hours also

514

implies an expected delay in the therapeutic effects of this drug.

515

A major unexpected finding of this work was the prolonged high levels of

516

ibuprofen in the GI tract. Our results show that ibuprofen was detected in the GI

517

tract over the course of the seven hours of sampling. Although this was limited to 7

518

hours based on our sampling schema, it is likely that some subjects may have local

519

concentrations in the GI tract for longer periods of time. The implications of

520

prolonged GI retention of ibuprofen have not been previously characterized.

521

Previously, the transit in stomach is estimated from 30 minutes to 2 hours and

522

transit time in small intestine is average of 3 hours and these estimates were used in

523

drug absorption model prediction. The high drug concentration in the stomach and

524

small intestine for 7 hours may challenge these previous assumptions in drug


25

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525

absorption prediction. Better models may need to be developed for better in vitro

526

and in vivo correlation and oral absorption prediction.

527

In addition, it is known that prolonged use of NSAIDs are associated with an

528

increase in gastroduodenal ulceration. From a theoretical perspective, sustained

529

exposure of local GI tissue to ibuprofen may contribute to the peptic ulcer disease

530

associated with this drug. Our results suggest that there is prolonged exposure to

531

ibuprofen in the GI tract, especially after taking ibuprofen with food. Additionally,

532

food increases the initial ibuprofen convention approximately 5 fold compared to

533

fasted subjects 15 minutes after dosing. Our findings suggest we may need to

534

reconsider taking ibuprofen with food. While taking with food might alleviate acute

535

symptoms of GI discomfort it may lead to long term consequences by delaying

536

gastric emptying and leading to prolonged exposure of the stomach lining to

537

ibuprofen.

538

One potential limitation for this study is that with any aspiration catheter going

539

past the pylorus in the stomach there is a possibility of altering gastric emptying by

540

altering how the pylorus opens and closes. Additionally, the presence of a catheter

541

could have an effect on duodenogastric reflux and this in turn could affect drug

542

dissolution and absorption. However, this was examined in work by Muller-Lissner

543

et al. using a catheter of the similar size (3.0 mm compared to our 3.3 mm catheter

544

diameter)17. They found no effect on gastric emptying or duodenogastric reflux

545

when the catheter was placed past the pylorus. No effect of the catheter was found

546

in both fed and fasted conditions. Therefore, the method of using an aspiration


26


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Page 28 of 32

547

catheter to study drug dissolution and absorption should be similar compared to the

548

catheter no being present.

549

Another potential limitation is that the use of aspiration catheters can be

550

considered uncomfortable to the subject due to the presence of a foreign object

551

placed down the subject’s throat. This caused generalized anxiety and

552

uncomfortable feeling in the subject’s throat. We did have 36 out of 60 subjects

553

complete the entire study that had the tube placed for approximately 15 hours. This

554

success rate was similar to a previous study using a similar multi-lumen catheter

555

where the tube was placed for a similar length of time14. While the success rate is

556

lower than other studies5, this could be due to the length of time the tube was

557

placed. For example, work from Hens et al. had a higher success rate for the study

558

but the tube was in place for much less time (approximately 4 hours)5. The

559

generalized anxiety of having the tube placed for 15 hours in our study may have

560

decreased the success rate. However, having the tube placed for this long allowed us

561

to obtain manometry data as well has aspirate fluid for 7 hours after dosing that

562

resulted in a very large data set.

563

The use on aspiration catheters allows us to better understand the in vivo

564

conditions involved in to study drug dissolution and absorption. In this study we

565

presented the data obtained for the gastric and small intestinal pH as well as the

566

concentrations of ibuprofen in the GI tract and plasma. Further analysis of the data

567

set obtained in this clinical study is described in the manuscript by Hens et al.18. In

568

this work, Hens et al. further described how ibuprofen concentration in the stomach

569

and small intestine correlate to buffer capacity as well as motility. Additionally Hens


27

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570

et al. looks at the effect of pH and drug dissolution by analyzing the levels of

571

undissolved ibuprofen in the GI tract.

572

The ability to directly sample small intestinal luminal samples allowed us to

573

follow drug dissolution in vivo. The use of multi-lumen catheters to aspirate GI fluid

574

to study drug dissolution has been pioneered over 30 years ago, however relatively

575

few studies have been performed since19 (reviewed by Hens20 and Brouwers21). In

576

the past few years multiple groups have begun to utilize this technique to aspirate

577

samples from the stomach and GI tract5, 14, 20, 22. Because of this we are beginning to

578

get a better understanding of the complex GI physiological parameters involved in

579

drug dissolution and absorption. A multi-lumen GI catheter is a powerful tool to be

580

able to independently sample multiple sites in the GI tract to compare regional and

581

temporal drug disintegration and dissolution. Future work is needed to connect

582

motility, gastric emptying, buffer capacity, viscosity to better understand in vivo

583

drug dissolution and absorption. We hope the in vivo results obtained in this study

584

can be used to validate in vitro dissolution methodologies in order to support future

585

computational and mathematical modeling efforts. This will aid in the development

586

of an oral drug product optimization process that can be applied to future drugs in

587

order to maximize oral drug safety and efficacy.

588 589 590

Conclusion: In this study we used a novel multi-lumen catheter with the ability to aspirate

591

luminal GI fluid from the stomach and small intestine. Using this catheter, we were

592

able to identify that ibuprofen remains in stomach and small intestine for 7 hours.


28


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Page 30 of 32

593

The fed state delayed transit of ibuprofen into the duodenum (presumably due to a

594

delay in gastric emptying) compared to the fasted state. The fed state increased drug

595

dissolution in stomach (presumably due to increase of pH in the fed state) compared

596

to the fasted state however this did not result in an overall increase in plasma levels

597

of ibuprofen.

598 599 600

Acknowledgments: This research was funded by FDA grant HHSF223201310144C. Clinical

601

samples collected with help from Michigan Institute for Clinical & Health Research

602

(MICHR) NIH grant UL1TR000433. We also thank Bart Hens for thoughtful

603

discussion of this manuscript.

604


29

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605

References:

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In Vivo Dissolution and Systemic Absorption of Immediate Release

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