Open AccessLinking the Gastrointestinal Behavior of Ibuprofen with the Systemic Exposure between and within Humans—Part 2: Fed State
Author(s) -
Paulo Paixão,
Marival Bermejo,
Bart Hens,
Yasuhiro Tsume,
Joseph Dickens,
Kerby Shedden,
Niloufar Salehi,
Mark J. Koenigsknecht,
Jason Baker,
William L. Hasler,
Robert Lionberger,
Jianghong Fan,
Jeffrey Wysocki,
Bo Wen,
Allen Lee,
Ann Frances,
Gregory E. Amidon,
Alex Yu,
Gail Benninghoff,
Raimar Löbenberg,
Arjang Talattof,
Duxin Sun,
Gordon L. Amidon
Publication year - 2018
Publication title -
molecular pharmaceutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.13
H-Index - 127
eISSN - 1543-8392
pISSN - 1543-8384
DOI - 10.1021/acs.molpharmaceut.8b00736
Subject(s) - cmax , postprandial , pharmacokinetics , in vivo , ibuprofen , drug , bioavailability , pharmacology , medicine , oral administration , gastrointestinal tract , area under the curve , physiology , chemistry , biology , microbiology and biotechnology , insulin
Exploring the intraluminal behavior of an oral drug product in the human gastrointestinal (GI) tract remains challenging. Many in vivo techniques are available to investigate the impact of GI physiology on oral drug behavior in fasting state conditions. However, little is known about the intraluminal behavior of a drug in postprandial conditions. In a previous report, we described the mean solution and total concentrations of ibuprofen after oral administration of an immediate-release (IR) tablet in fed state conditions. In parallel, blood samples were taken to assess systemic concentrations. The purpose of this work was to statistically evaluate the impact of GI physiology (e.g., pH, contractile events) within and between individuals (intra and intersubject variability) for a total of 17 healthy subjects. In addition, a pharmacokinetic (PK) analysis was performed by noncompartmental analysis, and PK parameters were correlated with underlying physiological factors (pH, time to phase III contractions postdose) and study parameters (e.g., ingested amount of calories, coadministered water). Moreover, individual plasma profiles were deconvoluted to assess the fraction absorbed as a function of time, demonstrating the link between intraluminal and systemic behavior of the drug. The results demonstrated that the in vivo dissolution of ibuprofen depends on the present gastric pH and motility events at the time of administration. Both intraluminal factors were responsible for explaining 63% of plasma C max variability among all individuals. For the first time, an in-depth analysis was performed on a large data set derived from an aspiration/motility study, quantifying the impact of physiology on systemic behavior of an orally administered drug product in fed state conditions. The data obtained from this study will help us to develop an in vitro biorelevant dissolution approach and optimize in silico tools in order to predict the in vivo performance of orally administered drug products, especially in fed state conditions.