Linking the Gastrointestinal Behavior of Ibuprofen with the Systemic Exposure between and within Humans-Part 2: Fed State

Abstract

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.

Keywords: bioavailability; bioequivalence; buffer capacity; fed state; ibuprofen; immediate release; in vivo dissolution; in vivo study; local drug concentration in the GI tract; manometry; motility; oral absorption.

Figure 1.

Illustration of the initiation of phase III contraction in subject 20 (visit 1) who ingested 420 calories of the Pulmocare meal. Motility pressure events were recorded via water-perfused manometry. Ports 1–3 represent the stomach; ports 4–6 represent the duodenum; ports 7–9 represent the jejunum.

Figure 2.

Individual (gray) and Mean (green) plasma profiles as a function of time for all subjects after oral administration of 800 mg ibuprofen IR tablets in fed state conditions.

Figure 3.

Individual and mean luminal solution concentrations as a function of time of ibuprofen after the oral administration of an 800 mg ibuprofen IR tablet in fed state conditions (from the left to the right: stomatch, duodenum, and jejunum)

Figure 4.

(A) Predicted versus observed absorption rates and (B) the average observed and predicted absorption rates as a function of time.

Figure 5.

Median luminal pH and ibuprofen concentrations in the stomach (A), duodenum (B), and jejunum (C). The pK_a value of ibuprofen (~4.85), the average tMMC-III, and the theoretical solubility are presented as well. Data were extracted from Hens et al.

Figure 6.

Linear-regression analysis between plasma C_max (μg/mL) and (A) average stomach pH, (B) ingested amount of calories, (C) average duodenum pH, and (D) time to phase III contractions postdose.

Figure 7.

Performance of the multiple-linear-regression model that was able to predict the individual plasma C_max, considering the tMMC-III and average stomach pH as key variables.

Figure 8.

Comparison between different PK indicators from the present study and from other studies of ibuprofen in the literature performed in fed state conditions (doses normalized for an 800 mg dose).