Meta-analysis of Magnetic Marker Monitoring data to characterize tablet movement through the gastrointestinal tract
Emilie Hénin, Martin Bergstrand, Mats O. Karlsson
Department of Pharmaceutical Biosciences, Uppsala University, Sweden
Objectives: The aim of this work was to develop a model predicting tablet movement through the Gastro-Intestinal (GI) tract, based on Magnetic Marker Monitoring data.
Data & Methods: Magnetic Marker Monitoring (MMM) is a novel technique to measure in real-time the location of a magnetically labeled formulation in the GI tract. In this work, 5 studies including in total 30 individuals in 94 occasions were considered. The mean residence time (MRT) of the tablet and associated uncertainty in proximal and distal stomach, small intestine, ascending, transverse and descending colon were estimated using a Markov model for probabilities of movement implemented in NONMEM 7 [1,2]. The effect of food intake and other covariates was also investigated on MRT for each GI region. The predictive performance of the model was evaluated based on simulations.
Results: Under fasting conditions, the typical MRT of the tablet was estimated to be 10.1 minutes in proximal stomach, 10.8 minutes in distal stomach, 228 minutes in small intestine (SI), 545 minutes in ascending colon, 135 minutes in transverse colon, and 285 minutes in descending colon.
A meal taken simultaneous to tablet intake was found to prolong tablet MRT 8.7 times in proximal stomach, and 20.1 times in distal stomach. A time-dependent function was added on the probability of gastric emptying, increasing the probability of tablet movement to SI of 73% each hour from 2.25 hours after meal.
The effect of a gastro-ileocecal reflex caused by a later meal (4 to 6 hours after tablet intake), described in the literature [3], could not be retrieved in the present data. Others covariates, such as time to censoring and study effect did not have a significant effect on the GI transit parameters.
Conclusion: This meta-model of MMM data represents an integration of information for tablet movement through GI tract under various food conditions. This model-based knowledge can be used as prior information in semi-mechanistic model for drug absorption, involving tablet position [4-5].
References:
[1] Beal S, Sheiner LB, Boeckmann A, Bauer RJ. NONMEM User’s Guides (1989-2009), Icon Development Solutions, Ellicott City, MD, USA, 2009.
[2] Bergstrand M, Söderlind E, Weitschies W, Karlsson MO. Mechanistic modeling of a magnetic marker monitoring study linking gastrointestinal tablet transit, in vivo drug release and pharmacokinetics. Clin Pharmacol Ther, 86:77-83, 2009.
[3] Yuen KH. The transit of dosage forms through the small intestine. Int J Pharm, 395:9-16, 2010.
[4] Hénin E, Bergstrand M, Karlsson MO. Tablet position in gastrointestinal tract derived from drug release measurements and plasma concentrations. PAGE 18, Abstr 1600, 2009.
[5] Hénin E, Karlsson MO. Semi-physiological modeling of absorption kinetics: application to diclofenac. PAGE 19, Abstr 1752, 2010.
