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Meta-analysis of Magnetic Marker Monitoring Data to Characterize the Movement of Single Unit Dosage Forms Though the Gastrointestinal Tract Under Fed and Fasting Conditions

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Abstract

Purpose

To develop a model predicting movement of non-disintegrating single unit dosage forms (or “tablet”) through the gastrointestinal tract and characterizing the effect of food intake, based on Magnetic Marker Monitoring data, allowing real-time location of a magnetically labeled formulation.

Methods

Five studies including 30 individuals in 94 occasions under 3 food status were considered. The mean residence time (MRT) of the tablet and the effect of food intake in proximal (PS) and distal stomach (DS), small intestine (SI), ascending (AC), transverse (TC) and descending colon (DC) were estimated using a Markov model for probabilities of movement.

Results

Under fasting conditions, tablet MRTs were 9.4 min in PS, 10.4 in DS, 246 in SI, 545 in AC, 135 in TC, and 286 in DC. A meal taken simultaneous to tablet intake prolonged tablet MRT to 99 min in PS and to 232 in DS; probability of gastric emptying increased of 89% each hour from 2.25 h after meal. The effect of a gastroileac reflex, caused by a secondary meal, accelerated the transit from terminal SI to AC.

Conclusion

This model-based knowledge can be used as a part of mechanism-based models for drug absorption, applied for bottom-up predictions and/or top-down estimation.

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Abbreviations

AC:

Ascending colon

DC:

Descending colon

DS:

Distal stomach

GE:

Gastric emptying

GI:

Gastro-intestinal

HPMC:

Hydroxypropylmethylcellulose

MF:

Meal Function

MF_1:

Primary meal function

MMM:

Magnetic marker monitoring

MRT:

Mean residence time

MTT:

Mean transit time

OFV:

Objective function value

PS:

Proximal stomach

SC:

Sigmoid colon

SE:

Standard error

SI:

Small intestine

SITT:

Small intestine transit time

TC:

Transverse colon

TTGE:

Time to gastric emptying

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ACKNOWLEDGMENTS AND DISCLOSURES

This work has received support from the Innovative Medicines Initiative Joint Undertaking (http://www.imi.europa.eu) under grant agreement number 115369, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies in kind contribution.

Dr Emilie Hénin was supported by a grant to Uppsala University from Novartis, and by the Lavoisier Program from the French Ministry of European Affairs.

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Author notes

  1. Emilie Hénin

    Present address: Université Claude Bernard, EMR 3738 Ciblage Thérapeutique en Oncologie - Faculté de Médecine Lyon Sud, BP12, 69921, Oullins Cedex, France

Authors and Affiliations

  1. Pharmacometrics Group, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 75124, Uppsala, Sweden

    Emilie Hénin, Martin Bergstrand & Mats O. Karlsson

  2. Department of Biopharmaceutics and Pharmaceutical Technology, University of Greifswald, Greifswald, D-17487, Germany

    Werner Weitschies

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  1. Emilie Hénin
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Correspondence to Emilie Hénin.

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Hénin, E., Bergstrand, M., Weitschies, W. et al. Meta-analysis of Magnetic Marker Monitoring Data to Characterize the Movement of Single Unit Dosage Forms Though the Gastrointestinal Tract Under Fed and Fasting Conditions. Pharm Res 33, 751–762 (2016). https://doi.org/10.1007/s11095-015-1824-x

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