Abstract
This study aimed to conduct a quantitative meta-analysis for the values of, and variability in, gastrointestinal (GI) transit times of non-disintegrating single-unit (“tablet”) and multiple-unit (“pellets/multi-unit tablet”) solid dosage forms, characterize the effect of food on the values and variability in these parameters and present quantitative meta-models of the distributions of GI transit times in the respective GI regions to help inform models of oral drug absorption. The literature was systemically reviewed for the values of, and the variability in, gastric, small intestinal and colonic transit times under fed and fasted conditions. Meta-analysis used the “metafor” package of the R language. Meta-models of GI transit were assumed to be log-normally distributed between the studied populations. Twenty-nine studies including 125 reported means and standard deviations were used in the meta-analysis. Caloric content of administered food increased variability and delayed the gastric transit of both pellets and tablets. Conversely, food caloric content reduced the variability but had no significant influence on the mean small intestinal transit time (SITT). Food had no significant effect on the transit time through the colon. The transit of pellets through the colon was significantly slower than that of single-unit tablets which is most likely related to their smaller size. GI transit times may influence the dissolution and absorption of oral drugs. The meta-models of GI transit times may be used as part of semi-physiological absorption models to characterize the influence of transit time on the dissolution, absorption and in vivo pharmacokinetic profiles of oral drugs.
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References
Connor A. Location, location, location: gastrointestinal delivery site and its impact on absorption. Ther Deliv. 2012;3(5):575.
Abrahamsson B, Alpsten M, Jonsson UE, Lundberg P, Sandberg A, Sundgren M, et al. Gastro-intestinal transit of a multiple-unit formulation (metoprolol CR/ZOK) and a non-disintegrating tablet with the emphasis on colon. Int J Pharm. 1996;140(2):229–35.
Kenyon C, Hooper G, Tierney D, Butler J, Devane J, Wilding I. The effect of food on the gastrointestinal transit and systemic absorption of naproxen from a novel sustained release formulation. J Control Release. 1995;34(1):31–6.
Fadda HM, McConnell EL, Short MD, Basit AW. Meal-induced acceleration of tablet transit through the human small intestine. Pharm Res. 2009;26(2):356–60.
Coupe AJ, Davis SS, Wilding IR. Variation in gastrointestinal transit of pharmaceutical dosage forms in healthy subjects. Pharm Res. 1991;8(3):360–4.
Maublant JC, Sournac M, Aiache J-M, Veyre A. Dissolution rate and transit times of technetium-99m DTPA-labeled tablets. J Nuclear Med. 1987;28(7):1199–203.
Mojaverian P, Chan K, Desai A, John V. Gastrointestinal transit of a solid indigestible capsule as measured by radiotelemetry and dual gamma scintigraphy. Pharm Res. 1989;6(8):719–24.
Lalezari D. Gastrointestinal pH profile in subjects with irritable bowel syndrome. Ann Gastroenterol. 2012;25(4):333.
Coupe A, Davis S, Evans D, Wilding I. Do pellet formulations empty from the stomach with food? Int J Pharm. 1993;92(1):167–75.
Yuen K, Deshmukh A, Newton J, Short M, Melchor R. Gastrointestinal transit and absorption of theophylline from a multiparticulate controlled release formulation. Int J Pharm. 1993;97(1):61–77.
Khosla R, Davis S. Gastric emptying and small and large bowel transit of non-disintegrating tablets in fasted subjects. Int J Pharm. 1989;52(1):1–10.
Khosla R, Feely L, Davis S. Gastrointestinal transit of non-disintegrating tablets in fed subjects. Int J Pharm. 1989;53(2):107–17.
Podczeck F, Course N, Newton J, Short M. The influence of non‐disintegrating tablet dimensions and density on their gastric emptying in fasted volunteers. J Pharm Pharmacol. 2007;59(1):23–7.
Davis S, Hardy J, Wilson C, Feely L, Palin K. Gastrointestinal transit of a controlled release naproxen tablet formulation. Int J Pharm. 1986;32(1):85–90.
Davis S, Hardy J, Taylor M, Whalley D, Wilson C. The effect of food on the gastrointestinal transit of pellets and an osmotic device (Osmet). Int J Pharm. 1984;21(3):331–40.
Davis S, Norring‐Christensen F, Khosla R, Feely L. Gastric emptying of large single unit dosage forms. J Pharm Pharmacol. 1988;40(3):205–7.
Youngberg CA, Berardi RR, Howatt WF, Hyneck ML, Amidon GL, Meyer JH, et al. Comparison of gastrointestinal pH in cystic fibrosis and healthy subjects. Dig Dis Sci. 1987;32(5):472–80.
Ewe K, Press AG, Bollen S, Schuhn I. Gastric emptying of indigestible tablets in relation to composition and time of ingestion of meals studied by metal detector. Dig Dis Sci. 1991;36(2):146–52.
Clarke G, Newton J, Short M. Comparative gastrointestinal transit of pellet systems of varying density. Int J Pharm. 1995;114(1):1–11.
Billa N, Yuen K-H, Khader MAA, Omar A. Gamma-scintigraphic study of the gastrointestinal transit and in vivo dissolution of a controlled release diclofenac sodium formulation in xanthan gum matrices. Int J Pharm. 2000;201(1):109–20.
Ibekwe VC, Fadda HM, McConnell EL, Khela MK, Evans DF, Basit AW. Interplay between intestinal pH, transit time and feed status on the in vivo performance of pH responsive ileo-colonic release systems. Pharm Res. 2008;25(8):1828–35.
Goodman K, Hodges LA, Band J, Stevens HN, Weitschies W, Wilson CG. Assessing gastrointestinal motility and disintegration profiles of magnetic tablets by a novel magnetic imaging device and gamma scintigraphy. Eur J Pharm Biopharm. 2010;74(1):84–92.
Cassilly D, Kantor S, Knight L, Maurer A, Fisher R, Semler J, et al. Gastric emptying of a non‐digestible solid: assessment with simultaneous SmartPill pH and pressure capsule, antroduodenal manometry, gastric emptying scintigraphy. Neurogastroenterol Motil. 2008;20(4):311–9.
Koziolek M, Grimm M, Becker D, Iordanov V, Zou H, Shimizu J, et al. Investigation of pH and temperature profiles in the GI tract of fasted human subjects using the Intellicap® system. J Pharm Sci. 2014.
Clarke G, Newton J, Short M. Gastrointestinal transit of pellets of differing size and density. Int J Pharm. 1993;100(1):81–92.
Weitschies W, Wedemeyer R-S, Kosch O, Fach K, Nagel S, Söderlind E, et al. Impact of the intragastric location of extended release tablets on food interactions. J Control Release. 2005;108(2):375–85.
Mojaverian P, Reynolds JC, Ouyang A, Wirth F, Kellner PE, Vlasses PH. Mechanism of gastric emptying of a nondisintegrating radiotelemetry capsule in man. Pharm Res. 1991;8(1):97–100.
Christensen F, Davis S, Hardy J, Taylor M, Whalley D, Wilson C. The use of gamma scintigraphy to follow the gastrointestinal transit of pharmaceutical formulations. J Pharm Pharmacol. 1985;37(2):91–5.
Maurer JM, Schellekens RC, van Rieke HM, Wanke C, Iordanov V, Stellaard F, et al. Gastrointestinal pH and transit time profiling in healthy volunteers using the IntelliCap system confirms ileo-colonic release of ColoPulse tablets. PLoS One. 2015;10(7):e0129076.
Mikolajczyk AE, Watson S, Surma BL, Rubin DT. Assessment of tandem measurements of pH and total gut transit time in healthy volunteers. Clin Trans Gastroenterol. 2015;6(7), e100.
Culen M, Rezacova A, Jampilek J, Dohnal J. Designing a dynamic dissolution method: a review of instrumental options and corresponding physiology of stomach and small intestine. J Pharm Sci. 2013;102(9):2995–3017.
Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36(3):1–48.
Card NA. Applied meta-analysis for social science research. Guilford Press; 2011.
Viechtbauer W. Metafor: Meta-analysis package for R. R package version. 2010;2010:1–0
R Core Team. R: A language and environment for statistical computing. Vienna, Austria R Foundation for Statistical Computing; 2014.
Viechtbauer W. Bias and efficiency of meta-analytic variance estimators in the random-effects model. J Educ Behav Stat. 2005;30(3):261–93.
Sterne JA, Egger M. Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis. J Clin Epidemiol. 2001;54(10):1046–55.
Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34.
Davis S, Hardy J, Fara J. Transit of pharmaceutical dosage forms through the small intestine. Gut. 1986;27(8):886–92.
Hénin E, Bergstrand M, Weitschies W, Karlsson MO. 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. 2015;1–12.
Hunt J. Some properties of an alimentary osmoreceptor mechanism. J Physiol. 1956;132(2):267–88.
Sirois PJ, Amidon GL, Meyer JH, Doty J, Dressman JB. Gastric emptying of nondigestible solids in dogs: a hydrodynamic correlation. Am J Physiol Gastrointest Liver Physiol. 1990;258(1):G65–72.
Hunt J, Knox M. A relation between the chain length of fatty acids and the slowing of gastric emptying. J Physiol. 1968;194(2):327–36.
Stephens J, Woolson R, Cooke A. Effects of essential and nonessential amino acids on gastric emptying in the dog. Gastroenterology. 1975;69(4):920–7.
Wald A, Van Thiel DH, Hoechstetter L, Gavaler JS, Egler KM, Verm R, et al. Gastrointestinal transit: the effect of the menstrual cycle. Gastroenterology. 1981;80(6):1497–500.
Gill R, Murphy P, Hooper H, Bowes K, Kingma Y. Effect of the menstrual cycle on gastric emptying. Digestion. 1987;36(3):168–74.
Leiper JB, Nicholas CW, Ali A, Williams C, Maughan RJ. The effect of intermittent high-intensity running on gastric emptying of fluids in man. Med Sci Sports Exerc. 2005;37(2):240–7.
Hirota N, Sone Y, Tokura H. Effect of postprandial posture on digestion and absorption of dietary carbohydrate. J Physiol Anthropol Appl Human Sci. 2002;21(1):45–50.
Goo R, Moore J, Greenberg E, Alazraki N. Circadian variation in gastric emptying of meals in humans. Gastroenterology. 1987;93(3):515–8.
Kaus LC, Fell JT. Effect of stress on the gastric emptying of capsules. J Clin Hosp Pharm. 1984;9(3):249–51.
Stewart L, Parmar M. Meta-analysis of the literature or of individual patient data: is there a difference? Lancet. 1993;341(8842):418–22.
Riley RD, Lambert PC, Abo-Zaid G. Meta-analysis of individual participant data: rationale, conduct, and reporting. BMJ. 2010;340:c221.
Tosetti C, Stanghellini V, Tucci A, Poli L, Salvioli B, Biasco G, et al. Gastric emptying and dyspeptic symptoms in patients with nonautoimmune fundic atrophic gastritis. Dig Dis Sci. 2000;45(2):252–7.
Cann P, Read N, Brown C, Hobson N, Holdsworth C. Irritable bowel syndrome: relationship of disorders in the transit of a single solid meal to symptom patterns. Gut. 1983;24(5):405–11.
Al Mushref M, Srinivasan S. Effect of high fat-diet and obesity on gastrointestinal motility. Annals of translational medicine. 2013;1(2).
Custodio JM, Wu CY, Benet LZ. Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption. Adv Drug Deliv Rev. 2008;60(6):717–33.
Carver PL, Fleisher D, Zhou SY, Kaul D, Kazanjian P, Li C. Meal composition effects on the oral bioavailability of indinavir in HIV-infected patients. Pharm Res. 1999;16(5):718–24.
Ali HM. Reduced ampicillin bioavailability following oral coadministration with chloroquine. J Antimicrob Chemother. 1985;15(6):781–4.
Fleisher D, Li C, Zhou Y, Pao L-H, Karim A. Drug, meal and formulation interactions influencing drug absorption after oral administration. Clin Pharmacokinet. 1999;36(3):233–54.
Wilding IR, Davis SS, Bakhshaee M, Stevens HN, Sparrow RA, Brennan J. Gastrointestinal transit and systemic absorption of captopril from a pulsed-release formulation. Pharm Res. 1992;9(5):654–7.
Bergstrand M, Söderlind E, Eriksson UG, Weitschies W, Karlsson MO. A semi-mechanistic modeling strategy for characterization of regional absorption properties and prospective prediction of plasma concentrations following administration of new modified release formulations. Pharm Res. 2012;29(2):574–84.
Abuhelwa AY, Mudge S, Hayes D, Upton RN, Foster DJ. Population in vitro-in vivo correlation model linking gastrointestinal transit time, pH, and pharmacokinetics: itraconazole as a model drug. Pharm Res. 2016;33(7):1782–94.
Acknowledgments
A.Y.A. is a PhD student receiving an Endeavour Scholarship granted by the Department of Education and Training of the Australian Government (Scholarship ID no. 4088). The Australian Centre for Pharmacometrics is an initiative of the Australian Government as part of the National Collaborative Research Infrastructure Strategy.
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Abuhelwa, A.Y., Foster, D.J.R. & Upton, R.N. A Quantitative Review and Meta-models of the Variability and Factors Affecting Oral Drug Absorption—Part II: Gastrointestinal Transit Time. AAPS J 18, 1322–1333 (2016). https://doi.org/10.1208/s12248-016-9953-7
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DOI: https://doi.org/10.1208/s12248-016-9953-7