Parameterization of small intestinal water volume using PBPK modeling
Abstract
To facilitate accurate predictions of oral drug disposition, mechanistic absorption models require optimal parameterization. Furthermore, parameters should maintain a biological basis to establish confidence in model predictions. This study will serve to calculate an optimal parameter value for small intestinal water volume (SIWV) using a model-based approach. To evaluate physiologic fidelity, derived volume estimates will be compared to experimentally-based SIWV determinations. A compartmental absorption and transit (CAT) model, created in Matlab-Simulink®, was integrated with a whole-body PBPK model, developed in PK-SIM 5.2®, to provide predictions of systemic drug disposition. SIWV within the CAT model was varied between 52.5mL and 420mL. Simulations incorporating specific SIWV values were compared to pharmacokinetic data from compounds exhibiting solubility induced non-proportional changes in absorption using absolute average fold-error. Correspondingly, data pertaining to oral administration of acyclovir and chlorothiazide were utilized to derive estimates of SIWV. At 400mg, a SIWV of 116mL provided the best estimates of acyclovir plasma concentrations. A similar SIWV was found to best depict the urinary excretion pattern of chlorothiazide at a dose of 100mg. In comparison, experimentally-based estimates of SIWV within adults denote a central tendency between 86 and 167mL. The derived SIWV (116mL) represents the optimal parameter value within the context of the developed CAT model. This result demonstrates the biological basis of the widely utilized CAT model as in vivo SIWV determinations correspond with model-based estimates.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
There is considerable uncertainty and ongoing debate over the relevant parameterisation of intestinal water volumes and the parameterisation of the colonic model compartments is uncertain.
“there is considerable uncertainty and ongoing debate over the relevant parameterisation of intestinal water volumes [71-73] and the parameterisation of the colonic model compartments is uncertain [74].”
Cites
Basic anatomical and physiological data for use in radiological protection: reference values
Valentin, J. (2002) · Annals of the ICRP · doi:10.1016/s0146-6453(03)00002-2 · Cited by 2,024 · see citing works
Dissolution Testing as a Prognostic Tool for Oral Drug Absorption: Immediate Release Dosage Forms
Dressman, J. B., Amidon, G. L., Reppas, C., & Shah, V. P. (1998) · Pharmaceutical Research · doi:10.1023/a:1011984216775 · Cited by 1,097 · see citing works
Rodgers, T., & Rowland, M. (2006) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20502 · Cited by 949 · see citing works
(2001) · Drugs and the pharmaceutical sciences · doi:10.1201/9780824741969.axh · Cited by 818 · see citing works
Rodgers, T., Leahy, D., & Rowland, M. (2005) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20322 · Cited by 776 · see citing works
Basic anatomical and physiological data for use in radiological protection : reference values
Valentin, J. (2002) · Medical Entomology and Zoology · Cited by 680 · see citing works
Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging
SCHILLER, C., FRÖHLICH, C. ‐., Gießmann, T., Siegmund, W., Mönnikes, H., Hosten, N., & Weitschies, W. (2005) · Alimentary Pharmacology & Therapeutics · doi:10.1111/j.1365-2036.2005.02683.x · Cited by 599 · see citing works
Predicting plasma protein binding of drugs: a new approach
Kratochwil, N. A., Huber, W., Müller, F., Kansy, M., & Gerber, P. R. (2002) · Biochemical Pharmacology · doi:10.1016/s0006-2952(02)01074-2 · Cited by 553 · see citing works
A compartmental absorption and transit model for estimating oral drug absorption
Yu, L. X., & Amidon, G. L. (1999) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(99)00147-7 · Cited by 455 · see citing works
Estimation of the increase in solubility of drugs as a function of bile salt concentration
Mithani, S. D., Bakatselou, V., TenHoor, C. N., & Dressman, J. B. (1996) · Pharmaceutical Research · doi:10.1023/a:1016062224568 · Cited by 303 · see citing works
Willmann, S., Höhn, K., Edginton, A. N., Sevestre, M., Solodenko, J., Weiß, W. W., Lippert, J., & Schmitt, W. (2007) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-007-9053-5 · Cited by 251 · see citing works
Self-citationCompartmental transit and dispersion model analysis of small intestinal transit flow in humans
Yu, L. X., Crison, J. R., & Amidon, G. L. (1996) · International Journal of Pharmaceutics · doi:10.1016/0378-5173(96)04592-9 · Cited by 235 · see citing works
Marciani, L., Cox, E. F., Hoad, C. L., Pritchard, S. E., Totman, J. J., Foley, S., Mistry, A., Evans, S., Gowland, P. A., & Spiller, R. E. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.10.055 · Cited by 217 · see citing works
Nicolaides, E., Symillides, M., Dressman, J., & Reppas, C. I. (2001) · Pharmaceutical Research · doi:10.1023/a:1011071401306 · Cited by 208 · see citing works
Drug Liposome Partitioning as a Tool for the Prediction of Human Passive Intestinal Absorption
Balon, K., Riebesehl, B. U., & Müller, B. W. (1999) · Pharmaceutical Research · doi:10.1023/a:1018882221008 · Cited by 198 · see citing works
Regulatory Experience With Physiologically Based Pharmacokinetic Modeling for Pediatric Drug Trials
Leong, R., Vieira, M. L. T., Zhao, P., Mulugeta, Y. A., Lee, C. S., Sm, H., & Burckart, G. J. (2012) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2012.19 · Cited by 188 · see citing works
Mechanistic Approaches to Predicting Oral Drug Absorption
Huang, W., Lee, S. L., & Yu, L. X. (2009) · The AAPS Journal · doi:10.1208/s12248-009-9098-z · Cited by 183 · see citing works
Poulin, P., Jones, R. D. O., Jones, H. M., Gibson, C. R., Rowland, M., Chien, J. Y., Ring, B. J., Adkison, K. K., Ku, M. S., He, H., et al. (2011) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.22550 · Cited by 174 · see citing works
Evaluation of a Generic Physiologically Based Pharmacokinetic Model for Lineshape Analysis
Peters, S. A. (2008) · Clinical Pharmacokinetics · doi:10.2165/00003088-200847040-00004 · Cited by 148 · see citing works
Rodgers, T., Leahy, D. E., & Rowland, M. (2005) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20323 · Cited by 131 · see citing works
Maharaj, A. R., Barrett, J. S., & Edginton, A. N. (2013) · The AAPS Journal · doi:10.1208/s12248-013-9451-0 · Cited by 123 · see citing works
Self-citationEffects of posture on the physiology of gastric emptying: A magnetic resonance imaging study
Steingoetter, A., Fox, M. R., Treier, R., Weishaupt, D., Marinček, B., Boesiger, P., Fried, M., & Schwizer, W. (2006) · Scandinavian Journal of Gastroenterology · doi:10.1080/00365520600610451 · Cited by 105 · see citing works
Transbuccal Delivery of Acyclovir: I. In Vitro Determination of Routes of Buccal Transport
Shojaei, A. H., Berner, B., & Li, X. (1998) · Pharmaceutical Research · doi:10.1023/a:1011927521627 · Cited by 104 · see citing works
Oral Absorption, Intestinal Metabolism and Human Oral Bioavailability
El‐Kattan, A. F., & Varm, M. (2012) · InTech eBooks · doi:10.5772/31087 · Cited by 104 · see citing works
Box, K. J., Völgyi, G., Baka, E., et al. (2006) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20613 · Cited by 102 · see citing works
Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Aciclovir
Arnal, J., González‐Álvarez, I., Bermejo, M., et al. (2008) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.21392 · Cited by 100 · see citing works
Normal small bowel wall characteristics on MR enterography
Cronin, C. G., Delappe, E., Lohan, D. G., et al. (2009) · European Journal of Radiology · doi:10.1016/j.ejrad.2009.04.066 · Cited by 94 · see citing works
Pharmacokinetics and tolerance of acyclovir, a new anti-herpesvirus agent, in humans
Laskin, O. L., Longstreth, J. A., Saral, R., et al. (1982) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.21.3.393 · Cited by 91 · see citing works
Prediction of pH-Dependent Aqueous Solubility of Druglike Molecules
Hansen, N. T., Kouskoumvekaki, I. A., Jørgensen, F. S., et al. (2006) · Journal of Chemical Information and Modeling · doi:10.1021/ci600292q · Cited by 91 · see citing works
Pharmacokinetics of acyclovir in humans following intravenous administration
Whitley, R. J., Blum, M. R., Barton, N. H., et al. (1982) · The American Journal of Medicine · doi:10.1016/0002-9343(82)90084-5 · Cited by 90 · see citing works
Shono, Y., Jantratid, E., & Dressman, J. (2011) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2011.04.005 · Cited by 89 · see citing works
Kortejärvi, H., Urtti, A. O., & Yliperttula, M. L. (2006) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2006.10.011 · Cited by 85 · see citing works
Disposition of intravenous radioactive acyclovir
de Miranda, P., Good, S. S., Laskin, O. L., et al. (1981) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1981.218 · Cited by 82 · see citing works
Role of Physiological Intestinal Water in Oral Absorption
Sutton, S. C. (2009) · The AAPS Journal · doi:10.1208/s12248-009-9087-2 · Cited by 80 · see citing works
Paixão, P. J. P. A., Gouveia, L. F., & Morais, J. (2012) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2012.03.019 · Cited by 79 · see citing works
Heikkinen, A. T., Baneyx, G., Caruso, A., & Parrott, N. (2012) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2012.06.013 · Cited by 76 · see citing works
Fraction of a dose absorbed estimation for structurally diverse low solubility compounds
Sugano, K. (2010) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2010.11.049 · Cited by 72 · see citing works
Li, G., Wang, K., Chen, R., Hao-ru, Z., Yang, J., & Zheng, Q. (2012) · Acta Pharmacologica Sinica · doi:10.1038/aps.2012.103 · Cited by 70 · see citing works
Siccardi, M., Marzolini, C., Seden, K., Almond, L. M., Kirov, A., Khoo, S., Owen, A., & Back, D. J. (2013) · Clinical Pharmacokinetics · doi:10.1007/s40262-013-0056-7 · Cited by 51 · see citing works
Marciani, L., Wright, J. W., Foley, S., Hoad, C. L., Totman, J. J., Bush, D., Hartley, C., Armstrong, A., Manby, P., Blackshaw, E., et al. (2010) · Alimentary Pharmacology & Therapeutics · doi:10.1111/j.1365-2036.2010.04395.x · Cited by 40 · see citing works
Pharmacokinetics and bioavailability of different formulations of aciclovir.
Vergin, H., Kikuta, C., Mascher, H. J., et al. (1995) · PubMed · Cited by 40 · see citing works
Welling, P. G., & Barbhaiya, R. H. (1982) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600710108 · Cited by 34 · see citing works
Hsu, F., Prueksaritanont, T., Lee, M. G., & Chiou, W. L. (1987) · Journal of Pharmacokinetics and Biopharmaceutics · doi:10.1007/bf01066519 · Cited by 27 · see citing works
Yeo, K. R., Kenny, J. R., & Rostami‐Hodjegan, A. (2013) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-012-1467-3 · Cited by 26 · see citing works
Apparent dose-dependent absorption of chlorothiazide in dogs
Resetarits, D. E., & Bates, T. R. (1979) · Journal of Pharmacokinetics and Biopharmaceutics · doi:10.1007/bf01062388 · Cited by 22 · see citing works
Bioavailability of chlorothiazide from 50, 100, and 250 mg solution doses
Osman, M. A., Patel, R. B., Irwin, D. S., et al. (1982) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.2510030202 · Cited by 21 · see citing works
Saturable kinetics of intravenous chlorothiazide in the rhesus monkey
Gustafson, J. H., & Benet, L. Z. (1981) · Journal of Pharmacokinetics and Biopharmaceutics · doi:10.1007/bf01060889 · Cited by 9 · see citing works
Thiazides XI: Partitioning of chlorothiazide in red blood cells after oral administration
Shah, V. P., Walker, M. A., Hunt, J. P., et al. (1984) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.2510050108 · Cited by 9 · see citing works
Absorption and disposition kinetics of chlorothiazide in protein‐calorie malnutrition
Jung, D. T., Lam, H. D., & Chu, M. (1990) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.2510110106 · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Miller, N. A., Reddy, M. B., Heikkinen, A. T., Lukacova, V., & Parrott, N. (2019) · Clinical Pharmacokinetics · doi:10.1007/s40262-019-00741-9 · Cited by 142 · see citing works
- Authors
- Maharaj, A., Fotaki, N., & Edginton, A.
- Affiliations
- University of Waterloo (CA)
- University of Bath (GB)
- Corresponding author
- Edginton, Andrea
- Venue
- European Journal of Pharmaceutical Sciences
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 67
- Pages
- 55-64
- ISSN
- 0928-0987 (ISSN-L)
- OpenAlex
- W2044778407
- Cited by
- 10
- References
- 49
- Citations by year
- 2026: 2 · 2025: 2 · 2023: 1 · 2022: 2 · 2021: 1 · 2019: 2
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Pharmaceutical Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Merck Canada
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- physiologically based pharmacokinetic modeling, oral drug absorption, acyclovir, chlorothiazide, urinary excretion, parameter estimation, pharmacokinetic simulation
- MeSH terms
- Acyclovir, Adult, Chlorothiazide, Humans, Intestine, Small, Male, Models, Biological, Water
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
