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In silico predictions of gastrointestinal drug absorption in pharmaceutical product development: application of the mechanistic absorption model GI-Sim.
Eur J Pharm Sci. 2013 Jul 16; 49(4):679-98.EJ

Abstract

Oral drug delivery is the predominant administration route for a major part of the pharmaceutical products used worldwide. Further understanding and improvement of gastrointestinal drug absorption predictions is currently a highly prioritized area of research within the pharmaceutical industry. The fraction absorbed (fabs) of an oral dose after administration of a solid dosage form is a key parameter in the estimation of the in vivo performance of an orally administrated drug formulation. This study discloses an evaluation of the predictive performance of the mechanistic physiologically based absorption model GI-Sim. GI-Sim deploys a compartmental gastrointestinal absorption and transit model as well as algorithms describing permeability, dissolution rate, salt effects, partitioning into micelles, particle and micelle drifting in the aqueous boundary layer, particle growth and amorphous or crystalline precipitation. Twelve APIs with reported or expected absorption limitations in humans, due to permeability, dissolution and/or solubility, were investigated. Predictions of the intestinal absorption for different doses and formulations were performed based on physicochemical and biopharmaceutical properties, such as solubility in buffer and simulated intestinal fluid, molecular weight, pK(a), diffusivity and molecule density, measured or estimated human effective permeability and particle size distribution. The performance of GI-Sim was evaluated by comparing predicted plasma concentration-time profiles along with oral pharmacokinetic parameters originating from clinical studies in healthy individuals. The capability of GI-Sim to correctly predict impact of dose and particle size as well as the in vivo performance of nanoformulations was also investigated. The overall predictive performance of GI-Sim was good as >95% of the predicted pharmacokinetic parameters (C(max) and AUC) were within a 2-fold deviation from the clinical observations and the predicted plasma AUC was within one standard deviation of the observed mean plasma AUC in 74% of the simulations. GI-Sim was also able to correctly capture the trends in dose- and particle size dependent absorption for the study drugs with solubility and dissolution limited absorption, respectively. In addition, GI-Sim was also shown to be able to predict the increase in absorption and plasma exposure achieved with nanoformulations. Based on the results, the performance of GI-Sim was shown to be suitable for early risk assessment as well as to guide decision making in pharmaceutical formulation development.

Authors+Show Affiliations

Department of Pharmacy, Uppsala University, BOX 580, S-751 23 Uppsala, Sweden.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23727464

Citation

Sjögren, Erik, et al. "In Silico Predictions of Gastrointestinal Drug Absorption in Pharmaceutical Product Development: Application of the Mechanistic Absorption Model GI-Sim." European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, vol. 49, no. 4, 2013, pp. 679-98.
Sjögren E, Westergren J, Grant I, et al. In silico predictions of gastrointestinal drug absorption in pharmaceutical product development: application of the mechanistic absorption model GI-Sim. Eur J Pharm Sci. 2013;49(4):679-98.
Sjögren, E., Westergren, J., Grant, I., Hanisch, G., Lindfors, L., Lennernäs, H., Abrahamsson, B., & Tannergren, C. (2013). In silico predictions of gastrointestinal drug absorption in pharmaceutical product development: application of the mechanistic absorption model GI-Sim. European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, 49(4), 679-98. https://doi.org/10.1016/j.ejps.2013.05.019
Sjögren E, et al. In Silico Predictions of Gastrointestinal Drug Absorption in Pharmaceutical Product Development: Application of the Mechanistic Absorption Model GI-Sim. Eur J Pharm Sci. 2013 Jul 16;49(4):679-98. PubMed PMID: 23727464.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In silico predictions of gastrointestinal drug absorption in pharmaceutical product development: application of the mechanistic absorption model GI-Sim. AU - Sjögren,Erik, AU - Westergren,Jan, AU - Grant,Iain, AU - Hanisch,Gunilla, AU - Lindfors,Lennart, AU - Lennernäs,Hans, AU - Abrahamsson,Bertil, AU - Tannergren,Christer, Y1 - 2013/05/29/ PY - 2013/03/14/received PY - 2013/04/24/revised PY - 2013/05/14/accepted PY - 2013/6/4/entrez PY - 2013/6/4/pubmed PY - 2014/2/12/medline KW - AAF KW - ABL KW - ACAT KW - ADAM KW - API KW - AUC KW - Absorption modeling KW - BCS KW - BSA KW - Biopharmaceutics Classification System KW - Boltzmann’s constant KW - CAT KW - CYP3A4 KW - Caco-2 apparent permeability KW - D KW - F KW - FaSSIF KW - Fraction absorbed KW - GI KW - In silico prediction KW - Intestinal permeability KW - L KW - M(w) KW - P KW - P(ABL) KW - P(app) KW - P(eff) KW - P(m) KW - R KW - S KW - Solubility KW - V(M) KW - active pharmaceutical ingredient KW - advanced compartmental absorption and transit KW - advanced dissolution absorption and metabolism KW - aqueous boundary layer KW - aqueous boundary layer thickness KW - area amplification factor KW - area under the plasma concentration time curve KW - bioavailability KW - bovine serum albumin KW - compartmental absorption and transit KW - cytochrome P450 3A4 KW - diffusion coefficient in water KW - f(0) KW - f(abs) KW - f(stirring) KW - fasted simulated small intestinal fluid KW - fraction absorbed KW - fraction of dissolved active pharmaceutical ingredient partitioned to micelles KW - fraction uncharged KW - gastrointestinal KW - human effective jejunal permeability KW - k KW - membrane permeability KW - molar density KW - molar volume KW - molar weight KW - molecule radius KW - particle radius KW - permeability KW - permeability in the aqueous boundary layer KW - q KW - r KW - solubility KW - stirring factor KW - transit time KW - viscosity of water KW - η KW - ρ KW - τ SP - 679 EP - 98 JF - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JO - Eur J Pharm Sci VL - 49 IS - 4 N2 - Oral drug delivery is the predominant administration route for a major part of the pharmaceutical products used worldwide. Further understanding and improvement of gastrointestinal drug absorption predictions is currently a highly prioritized area of research within the pharmaceutical industry. The fraction absorbed (fabs) of an oral dose after administration of a solid dosage form is a key parameter in the estimation of the in vivo performance of an orally administrated drug formulation. This study discloses an evaluation of the predictive performance of the mechanistic physiologically based absorption model GI-Sim. GI-Sim deploys a compartmental gastrointestinal absorption and transit model as well as algorithms describing permeability, dissolution rate, salt effects, partitioning into micelles, particle and micelle drifting in the aqueous boundary layer, particle growth and amorphous or crystalline precipitation. Twelve APIs with reported or expected absorption limitations in humans, due to permeability, dissolution and/or solubility, were investigated. Predictions of the intestinal absorption for different doses and formulations were performed based on physicochemical and biopharmaceutical properties, such as solubility in buffer and simulated intestinal fluid, molecular weight, pK(a), diffusivity and molecule density, measured or estimated human effective permeability and particle size distribution. The performance of GI-Sim was evaluated by comparing predicted plasma concentration-time profiles along with oral pharmacokinetic parameters originating from clinical studies in healthy individuals. The capability of GI-Sim to correctly predict impact of dose and particle size as well as the in vivo performance of nanoformulations was also investigated. The overall predictive performance of GI-Sim was good as >95% of the predicted pharmacokinetic parameters (C(max) and AUC) were within a 2-fold deviation from the clinical observations and the predicted plasma AUC was within one standard deviation of the observed mean plasma AUC in 74% of the simulations. GI-Sim was also able to correctly capture the trends in dose- and particle size dependent absorption for the study drugs with solubility and dissolution limited absorption, respectively. In addition, GI-Sim was also shown to be able to predict the increase in absorption and plasma exposure achieved with nanoformulations. Based on the results, the performance of GI-Sim was shown to be suitable for early risk assessment as well as to guide decision making in pharmaceutical formulation development. SN - 1879-0720 UR - https://www.unboundmedicine.com/medline/citation/23727464/In_silico_predictions_of_gastrointestinal_drug_absorption_in_pharmaceutical_product_development:_application_of_the_mechanistic_absorption_model_GI_Sim_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0928-0987(13)00198-X DB - PRIME DP - Unbound Medicine ER -