Evolution of a detailed physiological model to simulate the gastrointestinal transit and absorption process in humans, Part 1: Oral solutions

Thelen, Kirstin; Coboeken, Katrin; Willmann, Stefan; Burghaus, Rolf; Dressman, Jennifer B.; Lippert, Jörg

doi:10.1002/jps.22726

Cited by 117 publications

(103 citation statements)

References 153 publications

(267 reference statements)

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“…As a consequence, it has often been applied in mechanistic GI absorption models, i.e. GastroPlus™ (6), PK-Sim® (7,8), SimCYP® (9) and some inhouse absorption models (10,11), for the Bbottom-up^predic-tion of the rate and extent of oral drug absorption.…”

Section: Introductionmentioning

confidence: 99%

“…For instance, the majority of the aforementioned models can incorporate some of the physiological factors known to affect the drug's regional absorption. Remarkable progress has been made in the field of solubility and dissolution, where factors such as the pH-dependent solubility for ionisable compounds, variable GI fluid volumes, supersaturation and precipitation, presence of bile micelles and bile salt-mediated solubility enhancement, to name a few, have already been incorporated in these models (6,7,(26)(27)(28)(29)(30). Nevertheless, in terms of regional intestinal membrane permeability (once the intraluminal and intracellular processes have been accounted for), there is a need for improvements (6)(7)(8)26,28).…”

Section: Introductionmentioning

confidence: 99%

“…While in most of these mechanistic models, regional differences in the expression/abundance of intestinal transporters are already accounted to some extent (6)(7)(8)26,28), the approach with regard to the passive permeation along the GI tract is still not well defined. For example, in the physiologically based pharmacokinetic (PBPK) modelling of orally administered drugs, it is a common practice to assume that colonic absorption is insignificant compared to that in the small intestine.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

Olivares‐Morales

Lennernäs

Aarons

et al. 2015

AAPS J

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Abstract. Regional intestinal effective permeability (P eff ) values are key for the understanding of drug absorption along the whole length of the human gastrointestinal (GI) tract. The distal regions of the GI tract (i.e. ileum, ascending-transverse colon) represent the main sites for GI absorption when there is incomplete absorption in the upper GI tract, e.g. for modified release formulations. In this work, a new and pragmatic method for the estimation of (passive) intestinal permeability in the different intestinal regions is being proposed, by translating the observed differences in the available mucosal surface area along the human GI tract into corrections of the historical determined jejunal P eff values. These new intestinal P eff values or Bintrinsic^P eff (P eff,int ) were subsequently employed for the prediction of the ileal absorption clearance (CL abs,ileum ) for a set of structurally diverse compounds. Additionally, the method was combined with a semimechanistic absorption PBPK model for the prediction of the fraction absorbed (f abs ). The results showed that P eff,int can successfully be employed for the prediction of the ileal CL abs and the f abs . P eff,int also showed to be a robust predictor of the f abs when the colonic absorption was allowed in the PBPK model, reducing the overprediction of f abs observed for lowly permeable compounds when using the historical P eff values. Due to its simplicity, this approach provides a useful alternative for the bottom-up prediction of GI drug absorption, especially when the distal GI tract plays a crucial role for a drug's GI absorption.KEY WORDS: intestinal permeability; oral drug absorption; physiologically based pharmacokinetic modelling.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

Olivares‐Morales

Lennernäs

Aarons

et al. 2015

AAPS J

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“…The gastric water volume declined rapidly, within 12 min, releasing an average 94 mL of water into the small intestine, leading to approximately 15 pockets of 6 mL each. For the design of IPD, the small volume may be one important fact to consider, while the other factor is the turnover rate of fluids throughout 24 h. The summarized volume turnover reaches about 10 L, with only about 0.25 L not reabsorbed from the stool (16,17).…”

Section: Academia-rest Of Worldmentioning

confidence: 99%

Meeting Report: In Vivo Predictive Dissolution Conference

Krämer¹,

Stippler²

2015

Dissolution Technol.

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“…PBPK models have been increasingly applied in oral absorption and biopharmaceutics. This has been partly due to the development and availability of mechanistic absorption models such as the ones included in commercial software packages like SimCYP® (ADAM) (7), GastroPlus™ (ACAT) (8) and PK-Sim® (9,10), as well as some in-house developments coming from academia and industry (11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin

Olivares‐Morales

Ghosh

Aarons

et al. 2016

AAPS J

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Abstract.A new minimal Segmented Transit and Absorption model (mSAT) model has been recently proposed and combined with intrinsic intestinal effective permeability (P eff,int ) to predict the regional gastrointestinal (GI) absorption (f abs ) of several drugs. Herein, this model was extended and applied for the prediction of oral bioavailability and pharmacokinetics of oxybutynin and its enantiomers to provide a mechanistic explanation of the higher relative bioavailability observed for oxybutynin's modified-release OROS® formulation compared to its immediate-release (IR) counterpart. The expansion of the model involved the incorporation of mechanistic equations for the prediction of release, transit, dissolution, permeation and first-pass metabolism. The predicted pharmacokinetics of oxybutynin enantiomers after oral administration for both the IR and OROS® formulations were in close agreement with the observed data. The predicted absolute bioavailability for the IR formulation was within 5% of the observed value, and the model adequately predicted the higher relative bioavailability observed for the OROS® formulation vs. the IR counterpart. From the model predictions, it can be noticed that the higher bioavailability observed for the OROS® formulation was mainly attributable to differences in the intestinal availability (F G ) rather than due to a higher colonic f abs , thus confirming previous hypotheses. The predicted f abs was almost 70% lower for the OROS® formulation compared to the IR formulation, whereas the F G was almost eightfold higher than in the IR formulation. These results provide further support to the hypothesis of an increased F G as the main factor responsible for the higher bioavailability of oxybutynin's OROS® formulation vs. the IR.

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Evolution of a detailed physiological model to simulate the gastrointestinal transit and absorption process in humans, Part 1: Oral solutions

Cited by 117 publications

References 153 publications

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

Meeting Report: In Vivo Predictive Dissolution Conference

Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin

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