In silico predictions of gastrointestinal drug absorption in pharmaceutical product development: Application of the mechanistic absorption model GI-Sim

Sjögren, Erik; Westergren, Jan; Grant, Iain; Hanisch, Gunilla; Lindfors, Lennart; Lennernäs, Hans; Abrahamsson, Bertil; Tannergren, Christer

doi:10.1016/j.ejps.2013.05.019

Cited by 148 publications

(171 citation statements)

References 94 publications

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“…When developing the microcontainers as an oral drug delivery system, it is a positive indication that there is no difference in the transport characteristics of the drug when dosed as bulk or confined in microcontainers. The Caco-2 cell culture model is well developed and absorption through the cell monolayer is found to be a key parameter in estimating the in vivo performance of a drug after oral administration (Amidon et al, 1995;Sjogren et al, 2013). The in vitro-in vivo correlation seem to improve even further when the cell studies are performed in medium closely mimicking the properties of human intestinal fluid (as was done here) (Lind et al, 2007;Patel et al, 2006).…”

Section: Flux Of Furosemide Across the Caco-2 Monolayermentioning

confidence: 89%

Polymeric microcontainers improve oral bioavailability of furosemide

Nielsen

Melero

Keller

et al. 2016

International Journal of Pharmaceutics

117

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Microcontainers with an inner diameter of 223 µm are fabricated using the polymer SU-8, and evaluated in vitro, in situ and in vivo for their application as an advanced oral drug delivery system for the poorly water soluble drug furosemide. An amorphous sodium salt of furosemide (ASSF) is filled into the microcontainers followed by applying a lid using Eudragit L100. It is possible to control the drug release in vitro, and in vitro absorption studies show that the microcontainers are not a hindrance for absorption of ASSF. In situ perfusion studies in rats are performed with ASSF-filled microcontainers coated with Eudragit and compared to a furosemide solution. The absorption rate constant of ASSF confined in microcontainers is found to be significantly different from the solution, and by light microscopy, it is observed that the microcontainers are engulfed by the intestinal mucus. An oral bioavailability study in rats is performed with ASSF confined in microcontainers coated with Eudragit and a control group with ASSF in Eudragit-coated capsules. A relative bioavailability of 220% for the ASSF in microcontainers compared to ASSF in capsules is found. These studies indicate that the microcontainers could serve as a promising oral drug delivery system.

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Section: Flux Of Furosemide Across the Caco-2 Monolayermentioning

confidence: 89%

Polymeric microcontainers improve oral bioavailability of furosemide

Nielsen

Melero

Keller

et al. 2016

International Journal of Pharmaceutics

117

View full text Add to dashboard Cite

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“…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. Thus, colonic absorption, by default, is not allowed in such models (10,11,(31)(32)(33)(34). However, based on the large number of MR dosage forms labelled for once-daily administration, absorption from the colon appears to be a very crucial and common process (22,35).…”

Section: Introductionmentioning

confidence: 99%

“…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%

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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“…Modern drug discovery programs are often based on combinatorial chemistry and high-throughput screening, and a majority of the new drug candidates are suffering from poor water solubility (Augustijns et al, 2014). It is recognized that up to 90 % of the new chemical entities are classified as Class II and IV in the Biopharmaceutics Classification System (BCS) (Sjogren et al, 2013). Drug compounds that are classified as Class II are suffering from poor solubility, but are highly permeable, while the class IV compounds suffer both from insufficient solubility and permeability (Dressman and Reppas, 2000).…”

Section: Introductionmentioning

confidence: 99%