Predicting the impact of physiological and biochemical processes on oral drug bioavailability

Agoram, Balaji; Woltosz, Walter S.; Bolger, Michael B.

doi:10.1016/s0169-409x(01)00179-x

Cited by 572 publications

(436 citation statements)

References 88 publications

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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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“…Modeling and simulation (oral absorption modeling and IVIVC) has become an important tool in guiding formulation development (21,22). Application of computational modeling in drug development has several advantages such as integration of all available in vitro and in vivo data to provide a more holistic view of formulation bioperformance, provides a more mechanistic understanding of in vitro formulation performance and bioperformance, and allows exploration of multiple scenarios in a much shorter timeframe and with fewer experiments thus expediting product development.…”

Section: General Strategies For Fdc Developmentmentioning

confidence: 99%

Challenges and Opportunities in Achieving Bioequivalence for Fixed-Dose Combination Products

Mitra

2012

AAPS J

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Abstract. Fixed-dose combination (FDC) products are becoming a popular treatment option because of increased patient compliance and convenience, improved clinical effectiveness, and reduced cost to the patient, among several other reasons. A commonly applied approach for approval of a FDC product is demonstrating bioequivalence between the FDC and co-administration of individual mono-products, provided that there is adequate safety and efficacy data for co-administration of the individual agents. However, achieving bioequivalence between the FDC and individual mono-products can be very challenging, and sometimes not possible since combining multiple active ingredients, especially insoluble molecules, in a single drug product could complicate its biopharmaceutical and pharmacokinetic behavior. In this review, some of the major challenges often encountered while assessing bioequivalence during FDC development will be presented along with discussion of future opportunities to facilitate FDC development and approval.

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“…Extended release formulations in many cases provide further significant advantages, including improved therapeutic effect, increased patient compliance by reducing dosing frequency and decrease in incidence and /or intensity of adverse effect by a constant blood concentration [1].…”

Section: Introductionmentioning

confidence: 99%

Design and evaluation of sustained-release matrix once daily formulation of stavudine.

Kumar¹,

Dave²,

Lewis³

et al. 2010

Int j Drug delivery

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The aim of the present study was to formulate once daily sustained release matrix tablets of Stavudine to increase therapeutic efficacy, reduce frequency of administration and improve patient compliance. The sustained release tablets were prepared by direct compression and formulated using different drug: polymer ratios, formulations such as F1to F15. Hydrophilic polymers like Hydroxy propyl methyl cellulose (HPMC), Carboxymethyl cellulose (CMC) and Starch 1500 were used. Compatibility of the drug with various excipients was studied. The compressed tablets were evaluated and showed compliance with pharmacopoeial standards. Formulation containing Stavudine:HPMCK15: Na-CMC (1:2:0.5) with hardness 10-11kg/cm 2 showed the desired release profile which matched the theoretical release profile. SEM studies of the formulations were carried out for the confirmation of mechanism of drug release. The in vitro drug release characteristics were studied in both simulated gastric and intestinal fluids for a period of 24 hr using USP Type 2 dissolution apparatus. Mathematical analysis of the release kinetics indicated a coupling of diffusion and erosion mechanisms. The study proves that the developed sustained release tablet is capable of releasing the drug in a sustained manner for 24 hr.

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Predicting the impact of physiological and biochemical processes on oral drug bioavailability

Cited by 572 publications

References 88 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

Challenges and Opportunities in Achieving Bioequivalence for Fixed-Dose Combination Products

Design and evaluation of sustained-release matrix once daily formulation of stavudine.

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