The Provisional No-Effect Threshold of Sugar Alcohols on Oral Drug Absorption Estimated by Physiologically Based Biopharmaceutics Model

Yamane, Minoru; Matsui, Kazuki; Sugihara, Masahisa; Tokunaga, Yuji

doi:10.1016/j.xphs.2020.05.013

Cited by 15 publications

(14 citation statements)

References 40 publications

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“…Another potential impact of excipients on oral drug absorption is via alterations in luminal conditions, e.g., an increased water content due to osmotically active sugar alcohols, and increased paracellular transport due to altered lumen tonicity. ,, There is significant interest in these and other excipient effects on oral drug absorption, especially from a regulatory perspective. , As reviewed succinctly by Metry and Polli, changes in drug formulations require extensive studies to evaluate the impact of excipients, with special attention paid to regulatory requirements around bioequivalence testing both in vitro and in vivo. The rat continuous intestinal model presents a useful framework to evaluate changes in C – t profiles due to known or potential excipient effects such as transporter inhibition and the change in luminal velocity.…”

Section: Discussionmentioning

confidence: 99%

The Rat Continuous Intestine Model Predicts the Impact of Particle Size and Transporters on the Oral Absorption of Glyburide

et al. 2022

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Oral drug absorption is known to be impacted by the physicochemical properties of drugs, properties of oral formulations, and physiological characteristics of the intestine. The goal of the present study was to develop a mathematical model to predict the impact of particle size, feeding time, and intestinal transporter activity on oral absorption. A previously published rat continuous intestine absorption model was extended for solid drug absorption. The impact of active pharmaceutical ingredient particle size was evaluated with glyburide (GLY) as a model drug. Two particle size suspensions of glyburide were prepared with average particle sizes of 42.7 and 4.1 μm. Each suspension was dosed as a single oral gavage to male Sprague Dawley rats, and concentration–time (C–t) profiles of glyburide were measured with liquid chromatography coupled with tandem mass spectrometry. A continuous rat intestine absorption model was extended to include drug dissolution and was used to predict the absorption kinetics of GLY depending on particle size. Additional literature datasets of rat GLY formulations with particle sizes ranging from 0.25 to 4.0 μm were used for model predictions. The model predicted reasonably well the absorption profiles of GLY based on varying particle size and varying feeding time. The model predicted inhibition of intestinal uptake or efflux transporters depending on the datasets. The three datasets used formulations with different excipients, which may impact the transporter activity. Model simulations indicated that the model provides a facile framework to predict the impact of transporter inhibition on drug C–t profiles. Model simulations can also be conducted to evaluate the impact of an altered intestinal lumen environment. In conclusion, the rat continuous intestine absorption model may provide a useful tool to predict the impact of varying drug formulations on rat oral absorption profiles.

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Section: Discussionmentioning

confidence: 99%

The Rat Continuous Intestine Model Predicts the Impact of Particle Size and Transporters on the Oral Absorption of Glyburide

et al. 2022

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“…1) Rapid elimination 4,9,29,35 2) Inability of the in-vitro dissolution test to detect in-vivo relevant changes 27 29 3) Changing the levels of absorption modifying excipients in the formulation 28,30,35,36 4) Low permeability 4,14,37 5) Extensive first pass metabolism 9,22 4.1. BE Failures related to peak sharpness (t½Cmax), and gastric solubility In this analysis, drugs were categorised as to whether their t½Cmax was sharp or blunt depending on whether it was greater than or less than 5hrs.…”

Section: Discussionmentioning

confidence: 99%

“…As already identified in the literature, rapid elimination, especially during the initial elimination phase, makes the Cmax peak sharper, and therefore more vulnerable to changes in absorption kinetics. For many drugs, especially where there is biphasic elimination, the initial decline (alpha phase) may actually depend primarily on distribution kinetics 35 . A similar, perhaps counterintuitive risk factor to Cmax equivalence is absorption rate.…”

Section: Discussionmentioning

confidence: 99%

An Assessment of Occasional Bio-Inequivalence for BCS1 and BCS3 Drugs: What are the Underlying Reasons?

Butler

Augustijns

2022

Journal of Pharmaceutical Sciences

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“…Overall results support Chen et al’s observation that 1.25 g sorbitol can impact Class III drug absorption. An in silico model conducted by Yamane et al estimated that a threshold of 400 mg of sugar alcohols will not impact drug absorption ( 34 ).…”

Section: Potential Absortion-modifying Excipientsmentioning

confidence: 99%

Evaluation of Excipient Risk in BCS Class I and III Biowaivers

Metry

Polli

2022

AAPS J

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The objective of this review article is to summarize literature data pertinent to potential excipient effects on intestinal drug permeability and transit. Despite the use of excipients in drug products for decades, considerable research efforts have been directed towards evaluating their potential effects on drug bioavailability. Potential excipient concerns stem from drug formulation changes (e.g., scale-up and post-approval changes, development of a new generic product). Regulatory agencies have established in vivo bioequivalence standards and, as a result, may waive the in vivo requirement, known as a biowaiver, for some oral products. Biowaiver acceptance criteria are based on the in vitro characterization of the drug substance and drug product using the Biopharmaceutics Classification System (BCS). Various regulatory guidance documents have been issued regarding BCS-based biowaivers, such that the current FDA guidance is more restrictive than prior guidance, specifically about excipient risk. In particular, sugar alcohols have been identified as potential absorption-modifying excipients. These biowaivers and excipient risks are discussed here.

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The Provisional No-Effect Threshold of Sugar Alcohols on Oral Drug Absorption Estimated by Physiologically Based Biopharmaceutics Model

Cited by 15 publications

References 40 publications

The Rat Continuous Intestine Model Predicts the Impact of Particle Size and Transporters on the Oral Absorption of Glyburide

The Rat Continuous Intestine Model Predicts the Impact of Particle Size and Transporters on the Oral Absorption of Glyburide

An Assessment of Occasional Bio-Inequivalence for BCS1 and BCS3 Drugs: What are the Underlying Reasons?

Evaluation of Excipient Risk in BCS Class I and III Biowaivers

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