Preclinical Assessment of the Feasibility of Applying Controlled Release Oral Drug Delivery to a Lead Series of Atypical Antipsychotics

Eichenbaum, Gary; Pollock-Dove, Crystal; Nguyen, Joe; Li, S.; Evans, Juli; Borghys, Herman; Kennis, Ludo; Liang, Dong; Osdol, W. van; Dai, Wei; Scicinski, Jan; Chen, J.; Xu, Yining; Ashton, David; Mackie, Claire; Megens, Anton

doi:10.1002/jps.20550

Cited by 3 publications

(1 citation statement)

References 29 publications

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“…More effective in vitro prediction of the feasibility of developing successful MR formulations would allow MR to be considered at a much earlier stage in exploratory drug development, which might help to reduce the number of failures (Thombre, 2005;Eichenbaum et al, 2006). Basic permeability screens such as Caco-2 cell monolayers may be used to provide an initial assessment of the suitability of a drug candidate for MR development (Thombre, 2005), but there remains some uncertainty about their validity as a model of colonic absorption.…”

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confidence: 99%

Investigation of Regional Mechanisms Responsible for Poor Oral Absorption in Humans of a Modified Release Preparation of the α-Adrenoreceptor Antagonist, 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4 tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (UK-338,003): The Rational Use of ex Vivo Intestine to Predict in Vivo Absorption

Collett¹,

Stephens²,

Harwood³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Modified release (MR) formulations are used to enhance the safety and compliance of existing drugs by improving their pharmacokinetics. Predicting the likely success of MR formulations is often difficult before clinical studies. A systematic in vitro approach using mouse and human tissues was adopted to rationalize the in vivo pharmacokinetics of 9-and 15-h MR formulations of an ␣-adrenoreceptor antagonist, 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4 tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (UK-338,003). Immediate release UK-338,003 was well absorbed in humans consistent with moderate Caco-2 cell monolayer permeability. In contrast, 9-and 15-h modified release formulations showed marked reductions in C max (47.1 and 68.9%) and AUC 0-72 (32.6 and 54.0%). Colonic intubation resulted in 81.3 and 73.8% reductions in C max and AUC 0-72 . Mechanistic studies in isolated mouse tissues showed that colonic UK-338,003 permeability (P app < 0.5 ؋ 10 ؊6 cm/s) was at least 40 times lower than that for ileum with marked asymmetry. UK-338,003 was found to be a substrate for P-glycoprotein (PGP) with a weaker interaction for multidrug resistance-associated protein-type transporters in mouse intestine. PGP inhibition dramatically increased colonic UK-338,003 permeability to the levels observed in ileum. Low UK-338,003 apical to basolateral permeability was also observed in ex vivo human distal intestine, but both the asymmetry and increase in permeability after PGP inhibition were significantly lower. In conclusion, the poor absorption of MR UK-338,003 in humans can be explained by a combination of PGP-dependent efflux and low intrinsic permeability in the lower bowel. Regional permeability studies in ex vivo tissues used during drug development can highlight absorption problems in the distal bowel and assess the feasibility of developing successful MR formulations.Oral modified release (MR) formulation can improve the pharmacokinetic and pharmacodynamic properties of a drug and thus lead to both improved patient compliance and safety (Conley et al., 2006). However, predicting the success of MR formulations for a given drug has proved difficult, particularly for drugs with moderate intestinal permeability, and often the success or failure may only become apparent during clinical trials. One of the problems associated with prediction of absorption from a typical 8-to 24-h MR dosage form is that, unlike for immediate release (IR) forms, the drug is released throughout the GI tract with a significant proportion delivered to the distal intestine. As a result, regional differences and, in particular, the efficiency of colonic absorption will be a critical consideration. For a variety of reasons, drug absorption in the colon appears to be more challenging than absorption in the proximal bowel. In physical terms, the colon is a viscous, low-mixing environment with a lower surface area for absorption compared with the proximal bowel. Both paracellular and transcellular permeabilities appear to be lower in th...

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mentioning

confidence: 99%

Investigation of Regional Mechanisms Responsible for Poor Oral Absorption in Humans of a Modified Release Preparation of the α-Adrenoreceptor Antagonist, 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4 tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (UK-338,003): The Rational Use of ex Vivo Intestine to Predict in Vivo Absorption

Collett¹,

Stephens²,

Harwood³

et al. 2007

Drug Metab Dispos

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Enabling Discovery Through Leveraging and Miniaturizing Pharmaceutical Principles and Processes

Haskell

Foster

Tye

et al. 2014

Discovering and Developing Molecules With Optimal Drug-Like Properties

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Physiologically Based Absorption Modeling to Design Extended-Release Clinical Products for an Ester Prodrug

Ding

Day

Sperry

2016

AAPS J

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Absorption modeling has demonstrated its great value in modern drug product development due to its utility in understanding and predicting in vivo performance. In this case, we integrated physiologically based modeling in the development processes to effectively design extended-release (ER) clinical products for an ester prodrug LY545694. By simulating the trial results of immediate-release products, we delineated complex pharmacokinetics due to prodrug conversion and established an absorption model to describe the clinical observations. This model suggested the prodrug has optimal biopharmaceutical properties to warrant developing an ER product. Subsequently, we incorporated release profiles of prototype ER tablets into the absorption model to simulate the in vivo performance of these products observed in an exploratory trial. The models suggested that the absorption of these ER tablets was lower than the IR products because the extended release from the formulations prevented the drug from taking advantage of the optimal absorption window. Using these models, we formed a strategy to optimize the ER product to minimize the impact of the absorption window limitation. Accurate prediction of the performance of these optimized products by modeling was confirmed in a third clinical trial.

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Preclinical Assessment of the Feasibility of Applying Controlled Release Oral Drug Delivery to a Lead Series of Atypical Antipsychotics

Cited by 3 publications

References 29 publications

Enabling Discovery Through Leveraging and Miniaturizing Pharmaceutical Principles and Processes

Physiologically Based Absorption Modeling to Design Extended-Release Clinical Products for an Ester Prodrug

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