A Review of Current Methods for Food Effect Prediction During Drug Development

Zhang, Tao; Wells, Emily

doi:10.1007/s40495-020-00230-9

Cited by 14 publications

(4 citation statements)

References 84 publications

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“…The commercially available version of the ACAT model, GastroPlus TM , include several additional improvements that facilitated its usage. It has been used to justify a biowaiver for a selected BCS 2 compounds [124] and determine the impact of different formulation factors such as solubility, particle size, size distribution, and food on the absorption of drugs [125][126][127][128][129][130][131]. The ADAM model is also available commercially, Symcyp®, and is used to predict the effect of drug release rate on the absorption [120,[132][133][134], to allow the optimization of paediatric drug [135,136], and to investigate drug-drug interactions [137].…”

Section: Compartmental Modelsmentioning

confidence: 99%

Advances in Modeling Approaches for Oral Drug Delivery: Artificial Intelligence, Physiologically Based Pharmacokinetic, and First-Principal Models

Arav

2024

Preprint

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Oral drug absorption is the primary route for drug administration. However, this process hinges on multiple factors, including the drug’s physicochemical properties, formulation characteristics, and gastrointestinal physiology. Given its intricacy and the exorbitant costs associated with experimentation, the trial-and-error method proves prohibitively expensive. Theoretical models have emerged as a cost-effective alternative by assimilating data from diverse experiments and theoretical considerations. These models fall into three categories: data-driven models, encompassing classical pharmacokinetics, quantitative-structure models (QSAR), and machine/deep learning. Mechanism-based models include quasi-equilibrium, steady-state, and physiologically based pharmacokinetics, alongside first principles such as molecular dynamics and continuum models. This review provides an overview of recent modeling endeavors across these categories, evaluating their respective advantages and limitations. Additionally, a primer on partial differential equations and their numerical solutions is included in the supplementary materials, recognizing their utility in modeling physiological systems despite their mathematical complexity limiting their widespread application in this field.

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Section: Compartmental Modelsmentioning

confidence: 99%

Advances in Modeling Approaches for Oral Drug Delivery: Artificial Intelligence, Physiologically Based Pharmacokinetic, and First-Principal Models

Arav

2024

Preprint

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“…FDA has provided recommendations for the development of clinically relevant dissolution specifications (method and acceptance criteria), and for the development, evaluation, and use of physiologically based pharmacokinetic (PBPK) analyses for biopharmaceutics applications in support of drug product development [ 13 ]. Various in silico , in vitro , and in vivo tools and techniques have been reviewed for the food effect prediction during drug development [ 2 , 14 ]. Characterization of the luminal environment after food intake, selection of appropriate biorelevant dissolution media for fed state and various in vitro methodologies for evaluating drug product performance in the fed state has also been reviewed [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…This does not leave a lot of room to improve wettability and surface area limitations of "grease ball molecules" at this stage of development. The commonly used techniques to predict the food effect [ 2 , 14 ] require either large quantities of DS or drug product (DP) formulation for the test. This warrants for a technique to reliably predict the food effect using a small quantity of DS and provides a middle ground between physicochemical throughput screening and a final product testing.…”

Section: Introductionmentioning

confidence: 99%

Food effect risk assessment in preformulation stage using material sparing µFLUX methodology

2022

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The intake of food and meal type can strongly impact the bioavailability of orally administered drugs and can consequently impact drug efficacy and safety. During the early stages of drug development, only a small amount of drug substance is available, and the solubility difference between fasted state simulated intestinal fluid and fed state simulated intestinal fluid may provide an early indication about the probable food effect. But higher drug solubility in fed state simulated intestinal fluid may not always results in an increased oral absorption. In the present research, we demonstrated using 11 model compounds that in addition to the drug dissolution in biorelevant media, the evaluation of the diffusion flux of a drug in solution, across artificial lipid coated membrane, where only the unbound drug crosses the membrane, is a reliable way to predict the food effect. Although, the combination of dissolution and diffusion flux may not reliably predict the food effect in case of drugs undergoing intestinal metabolism or when transporters are involved in the drug absorption, the technique generally provides good information about the food effect at very early stages of drug development that may help in designing a clinical plan by adjusting the drug dose in the fed state.

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“…Although drug safety profiles are evaluated in the fasted state during clinical trials, FE prediction is required for the first-in-human fed state trials. The current practices of FE assessment during drug development typically involve dissolution studies in the fed state simulated gastric or intestinal media [ 20 ]. In general, food can influence dissolution and/or permeability.…”

Section: Introductionmentioning

confidence: 99%

Meta-Analysis of Food Effect on Oral Absorption of Efflux Transporter Substrate Drugs: Does Delayed Gastric Emptying Influence Drug Transport Kinetics?

Sharma

2021

Pharmaceutics

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The oral route of drug administration is the most convenient method of drug delivery, but it is associated with variable bioavailability. Food is one of the major factors that affect oral drug absorption by influencing drug properties (e.g., solubility and dissolution rate) and physiological factors (e.g., metabolism and transport across the gastrointestinal tract). The aim of this work was to investigate the effect of food on the high-affinity intestinal efflux transporter substrate drugs. We hypothesized that transport efficiency is higher in the fed state as compared to the fasted state because of the lower intestinal lumen drug concentration due to prolonged gastric emptying time. A systematic analysis of reported clinical food-effect (FE) studies on 311 drugs was performed and the association of the efflux transport efficiency was investigated on the FE magnitude, i.e., changes in maximal plasma concentration and area under the plasma concentration–time profile curve for both solubility and permeability-limited drugs. In total, 124 and 88 drugs showed positive and negative FE, respectively, whereas 99 showed no FE. As expected, the solubility-limited drugs showed positive FE, but interestingly, drugs with a high potential for efflux transport, were associated with negative FE. Moreover, a high-fat diet was associated with a higher magnitude of negative FE for high-affinity efflux transporter substrates as compared to a low-fat diet. To account for changes in drug absorption after food intake, the prolonged gastric emptying time should be considered in the physiologically based pharmacokinetic (PBPK) modeling of orally absorbed efflux transporter substrate drugs.

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A Review of Current Methods for Food Effect Prediction During Drug Development

Cited by 14 publications

References 84 publications

Advances in Modeling Approaches for Oral Drug Delivery: Artificial Intelligence, Physiologically Based Pharmacokinetic, and First-Principal Models

Advances in Modeling Approaches for Oral Drug Delivery: Artificial Intelligence, Physiologically Based Pharmacokinetic, and First-Principal Models

Food effect risk assessment in preformulation stage using material sparing µFLUX methodology

Meta-Analysis of Food Effect on Oral Absorption of Efflux Transporter Substrate Drugs: Does Delayed Gastric Emptying Influence Drug Transport Kinetics?

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