The impact of food intake on the luminal environment and performance of oral drug products with a view to <i>in vitro</i> and <i>in silico</i> simulations: a PEARRL review

Pentafragka, Christina; Symillides, Mira; McAllister, Mark; Dressman, Jennifer B.; Vertzoni, Maria

doi:10.1111/jphp.12999

Cited by 55 publications

(29 citation statements)

References 162 publications

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“…However, within the pharmaceutical industry, significant resources are often invested to anticipate, characterize, and mitigate a food effect, since clinical studies alone do not provide the mechanistic insights needed to predict and understand food effects ( 2 ). Recent reviews have covered the multiple mechanisms for food effect ( 5 ) and the tools available to understand them ( 6 ). Among them, PBPK modeling has gained critical attention for the prediction of food effects using the advanced absorption models in commercial software platforms such as GastroPlus™ and Simcyp® ( 7 – 9 ).…”

Section: Introductionmentioning

confidence: 99%

Use of Physiologically Based Pharmacokinetic (PBPK) Modeling for Predicting Drug-Food Interactions: an Industry Perspective

Riedmaier

DeMent

Huckle

et al. 2020

AAPS J

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The effect of food on pharmacokinetic properties of drugs is a commonly observed occurrence affecting about 40% of orally administered drugs. Within the pharmaceutical industry, significant resources are invested to predict and characterize a clinically relevant food effect. Here, the predictive performance of physiologically based pharmacokinetic (PBPK) food effect models was assessed via de novo mechanistic absorption models for 30 compounds using controlled, pre-defined in vitro, and modeling methodology. Compounds for which absorption was known to be limited by intestinal transporters were excluded in this analysis. A decision tree for model verification and optimization was followed, leading to high, moderate, or low food effect prediction confidence. High (within 0.8- to 1.25-fold) to moderate confidence (within 0.5- to 2-fold) was achieved for most of the compounds (15 and 8, respectively). While for 7 compounds, prediction confidence was found to be low (> 2-fold). There was no clear difference in prediction success for positive or negative food effects and no clear relationship to the BCS category of tested drug molecules. However, an association could be demonstrated when the food effect was mainly related to changes in the gastrointestinal luminal fluids or physiology, including fluid volume, motility, pH, micellar entrapment, and bile salts. Considering these findings, it is recommended that appropriately verified mechanistic PBPK modeling can be leveraged with high to moderate confidence as a key approach to predicting potential food effect, especially related to mechanisms highlighted here.

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Section: Introductionmentioning

confidence: 99%

Use of Physiologically Based Pharmacokinetic (PBPK) Modeling for Predicting Drug-Food Interactions: an Industry Perspective

Riedmaier

DeMent

Huckle

et al. 2020

AAPS J

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“…It is known that food can have such effects for a variety of reasons, such as interacting physically or chemically with the drug substance, delaying gastric emptying, stimulating bile release, and changing the pH within the gastrointestinal tract and altering its blood flow. 22,23 For this reason, the US Food and Drug Administration (FDA) recommends evaluation of bioequivalence following ingestion of a 800-to 1000-kcal meal in which around 50% of the total calories come from fat (as was employed here) to maximize the potential for demonstrating a food effect. 22 In our analysis, food intake seemed to slow the absorption of nifurtimox slightly based on the change in time from dosing to peak plasma concentration (median t max increased from 3 to 4 hours).…”

Section: Discussionmentioning

confidence: 99%

Biopharmaceutical Characteristics of Nifurtimox Tablets for Age‐ and Body Weight‐Adjusted Dosing in Patients With Chagas Disease

Staß

Feleder²,

García-Bournissen

et al. 2020

Clinical Pharm in Drug Dev

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Treatment of Chagas disease with nifurtimox requires age-and body weight-adjusted dosing, resulting in complex dosing instructions. Appropriate formulations are needed for precise and compliant dosing, especially in pediatric patients. We characterized the biopharmaceutical features of a standard nifurtimox 120-mg tablet and a 30-mg tablet developed to improve dose accuracy. Two open-label, randomized crossover studies were conducted in adult outpatients with Chagas disease.One study investigated whether 4 × 30-mg tablets and 1 × 120-mg tablet were bioequivalent and whether tablets can be administered as an aqueous slurry without affecting bioavailability. The second study investigated the effect of a high-calorie/high-fat diet versus fasting on the absorption of nifurtimox after a single 4 × 30-mg dose. Interventions were equivalent if the 90% confidence interval (CI) of their least-squares (LS) mean ratios for both AUC 0-tlast and C max were in the range of 80%-125%. The 4 × 30-mg and 1 × 120-mg tablet doses were bioequivalent (AUC 0-tlast : LS mean ratio, 104.7%; 90%CI, 99.1%-110.7%; C max : LS mean ratio, 101.7%; 90%CI, 89.4%-115.6%; n = 24). Exposure when giving the 4 × 30-mg dose as a slurry or as tablets was comparable, with an AUC 0-tlast ratio of 93.2% (84.2%-103.1%; n = 12) and a slightly decreased C max ratio for the slurry of 76.5% (68.8%-85.1%). Food improved the bioavailability of nifurtimox substantially (AUC 0-tlast ratio fed/fasted , 172%; 90%CI, 154%-192%; C max ratio fed/fasted , 168%; 90%CI, 150%-187%). The data indicate that the 30-and 120-mg tablets are suitable for dosing adult and pediatric patients accurately; nifurtimox should be administered under fed conditions.

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“…In the fed state the physicochemical composition of the gastrointestinal fluid, including its volume, pH, osmolality, surface tension, hydrodynamics and overall composition change. These changes have been extensively reviewed by Pentafragka et al . in the current issue.…”

Section: Food Effects; Causes and Clinical Consequencesmentioning

confidence: 89%

“…While there has been comprehensive review and analysis of the mechanisms underlying the food effect, and more recently of current approaches to predict food effect (Pentafragka et al .,), to date there has been limited analysis of the relative abundance of medicines which display food effect and the systematic approaches utilised to eliminate food‐mediated changes in bioavailability. The aims of the current review are, therefore, to briefly summarise the main causes of food‐mediated changes in bioavailability, discuss the clinical and regulatory impact with regard to the types of and abundance of preparations which display significant food effects and to describe the various formulation approaches currently implemented to overcome the food effect.…”

Section: Introductionmentioning

confidence: 99%

Food for thought: formulating away the food effect – a PEARRL review

O’Shea

Holm

O’Driscoll

et al. 2019

Journal of Pharmacy and Pharmacology

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There are clinical and commercial advantages to predicting the presence of food effects early in the drug development process, in order to mitigate this risk of variable food effect bioavailability. Formulation approaches aimed at reducing variable food-dependent bioavailability, through the use of bio-enabling formulations, are an essential tool in addressing this challenge and the latest state of the art in this field are summarised here.

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The impact of food intake on the luminal environment and performance of oral drug products with a view to in vitro and in silico simulations: a PEARRL review

Cited by 55 publications

References 162 publications

Use of Physiologically Based Pharmacokinetic (PBPK) Modeling for Predicting Drug-Food Interactions: an Industry Perspective

Use of Physiologically Based Pharmacokinetic (PBPK) Modeling for Predicting Drug-Food Interactions: an Industry Perspective

Biopharmaceutical Characteristics of Nifurtimox Tablets for Age‐ and Body Weight‐Adjusted Dosing in Patients With Chagas Disease

Food for thought: formulating away the food effect – a PEARRL review

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