FOOD EFFECTS In BA & BE STUDy dhara

Guided by : Dr. Dhaivat ParikhPrepared by: Dhara Patel

14MPH103

Effect of food on

Bioavailability of drug

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• This guidance provides recommendations to sponsors and/or applicants planning to conduct food-effect bioavailability (BA) and fed bioequivalence (BE) studies for orally administered drug products as part of investigational new drug applications (INDs), new drug applications (NDAs), abbreviated new drug applications (ANDAs), and supplements to these applications.

• This guidance applies to both immediate-release and modified-release drug products.

• This guidance provides recommendations for food-effect BA and fed BE study designs, data analysis, and product labelling .

• It also provides information on when food-effect BA and fed BE studies should be performed.

INTRODUCTION

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• Food can alter BA by various means, including– Delay gastric emptying– Stimulate bile flow– Change gastrointestinal (GI) pH– Increase splanchnic blood flow– Change luminal metabolism of a drug substance– Physically or chemically interact with a dosage

form or a drug substance

POTENTIAL MECHANISMS OF FOOD EFFECTS ON BA

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• Case 1: Food Prolongs Absorption Rate• Case 2: Food Decreases Absorption• Case 3: Food Increases Absorption• Case 4: No Food Effect

FOOD EFFECTS ON BA OF DRUG SUBSTANCE

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• Commonly seen with highly soluble, highly permeable, rapidly absorbed drug substances

• Major mechanism : Delayed gastric emptying

CASE 1: FOOD PROLONGS ABSORPTION RATE

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CASE STUDY : LAMIVUDINE

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• Mechanisms include– Instability in gastric acids;– Physical/chemical binding with food components;– Increased first-pass metabolism & clearance.

• Can result in decreased efficacy

CASE 2: FOOD DECREASES ABSORPTION

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CASE STUDY : DIDANOSINE

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• Mechanisms include– Inhibition of first-pass effect;– Physicochemical/physiological effects;– Increased bile release; or– Longer gastric residence time

• Food can affect efficacy or safety

CASE 3: FOOD INCREASES ABSORPTION

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CASE STUDY : ISOTRETINOIN

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CASE STUDY : EFAVIRENZ

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• Mechanisms include• –Relatively insensitive to changes in GI tract• –Rapidly, completely absorbed• –Well-absorbed from both large & small intestine

CASE 4: NO FOOD EFFECT

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CASE STUDY : FINASTERIDE

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Food Effects on BE of Different Formulations

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• Often seen with MR formulations.• Release-controlling excipients depend on

environmental conditions of GI tract.• Food can affect drug absorption from MR formulations

by changing physiological conditions in GI tract.

FOOD-FORMULATION INTERACTIONS

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• Defined as the rapid release of the active ingredient from a MR formulation.

• First characterized in the 1980s in studies of theophylline MR formulations.

• Administration with food caused dose-dumping from some theophylline products.

• This was a serious safety issue because theophylline has a narrow therapeutic index.

ILLUSTRATION OF A FOOD-FORMULATION INTERACTION: THEOPHYLLINE DOSE-DUMPING

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• Food can have different effects on drug BA from IR versus MR formulations.

• Food increased Cmax by 23%, had no effect on AUC from IR azithromycin (Zithromax®).

• However, food increased Cmax by 115% and AUC by 23% from MR azithromycin (Zmax®).

COMPARING FOOD EFFECTS ON IR AND MR FORMULATIONS

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• For some products, delayed-release (DR) and/or extended-release (ER) formulations are developed after IR formulation approval.

• FDA requests new food-effect BA studies on the new MR formulation.

CHARACTERIZING FOOD-FORMULATION INTERACTIONS FOR NDA’S

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• Under Food and Drug laws and FDA’s regulations, a generic drug product’s formulation/release mechanism can differ from those of the reference.

• Fed BE studies are designed to show whether the generic formulation performs the same as the reference formulation when products are given with food.

• The generic must be bioequivalent to the reference when given with food.

CHARACTERIZING FOOD-FORMULATION INTERACTIONS FOR ANDAS

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• Acceptance criteria for fed BE studies are that the 90% confidence intervals of the test/reference AUC and Cmax ratios must fall within limits of 80-125%.

• FDA generally requests fed BE studies for generic IR solid oral dosage forms except for products which

• –Are BCS Class 1 drugs• –Must be taken on an empty stomach• FDA generally requests fed BE studies for generic MR

solid oral dosage forms with very few exceptions.

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• FDA uses label information in deciding when to request fed BE studies

• Such information includes• Information about high in vivo permeability• -Potential BCS Class 1 biowaiver• Whether to take on an empty stomach• Safety information

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STUDY CONSIDERATIONS

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• A. General Design• B. Subject Selection• C. Dosage Strength• D. Test Meal• E. Administration• F. Sample Collection

STUDY CONSIDERATIONS

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• FDA recommends a randomized, balanced, single-dose, two-treatment (fed vs. fasting), two-period, two-sequence crossover design for studying the effects of food on the BA of either an immediate-release or a modified-release drug product.

• The formulation to be tested should be administered on an empty stomach (fasting condition) in one period and following a test meal (fed condition) in the other period.

A. GENERAL DESIGN

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• FDA recommends a similar, two-treatment, two-period, two sequence crossover design for a fed BE study except that the treatments should consist of both test and reference formulations administered following a test meal (fed condition).

• An adequate washout period should separate the two treatments in food-effect BA and fed BE studies.

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• Both food-effect BA and fed BE studies can be carried out in healthy volunteers drawn from the general population.

• Studies in the patient population are also appropriate if safety concerns preclude the enrollment of healthy subjects.

• A sufficient number of subjects should complete the study to achieve adequate power for a statistical assessment of food effects on BA to claim an absence of food effects, or to claim BE in a fed BE study.

• A minimum of 12 subjects should complete the food-effect BA and fed BE studies.

B. SUBJECT SELECTION

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• In general, the highest strength of a drug product intended to be marketed should be tested in food-effect BA and fed BE studies.

• In some cases, clinical safety concerns can prevent the use of the highest strength and warrant the use of lower strengths of the dosage form.

• For ANDAs, the same lot and strength used in the fasting BE study should be tested in the fed BE study.

• For products with multiple strengths in ANDAs, if a fed BE study has been performed on the highest strength, BE determination of one or more lower strengths can be waived based on dissolution profile comparisons.

C. DOSAGE STRENGTH

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• FDA recommends that food-effect BA and fed BE studies be conducted using meal conditions that are expected to provide the greatest effects on GI physiology so that systemic drug availability is maximally affected.

• A high-fat (approximately 50 percent of total caloric content of the meal) and high-calorie (approximately 800 to 1000 calories) meal is recommended as a test meal for food-effect BA and fed BE studies.

• This test meal should derive approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively.

D. TEST MEAL

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• Fasted Treatments: • Following an overnight fast of at least 10 hours,

subjects should be administered the drug product with 240 mL (8 fluid ounces) of water.

• No food should be allowed for at least 4 hours post-dose.

• Water can be allowed as desired except for one hour before and after drug administration.

• Subjects should receive standardized meals scheduled at the same time in each period of the study.

E. ADMINISTRATION

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• Fed Treatments: • Following an overnight fast of at least 10 hours, subjects

should start the recommended meal 30 minutes prior to administration of the drug product.

• Study subjects should eat this meal in 30 minutes or less; however, the drug product should be administered 30 minutes after start of the meal.

• The drug product should be administered with 240 mL (8 fluid ounces) of water.

• No food should be allowed for at least 4 hours post-dose. • Water can be allowed as desired except for one hour before

and after drug administration. • Subjects should receive standardized meals scheduled at

the same time in each period of the study.

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• For both fasted and fed treatment periods, timed samples in biological fluid, usually plasma, should be collected from the subjects to permit characterization of the complete shape of the plasma concentration-time profile for the parent drug.

F. SAMPLE COLLECTION

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• The following exposure measures and pharmacokinetic parameters should be obtained:

• Total exposure, or area under the concentration-time curve (AUC0-inf, AUC0-t)

• Peak exposure (Cmax)• Time to peak exposure (Tmax)• Lag-time (tlag) for modified-release products, if present• Terminal elimination half-life• Other relevant pharmacokinetic parameters

• Individual subject measurements, as well as summary statistics (e.g., group averages, standard deviations, coefficients of variation) should be reported.

DATA ANALYSIS

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• For new solid oral dosage forms• –Food-effect BA studies should be conducted early in

drug development• –Study results should be summarized in label• –Label should describe relationship of food to drug

administration

SUMMARY AND CONCLUSIONS

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• For generic drug IR and MR solid oral formulations, fed BE studies generally should be conducted, in addition to fasting BE studies (with some exceptions)

• For a generic drug formulation to be deemed bioequivalent to the reference formulation, both fed and fasting BE studies must be acceptable

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• Crossover study designs are optimal for food-effect BA and fed BE studies

• Food effects should generally be studied with a high-fat, high-calorie meal

• Acceptable sprinkle relative BA (for NDAs) or BE (for ANDAs) studies should be conducted in certain circumstances

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• CDER Guidance for Industry. Food-Effect Bioavailability and Fed Bioequivalence Studies, December 2002.

• CDER Guidance for Industry, Individual Product Bioequivalence Recommendations.

• Davit BM & Conner DP. Food Effects on Drug Bioavailability.

• U.S. Department of Health and Human services• Food and Drug Administration

REFERENCE

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