Webinar revisiting food drug interactions

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Revisiting Food-Drug interactionsusingthe ADME/DDI database®
19/04/2011
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AurSCOPE ADME/DDI Knowledge Base March 2011

Food-drug, drug-dietary supplement, drug-citrus fruit interactions
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Dietary supplement
- St John’s Wort
- Echinacea
- Ginkgo biloba
Food
- High fat meal
- Standard meal
- Other meal
drug
Fruitjuice
- Grapefruit juice
- Other fruitjuice

Food-drug, drug-dietary supplement, drug-juice interactions extracted from Aureus ADME/DDI database
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Drug
Food
Juice
Dietary
AUC ratio <0.5
AUC ratio >2

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Food-drug, drug-dietary supplement, drug-juice interactions extracted from Aureus ADME/DDI database
Drug
Food
Juice
Dietary
AUC ratio <0.5
AUC ratio >2

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Food-drug interactions

Drug regulatory agencies recommendations
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Effect of food intake:
- Assessment of the effect of food on the rate and extent of absorption of a drug
- Ensure optimal dosing recommendations in the phase II and III clinical studies
1- Standardized high-fat meal
High-fat meal : worst case scenario of interaction
800-1000 kcal
150, 250 and 500 calories from protein, carbohydrate and fat respectively
Composition : 2 eggs fried in butter, 2 strips of bacon, 2 slices of toast with butter,
120 mL hash brown potatoes and 240 mL whole milk
2- Lighter meal
for drug administrated with food

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Drug regulatory agencies recommendations
Procedure for food interaction studies:
- Fasted 10h
- Meal consumed in 30 min or less
- Drug with 240 mL water at +30min
Analysis: AUC, Cmax, Tmax , t1/2el …
90 percent CI (CL-90) in the equivalence limits of 80-125 percent for AUC
and Cmax
 Specific recommendation on the clinical significance if outside the limits.
(1) Guidance for Industry: Food-effect bioavalaibility and fed bioequivallence studies (2002)
(2) Guideline on the Investigation of Drug Interactions (2010)

Aureus ADME/DDI® Knowledgebase Query
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 To compare AUC ratio between drugs we focus on “High-Fat meal” interaction

Food interaction: Change in the extent of absorption (AUC) from Aureus ADME/DDI
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149 drugs

Food effect mechanism
Clinically relevant food-drug interactions are generally caused by food-induced
change in the Bioavailability of the drug
 Important pharmacokinetic effect
Delay gastric emptying
Stimulate blood flow
Change gastrointestinal pH
Increase splanchnic blood flow
Change luminal metabolism of a drug
Physically or chemically interact with a dosage form or a drug substance
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Biopharmaceutical Classification System (BCS)
BCS
Fundamental parameters controlling the rate and extent of oral absorption :
Solubility
Gastrointestinal permeability
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High permeability: absorption >90%
High solubility: soluble in 250 mL
of aqueous media (pH 1-7.5)
from Wu and Benet, Pharm. Res. vol.22 p.11

Biopharmaceutical Classification System (BCS)
from Wu and Benet, Pharm. Res. vol.22 p.11

Assessment: transporters inhibition as the primary mechanism of food effect
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High-fat meal effect
- Increase solubility and
efflux transporter inhibition
( Fextent)
- Delay gastric emptying
( Tmax, Cmax)
( Tmax, Cmax)
- Influx transporter inhibition
( Fextent)
( Tmax, Cmax)
- Increase solubility
- Efflux and influx
transporter inhibition

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Food-dietarysupplement interactions

Drug-dietary supplement interactions
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Dietary supplements:
What is a dietary supplement ?
Vitamin
Mineral
Herb or botanical
Amino acid
Enzymes or tissues from organ or gland (to supplement diet)
Concentrate, metabolite, constituent
from FDA:
http://www.fda.gov/food/dietarysupplements/consumerinformation/ucm110417.htm

Drug-dietary supplement interactions
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Dietary supplements with potential pharmacokinetic interactions
1- St John’s wort
 use for depression
Chronic administration induces CYP3A and P-gp
 Consequently can alter the PK of CYP3A and P-gp substrates.
2- Ginkgo biloba
 use for memory improvement
Inducer of CYP2C19
Inhibitor of P-gp and or CYP3A4 ??

ADME/DDI®Knowledgebase Query
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Drug - St John’s wortinteractions from Aureus ADME/DDI
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30 drugs

Drug - Ginkgo bilobainteractions from Aureus ADME/DDI
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10 drugs

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Grapefruit juice interactions

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Aureus ADME/DDI® Knowledgebase Query

Drug – grapefruit juice interactions from Aureus ADME/DDI
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61 drugs

Grapefruit juice interaction mechanism
Significant clinically interactions  Important pharmacokinetic effect
CYP3A4 inhibition in the small intestine
Pgp inhibition
OATP inhibition (> Pgp inhibition)
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Active components in grapefruit juice
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Flavonoids
Naringin
% Inhibition OATP2B1 = 39% (at 10µM) (1)
% Inhibition CYP3A4 = 6% (at 100µM) (2)
% Inhibition OATP2B1 = 28% (at 10µM) (1)
IC50 CYP3A4 = 87 µM (3)
Naringenin
(1) Satoh et al. Drug Metab Dispos (2005) 33:518
(2) Ho et al. J Pharm Pharm Sci (2001) 4:217
(3) Haehner et al. Arzneimittelforschung (2004) 54:78

Active components in grapefruit juice
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Furanocoumarin
Bergamottin
Ki 3A4 (HIM) = 13.3 µM (4)
KI (HIM) = 23.5 µM
Kinact (HIM) = 0.36 min-1 (4)
6’,7’-Dihydroxybergamottin
Ki 3A4 (HIM) = 3.5 µM (4)
KI (HIM) = 3.5 µM
Kinact (HIM) = 0.31 min-1 (4)
(4) Paine et al. Drug Metab Dispos (2004) 32:1146

Mechanism of grapefruit juice interactions
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BLOOD
_
CYP3A4
intestinal epithelium
GFJ
_
OATP
Pgp
_
GFJ
drug
LUMEN

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CYP3A4 substrates

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OATP and Pgp substrates
celiprolol
talinolol
fexofenadine

AfterthisWebinar
An individual account will be created for each of you on www.aureus-sciences.com
It is unique in offering access to editorial content, Aureus data & applications and community networks.
Your new account will allow you to access our data and our tools including Food-Drug Interaction through AurQUESTfor free during 2 days.
19/04/2011
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Food-Drug Interactions Webinar

Special Offer for this Webinar
After the 2 free-trial days, we offer a special Access through the web during 1 year to data related to:
Metabolism
PK (Pharmacokinetics)
Drug-Drug interactions
Food Drug interactions
Our Offer: 5 000 €, one user, 12 months.
19/04/2011
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Food-Drug Interactions Webinar

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Webinar revisiting food drug interactions

by Aureus Sciences on Apr 20, 2011

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