current methods for the prediction of food effect on drug absorption

1. Under the guidance of:
Dr. Saranjit Singh
Professor and Head
Presented by:
Sandeep Kumar
M.S. (Pharm.) Semester - I
Department of Pharmaceutical Analysis
National Institute of Pharmaceutical Education and Research (NIPER)
Sector-67, S.A.S. Nagar, Punjab-160 062
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3. Food effect-why to study?
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 Can cause an ADR
 Efficacy of a drug may be effected
 We do not want a drug to fail in drug
development stage
 Potential safety or efficacy concerns
with food are determined during early
discovery stages
https://www.nature.com/articles/nrd805/figures/2

4. Food drug interaction
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And many
more…..
https://pharmalinkjo.com/en/Gallery/85

5. Food drug interaction
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Effect of absorption interactions on drug plasma
concentration profiles-
(a) accelerated absorption
(b) delayed absorption
(c) decreased absorption
(d) increased absorption
Effect of food on drug absorption may be
Positive Negative Neutral
Parrott et al ,The AAPS Journal 11 45-53. (2009)

6. Food-drug interaction
Food effect =
AUCFed
AUCFasted
or
Cmax(Fed
Cmax(Fasted
Food Effect AUCR or CmaxR
Positive >1.25
Negative <0.8
Neutral (Absence) 0.8-1.25
Parrott et al ,The AAPS Journal 11 45-53. (2009) 6

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Gastric emptying time and pH
Gastric emptying time and pH increases with food administration
Effect of GI physiology on drug absorption
Improvement of
absorption of poorly
soluble weak acidic drug
e.g. tolbutamide
Decrease in absorption of
poorly soluble weak basic
drugs e.g. ephedrine
Welling ,Journal of Pharmacokinetics and Biopharmaceutics 5 291-334. (1977)

8. Effect of GI physiology on drug absorption
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 Gastric emptying time is an important factor in deciding the fate of
drug
 Gastric emptying is affected by many factors like stomach content
volume, pH, food calorie, osmolarity, viscosity, temperature, and
calcium sequestrant capacity of the food
Welling ,Journal of Pharmacokinetics and Biopharmaceutics 5 291-334. (1977)

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pH change
Effect of GI physiology on drug absorption
 Gastric pH increases when food is administered
 It plays an important role in regulating bioavailability of
a drug
 For poorly soluble weak basic drugs, with increase in
gastric pH solubility of drug decreases
 For poorly soluble weak acidic drugs, absorption
increases due to greater ionisation and prolonged gastric
residence time leading to better dissolution
 But for drugs which are unstable in gastric environment
(e.g. penicillin) increased gastric residence time increases
degradation and reduces bioavailability
Fleisher et al ,Clinical Pharmacokinetics 36 233-254. (1999)

10. Effect of GI physiology on drug absorption
 Lumenal interactions
 Intestinal transit, biliary and pancreatic secretions
 Meal effects on drug diffusivity
 Splanchnic blood flow
 Carriers and membrane bound enzymes
Other factors influencing drug absorption
Charman et al,Journal of Pharmaceutical Sciences 86 269-282. (1997) 10

11. Predicting food effects via application of BCS
 Biopharmaceutical classification system (BCS) is an
experimental model that measures permeability and
solubility under prescribed conditions
 Divided into 4 classes- Class I, Class II, Class III and
Class IV
What is BCS?
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12. Predicting food effects via application of BCS
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• High solubility, high
permeability
• Well absorbed and
least affected by
interactions
• Good candidate for
controlled release
dosage forms
• Low Solubility, high
permeability
• More likely to show
positive food effect due to
increased in vivo solubility
in fed state
• High solubility, low
permeability
• Show negative food
effect particularly if
food interacts with drug
absorption
• Low solubility, low
permeability
• It is difficult to predict
the direction of the
change in AUC
Heimbach et al, The AAPS Journal 15 143-158. (2013)

13. Approaches to predict food effect
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Caco-2 cells
study
Clinical
aspects
In silico
methods
Biorelevant
dissolution methods
Preclinical
aspects
Free fraction of
drug in GI column

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 Animals like dog, rat and monkey are used
 Beagle dogs are the best candidate, because:
 Solid oral dosage forms designed for human can be administered
 Canine food composition are similar to human meals
 Disadvantages: Physiological differences (gastric pH, gastric
emptying, and intestinal transit time) between dog and human can
result in differences in food effect
Preclinical studies
USFDA, Food-Effect Bioavailability and Fed Bioequivalence Studies, 2002

15. Clinical studies
 Conduct randomized, balanced, single-dose, two-treatment (fed vs.
fasting) clinical trial design for studying the effects of food on the
bioavailability of the drug
 Done on a minimum of 12 healthy individuals
 Highest strength of the drug product intended for marketing is tested
 Effect of food on exposure parameters is evaluated
USFDA, Food-Effect Bioavailability and Fed Bioequivalence Studies, 2002 15

16. Biorelevant dissolution method
 Allows a reliable qualitative prediction of food effect on drug
absorption
 Useful for the prediction of in vivo performance of oral dosage forms
 In vitro dissolution media that aims to mimic in vivo GI conditions is
used in this method
 Various biorelevant media used are:- Fasted state simulated gastric
fluid (FaSSGF), Fed state simulated gastric fluid (FeSSGF), Fasted
state simulated intestinal fluid (FaSSIF), Fed state simulated
intestinal fluid (FeSSIF), Simulated colon fluid (SCF)
Wagner et al, European Journal of Pharmaceutics and Biopharmaceutics 82 127-138. (2012) 16

17. Biorelevant dissolution method
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FaSSGF FeSSGF
Composition of media
Wagner et al, European Journal of Pharmaceutics and Biopharmaceutics 82 127-138. (2012

18. Biorelevant dissolution method
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Composition of media
FaSSIF FeSSIF
Wagner et al, European Journal of Pharmaceutics and Biopharmaceutics 82 127-138. (2012

19. Free fraction of drug in GI column
 Bile micelles increase the solubility of lipophilic compounds
 In addition, bile micelles decrease the effective permeability
 Bound fraction is not able to permeate and thus due to decreased
unbound fraction absorption of the drug is decreased
fmono =
Sblank
Sdissolv
Sblank is the solubility in a buffer without bile micelles
Singh et al, Drug Development Research 65 55-75. (2005) 19

20. Caco-2 cells
 Human colon adenocarcinoma (Caco-2) cells used as
in vitro models to evaluate drugs transfer across
intestinal epithelial barrier
 Buffer is taken on the basolateral side in case of
fasted state and in case of fed state biorelevant media
is taken on basolateral side
 Best method to predict intestinal drug absorption
Markopoulos et al, European Journal of Pharmaceutics and Biopharmaceutics 86 438-448. (2014) 20

21. In silico methods
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1. Use of physicochemical properties like
 Aqueous solubility
 Dose/solubility ratio and
 Partition coefficient
2. Physiologically based pharmacokinetic
(PBPK) modelling
 For lower food effect; directly predict with the model
 For higher food effect; verify with clinical data and label for wider use
Singh et al, Drug Development Research 65 55-75. (2005)

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Physicochemical factors such as aqueous solubility, solubility ratio and
logP can be used to qualitatively predict the effect of food.
 Aqueous solubility
 Food effect on clinical pharmacokinetics can be quantitatively
predicted using solubility and in vitro dissolution data
 A strong negative correlation exist between food effect and logarithm
of aqueous solubility which can be observed in the equation given
below:
AUCFed
AUCFasted
= 1.7709 ∗ S−0.0697
In silico methods
Singh et al, Drug Development Research 65 55-75. (2005)

23. In silico methods
 Solubility ratio
 The dose to solubility ratio (SR) is
defined as the calculated value that is
compared to the physiologically
assumed volume of GI fluids
 Positive correlation exists between
food effect and solubility ratio
AUCFed
AUCFasted
= 1.2836 ∗ SR0.0563
 logP
 The partition coefficient (logP) is
considered and indicator of drug
lipophilicity and it correlated well
with intestinal absorption of drugs
 Food causes increase in BA of
lipophilic drug if logP ≥3
AUCFed
AUCFasted
= 0.9048e0.1085(LogP
23Singh et al, Drug Development Research 65 55-75. (2005)

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 PBPK modelling attempts to reflect the complexity of physiology with
mathematical equations which model the processes involved and
integrate drug- and physiology-specific parameter values
 PBPK models combine information of the drug with independent prior
knowledge of the physiology and biology at the organism level to
achieve a mechanistic representation of the drug in biological systems
 It can be used to simulate dynamic pharmacokinetic profiles under
fasted and fed stages and to investigate variability
PBPK modelling to predict food effect
Kuepfer et al, CPT: Pharmacometrics and Systems Pharmacology 5 516-531. (2016)

25. PBPK modelling to predict food effect
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Main changes between Fasted and
Fed state
 Higher stomach volume
 Change in pH (stomach and
upper small intestine)
 Longer gastric emptying
 Higher bile salt concentrations
 Increased liver blood flow
Markopoulos et al,European Journal of Pharmaceutics and Biopharmaceutics 86 438-448. (2014)

26. Fasted vs. Fed state physiology
26Heimbach et al, The AAPS Journal 15 143-158. (2013)

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PBPK modelling to predict food effect
Effect of splanchnic blood flow
 Class I drugs with high extraction ratio (i.e. greater than 0.8);
shows positive food effect due to decrease in presystemic
circulation
 This occurs as a result of increase in splanchnic blood flow leading
to increased blood circulation in portal vein
 Difficult to predict the extent of decrease in presystemic
metabolism using in vitro experiments. e.g. propanolol,
metoprolol, buspirone
Rose et al, The AAPS Journal 19 1205-1217. (2017)

28. Conclusion
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 In vitro models which consider drug solubility and intestinal permeability are useful for
determining if a compound is likely to show a tendency for a food effect in humans
 Dissolution in biorelevant media has been shown to predict fed state pharmacokinetic
profiles for several lipophilic compounds and can allow for the comparison of various
formulations prior to in vivo clinical testing
 One or more methods described herein may be required depending whether the goal is
to determine potential for a food effect, predict the magnitude of change to
pharmacokinetic parameters in the fed/fasted state, or determine whether formulation
efforts have the ability to mitigate food effect

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Thank You !