Clinical Research on fast vs. fed states affecting the PK and PD parameters of medicationsDaniel LeUNMC College of Pharmacy

Objectives• Why is research important for fed vs. fast ?• FDA’s guidance on designing fed vs. fast clinical research• Sprinkling medication on food and liquid formulation

differences• Results of past research that have looked at fed vs. fast drug

efficacy • What members of allied health can do for their patients

Why Do Research?• Everyone Eats• Most people take

medications • Medications need to be

within target range to have efficacy and to avoid/reduce possible side effects

• Therefore food effecting medication is an important situation to look over

• Team work for allied health professionals

So Many Medications!!!!• With so many medications on

the market and also many that are currently in clinical research

• Its important we are aware of the situation, and although its not possible to memorize every single medication, we must know how to look up the information

• Aware that there have been pass research that has look at the topic !

Recommendations on Designing Fed-Fast Studies by FDA

• General Design• Subject Selection• Dosage Strength• Test Meal• Administration• Sample Collection• Data Analysis

Design• Randomized• Balanced• Single dose• Two Treatments (fed

vs. fast)• Two periods of drug

administration • Make sure that all

food is wash out before 2nd period

Subject Selection• Volunteers should be

healthy and drawn from the general population

• Co-Morbidities often would interfere with results

• Larger numbers of participants is recommended to have good statics credibility

• Minimum of 12 subjects is recommended to compete the food-effect studies

Dosage

• Highest strength of a drug in the market is preferred to test the food effect• Unless clinical safety is a

concern and then lower dose should be used• If previous studies have been

done on the highest dose, it can also be possible to test a smaller dose to see how food effects the smaller dose

Test Meal• High in Fat (50% of total calories of

the meal)• High in Calories ( 800-1000 calories)• Balance in protein(150), fat (500-

600), and carbohydrates(250) • The breakdown of the calories

between protein, fat, carb and total calories should always be in the study report

• Reason: have the greater effect on GI physiology

• If for whatever reason the meal test has a different caloric breakdown then what is mentioned above, scientific rational for why that is

Test Meal (2)• Reason: have the greater

effect on GI physiology • Smaller meals will not show

much difference between the fast-fed states and therefore not accurate to compare

• If for whatever reason the meal test has a different caloric breakdown then what is mentioned above, scientific rational for why that is

Administration

Fasted Treatment

• Overnight fast for 10 hours• 240 ml of fluids• No food for 4 hours after

the dose• Water is allowed except

one hour before and one hour after

Fed Treatment• Overnight fast for 10 hours

then start recommended 30 minutes before drug admin

• Eat the meal in 30 minutes• 240 ml of water• No food for four hours after

the dose• Water is allowed except one

hour before and one hour after

Sample Collection• Plasma is ideal• Make sure the time

and intervals that blood is drawn is the in both fed and fast are documented• Analysis blood for any

other disease that are unknown that might have an effect on drug

Sample Collection (2)

• Food can have an effect on the time course of plasma drug concentrations • Therefore it is

acceptable that fasted and fed treatments can have different sample collection times

Data Analysis• Total Exposure (AUC)• Peak Exposure (Cmax)• Time to peak

exposure (Tmax)• Half-Life

( elimination)• For modified-release

products also include lag-time

Sprinkles• Controlled release Capsules• Can be sprinkled on soft

foods• Additional studies should be

done with intact capsules on both fed and fast patients

• Documented that there was no differences in efficacy between sprinkling the the beads onto foods vs. swallowing a intact capsule

Liquid Formulations • Liquid medications when

mixed with a beverage before administration can change the BA

• Always test the solution that is intended to mix the medication with

• Document the liquid that was mixed and provide evidence that it did not have an effect on the medication.

Examples Articles of Research

Where ?• Many articles from both

humans and animals• All the articles

mentioned will be based on human studies• Have been studied for

many years• Many different parts of

the world.

Alacepril• Research done in Fukuoka, Japan• 1985 • ACE- inhibitor use to treat hypertension• Shows that this has been an important topic and is concern to

people for many years• Alacepril converts to Captopril

Alacepril

• Fed state delayed the tmax of free captopril, but not significantly • AUC was unchanged• Fed states increases free

captopril in blood, perhaps its because its converted from Alacepril after absorption• Fed-Fast did not sign. role

Omeprazole • According to prescribing

information drug is to be taken 30 minutes prior to a meal

• Two formulas tested Ompranyt & Mopral

• Both formulas when taken on a high fat diet reduces Cmax and AUC

• Shows that drug should be taken as directed on a empty stomach

Pantoprazole• Two-Single dose, open label,

7 days apart (washout period) randomized between 2 groups of fed or fast

• Fed State increases the Tmax• Fed State has more variability

(erratic absorption)• Fed state also takes longer to

be detected in the blood• Similar to Omeprazole should

take as directed, 30 minutes before meal

Clopidogrel• Drug vs placebo and then

the drug between fast-fed states• Fed vs. fast shows no

difference in antiplatlet response ( Pharmacodynamics)• Half-life, Tmax, Cmax, AUC

all did not have significant difference (Pharmacokinetic) • Can be taken with or

without food !

Cefalexin• Beta-lactam antibiotic• 2012 in Xijing, China• Study was done on healthy

males to determine the effect that food has on the drug

• Two groups one group had a 8 h fast period, while the other was postprandial

• Drugs given to both groups at 8am and 8pm daily

• Half-life and Cmax both increased at 8pm compared to 8am in the fed patients, while it stayed the same in the fasting patients

Cefalexin Results• Often we recommend

antibiotics to be taken with food ! • Often antibiotics will

cause GI upset• Tough situation ! • Balance between side

effects or the efficacy of the antibiotic

Abacavir• Medication used to

treat HIV• Was tested to see if

the generic would be just as equally effective as other products• Research also looked

at fed-fast and see if it had a role

Abacavir

• Results shows that the generic is equally effective

• Fed-Fast did not have an effect on the efficacy of the drug

• Examples shows that generic vs. name brand products, food effect is also a concern !

• Therefore should always be tested before it can be considered AB equivalent

Conclusion• Varies according to the type

of medication, some types of medication will be more effected than others

• Co-Morbidities will play a role in the effect of the food and how it can effect drug efficacy

• Most of the studies have the fed group eat food high in calories and in fat

• Which shows that the type of food we eat matters

Importance

• We can inform patients on what medications can they take on empty stomach• If medications do get

effected on full stomach patients can determine when would be the best time to take medications• Keep patients healthy since

we are keeping their medications within the therapeutic window

Importance (2)• From the different results that

the articles provided we can see there was variation

• Its important as members of the allied health to understand to the extent which medications have are effected by food

• In clinical research it would determine how the studies are designed based on the drug being tested

• We in any setting it will be important to know what resources we can use to have a more clear understanding of food and its effect on medications

What to take away?• Why research is

important?• Be aware of variation

that results has shown • To understand that

there are resources available• At times we must use

our clinical skills to make appropriate recommendations

References • Hurbin F., Boulenc X., Daskalakis N., Farenc C., Taylor T., Bonneau D., LaCreta, F., Cheng, S. & Sultan E.

(2012). Clopidogrel pharmacodynamics and pharmacokinetics in the fed and fasted state: A randomized crossover study of healthy men. Journal of Clinical Pharmacology, 52(10), 1506-1515.

• Vaz-da-Silva M., Loureiro A.I., Nunes T., Maia J., Tavares S., Falcao A., Silveira, P., Almeida, L. & Soares-da-Silva P. (2005). Bioavailability and bioequivalence of two enteric-coated formulations of omeprazole in fasting and fed conditions. Clinical Drug Investigation, 25(6), 391-399.

• Ding Y., Jia Y.Y., Liu W.X., Lu C.T., Zhu Y.R., Yang J., Ding L.K., Yang L. & Wen A.D. (2012). Chronokinetic study of cefalexin in postprandial and fasting volunteers. Biological Rhythm Research, 43(5), 505-513.

• Onoyama K., Hirakata H.,Tsuruda H. Ohchi, N. Tomooka, S., Motomura, K., Omae, T., Hayashi, K. & Fujishima, M. (1985). Pharmacokinetics of a new angiotensin I converting enzyme inhibitor (alacepril) after oral dosing in fasting or fed states. Clinical Pharmacology and Therapeutics, 38(4), 462-468.

• Rossi de Campos D., Viera N.R, Bernasconi G., Proenca Barros F.A., Meurer E.C., Marchioretto M.A., Coelho E.C., Calafatti S.A., Sommer C., Moreira Couto J., Buranello S. Cristino Silva A.R., Amarante A.R., Abib E., & Pedrazzoli J. (2007). Bioequivalence of Two Enteric Coated Formulations of Pantoprazole in Healthy Volunteers under Fasting and Fed Conditions. Arzneimittel-Forschung(Drug Research). 57(6) 309-14

• Marier J.F., Borges M., Plante G., DiMarco M., Morelli G., Tippabhotla S.K., Vijan, T., Singla, A. K. Garg M. & Monif T. (2006). Bioequivalence of abacavir generic and innovator formulations under fasting and fed conditions. International Journal of Clinical Pharmacology and Therapeutics, 44(6), 284-291.

• FDA Guidance for Industry, Food-Effect Bioavailability and Fed Bioequivalence Studies