Bioequivalence and Bioavailability Forum

Dear Kaushik!

❝ My question is most of the protocol says to abstain xanthine foods …

Xanthine? Stupid protocols. See the commentary document, p.69:

• Comment:
  Food and beverages do not contain xanthine, only methylxanthines, namely 1,3,7-tri­me­thyl­xan­thine (caffeine: coffee, tea, cola, energy drinks), 3,7-dimethylxanthine (theobromine: cocoa, cho­colate), and 1,3-dimethylxanthine (theophylline: traces in tea). The term xanthines for the methy­lated derivatives of xanthine – although sloppily used – is unknown in biochemistry.
  
• Response:
  Noted. We have also changed the text to a less strict version. There is no longer a requirement to abstain from xanthine containing products.

Many (most?) people are used to tea/coffee. Withdrawal might increase the rate of volunteers experi­encing AEs (headaches or even migraine) up to 30%. If interactions are unlikely (see below) nothing speaks against a decent cup of coffee/tea in the morning.

❝ & grape fruits, but the confinement of the study will be for 12.00hrs before & 24.00 hrs after drug administration, will this doesn't impact on the pk profile?

In a cross-over it should not substantially matter. Interactions with methylxantines are only likely if the drug is mainly metabolized by CYP450 1A2. Concerning grapefruit juice check whether the drug is metabolized by CYP450 3A4.

❝ what is the elimination time for xanthine

Xanthine: No idea, but irrelevant.
Caffeine: ~5 hours
Theobromine: ~7 hours
Theophylline: ~6 hours (irrelevant)

❝ and grape fruits?

The maximum observed GIT-passage time was 72 hours – that’s were AUC₇₂ comes from. .
Interactions are caused by naringin, bergamottin, and 6’,7’-dihydroxybergamottin. Half-life: no idea. Recovery of the CYP450 3A4 system after a single dose of grapefruit juice was reported with ~three days.* Might be important in a parallel study.

❝ how to ensure that the subjects hasn't consumed the above foods before participation in a trial.

Ensure? Difficult ⇒ impossible. Only if necessary (known interactions & parallel design): Check the baggage (embarrassing: state in the ICF), go for three days of hospitalization.

Note that there’s a lot of stuff which can interact as well. Examples are other fruits of the citrus genus (especially bitter oranges), apple juice, avocado, members of the brassicaceae family (broccoli, cabbage, cauliflower, horseradish, …), soja, garlic, ginger, and some natural remedies like St John’s wort, gin­seng, Ginkgo biloba, …
That’s why the European GL contains a more general statement:

The subjects should abstain from food and drinks, which may interact with circulatory, gastro­intestinal, hepatic or renal function (e.g. alcoholic drinks or certain fruit juices such as grape­fruit juice) during a suitable period before and during the study. Subjects should not take any other concomitant medication (including herbal remedies) for an appropriate interval before as well as during the study.

It’s up to you to justify what you plan to do. Better to check the literature instead of copypasting protocols unquestioned.

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• Greenblatt DJ, von Moltke LL, Harmatz JS, Chen G, Weemhoff JL, Jen C, Kelley CJ, LeDuc­ BW, Zinny MA. Time course of recovery of cytochrome P450 3A function after single doses of grapefruit juice.
  Clin Pharm Ther. 2003; 74(2): 121–9. doi:10.1016/S0009-9236(03)00118-8.