Importance of Study Restriction: Food/Beverage Drug Interaction Part 2

In Part 1, we have mentioned that drug interaction is a significant concern in designing clinical trials, especially those focusing on pharmacokinetic endpoints. The interaction could be both expected or unexpected, which may arise from the prescribed treatment regimen and emerging therapy for side effects. Drug-drug interaction is a wide topic but it is relatively easier to spot and place a strategic exclusion criterion or a restriction.

However, the participants’ lifestyle or dietary choices can also lead to a significant impact on the study outcome. It may impact the clinical results or even pose risks similar to drug-drug interaction, however, these food-drug interactions have usually been neglected. Proactive identification of potential food-drug interactions and the establishment of appropriate study restriction protocols during protocol development can standardize procedures, enhance participant compliance, and safeguard the integrity of data.

This blog continues exploring the common study restrictions and targets on the food/beverage-drug interactions which should be considered to be included as a restriction in protocols, alongside BioPharma Services (BPSI) recommendations best practice for such cases.

Refer to Table 1 for the summary of Food/Beverage-Drug interaction discussed in this blog.

Table 1: Common food-drug interactions and study restrictions

1. CYP1A2 inhibitor

1.1. Mechanism

During breakfast or any time of the day, people will consume tea or coffee to assist them in staying focused or as a habit to start their day. These beverages contain a variety of bioactive compounds, especially methylxanthines and polyphenols. Similarly, chocolate or energy drinks, the daily indulgences for many, also contain significant levels of these compounds.

In humans, methylxanthines, of which caffeine is the primary one, are competitive substrates for CYP1A2 meaning they will compete with other CYP1A2 substrates for this metabolism pathway. If the investigation product (IP) is also a substrate of CYP1A2, a restriction on beverages and food that contains methylxanthines and caffeine is recommended.

1.2. Example

A case of a 19-year-old, nonsmoking, white woman who had an elevation of clozapine and its primary metabolites in serum concentration due to an excessive amount of Coca-Cola drink with an amount of 6 glasses of cola per day was reported in 2012. The elevation was resolved shortly after the discontinuation of the cola consumption. From this example, it is suggested that any form of caffeine or methylxanthine-containing beverages could cause a beverage-drug interaction. The interaction could pose a risk to the study participants.

Another example is zolpidem, where caffeine co-administered with zolpidem will lead to an increase in Cmax and AUC of zolpidem by 30 – 40%. Additionally, caffeine could affect the sedative effect of zolpidem. If the IP is zolpidem, the consumption of caffeinated products may significantly affect the study outcome depending on the objective of the clinical study.

1.3. Restriction recommendation

A recommended restriction of about 48 hours prior to dosing is considered sufficient, given that the average half-life of caffeine/methylxanthine is about 4 to 6 hours.  

Consideration should be given to both the amount of caffeine consumed and the duration before dosing when evaluating this restriction for food-drug interactions.

2. CYP3A inhibitor

2.1. Mechanism

Apart from methylxanthines or caffeine-containing beverages, fruits can cause significant food-drug interaction as well. In specific, fruits contain a wide range and diverse bioactive compounds like flavonoids, carotenoids, and vitamins which makes the food-drug interactions caused by fruits often more complicated than drug-drug interactions.

Most citrus juices will affect the pharmacokinetics of a drug whereas grapefruit is generally the worst as it causes notable CYP3A4 inhibition. The mechanism behind such food-drug interactions is mostly related to phytochemicals in the fruits interacting with the activity of different CYPs or even drug transporters.

2.2. Example

Grapefruit juice can reduce the level of CYP3A4 by 47% within 4 hours after consumption (250mL or a whole grapefruit at once) and the effect can be persistent in intestinal and liver cells for at least 24 hours after ingestion. Indeed, grapefruit juice can lead to a possible food-drug interaction or alter the metabolism of CYP3A4 substrate for a longer duration with a single consumption. Take tacrolimus as an example, a delayed increase in Cmax from 4.7ng/mL to 47.4ng/mL was reported after one week of the last grapefruit juice intake (250mL, 4 times a day for 3 days). The patient developed a severe headache with nausea, fortunately without nephrotoxicity. For more examples, please refer to Table 2.

Table 2: Some of the common fruit juices and the mechanism of interaction

2.3. Restriction recommendation

When considering the restrictions for fruit and fruit juices related to CYP3A4 metabolism, especially grapefruit, and pomelo, a time frame of at least 7 – 10 days is highly recommended as the extent of inhibition and recovery depends on each individual. This restriction should always be considered in the clinical study protocol due to the common presence of citrus in daily diet, to protect the participants from unwanted food-drug interactions that risk their safety and study outcome.

3. Dietary tyramine

3.1. Mechanism

Monoamine oxidase inhibitor (MAOI) inhibits the monoamine oxidase enzyme which is used for the breakdown of tyramine – a catecholamine-releasing agent. The excess tyramine will lead to overstimulation of postsynaptic adrenergic receptors. With as little as 8 to 10 mg of tyramine consumption associated with the use of MAOI could cause life-threatening blood pressure elevation due to excessive norepinephrine release.

3.2. Examples

A case of a 34-year-old patient without any other history of hypertension, nor other neurological or cardiac symptoms has developed a hypertensive crisis after ingestion of cheese approximately 3 hours after a dose of phenelzine, a monoamine oxidase inhibitor (MAOI), was reported in 2010. The patient developed chest pain, breathlessness, and severe headache within 1 to 2 hours after the consumption. The patient then went to the hospital with blood pressure at 176/80 mmHg and was hospitalized for 3 days. The results of the diagnosis proved the hypertensive crisis was a tyramine-induced MAOI reaction with a baseline blood pressure of the patient was 99/60 mmHg prior to discharge. It demonstrated there was a significant change in systolic and diastolic blood pressure when having high tyramine food with the use of MAOI. 

In general, a meal containing about 40mg of tyramine is considered a high-tyramine diet. Aged cheeses and meats are significant sources of tyramines. In addition, fruit juices not only impact cytochrome P450 enzymes and transporters but also contain high levels of biogenic amines, particularly tyramine. Plum and avocado juices, for instance, are notable sources of tyramine, which, co-administration with MAOIs can potentially retain tyramine and cause a hypertensive crisis.5 There are more examples in Table 3 which shows tyramine-containing food and the amount that is equivalent to 150 mg of tyramine.

Table 3: Food contained tyramine and the amount equivalent to 150mg

3.3. Restriction recommendation

The reported half-life of tyramine ranged from 0.50 – 1.00h and a normal unmedicated person should have a high tolerance towards tyramine (~400mg before elevating blood pressure). Thus, in most cases, a restriction on food with high tyramine content may not be required unless the IP is a MAOI, then having a restriction on food with high tyramine content 24 hours before dosing of the MAOI drug should be sufficient.

Why Choose  BioPharma services for your Next Drug Development Project?

Not only are drug-drug interactions common in clinical trials, but dietary and lifestyle considerations could also beconcerns. The above are the most general and common restrictions with respect to food/beverage drug interaction that could be considered during the study design depending on various situations, the drug class, and the mechanism of actions of your investigational product.

In summary, study restrictions are crucial and not only serve to standardize the lifestyle and diet of the study participants but also enhance participant compliance to provide reliable and repeatable study observation and data. Additionally, they play an important role in protecting the subjects’ safety by mitigating the risk associated with any potential interactions with the investigational product.

With our extensive experience in bioanalysis, we can accurately evaluate and predict potential drug-drug and food-drug interactions, applying the necessary restrictions to safeguard your clinical trials and ensure reliable outcomes. Our team is equipped with the knowledge and experience to evaluate and predict possible drug-drug and food-drug interactions and, thus, to apply applicable restriction or exclusion criteria.

With our expertise in pharmacokinetics and a thorough understanding of regulatory requirements, we can navigate you through the obstacles during drug development, ensuring your product meets the expected safety and efficacy requirements.

Written by: Wu Pak (Anson) Kwan, Pharmacokinetic Associate.