Dose – Only a Piece of the Puzzle

This week I put together a summary of some data from our ongoing clinical trial along with an explanation of significance to send out as an update to our shareholders. Communicating very technical information to audiences of varied backgrounds in a way that resonates has been one of the many challenging yet rewarding aspects of my job. Although I can’t share our data at this point, the general topic is relevant to all drug development programs and (as was pointed out to me) those who find themselves in the position of patient.

Context for the Update

At Quintessence, we are in the midst of an oncology Phase I clinical trial, which primarily involves increasing the dose of our drug from low levels to higher levels while monitoring and managing side effects. As a result, potential partners, shareholders and colleagues often ask what dose level we’re currently using to treat patients. The answer is straightforward but, particularly as the trial has progressed, not very fulfilling for me to give. The reason is that dose is just the first step in answering the question: Can you give enough drug to patients to see benefit?

There are two sets of information that take the next steps in addressing this question in a first in human trial.

  • What are the pharmacokinetics (PK, often referred to as exposure) of the drug in this trial?
  • Are drug levels in humans similar to the levels needed to see efficacy/benefit in model systems?

I had to pull our data, but below is a straightforward look at the significance of understanding exposure.

On Dose and Exposure

Dose is a straightforward way to refer to how much drug is given to a patient. However, the dose is not the only factor that contributes to how much drug a patient is actually exposed to.  The same dose of drug may result in different exposure levels in the same person on different days and/or in different patients. There are a variety of common examples and two are provided.

For many calcium channel blockers (used to treat high blood pressure), the addition of grapefruit juice to a patient’s diet can increase the amount of the drug in the patient’s bloodstream. Grapefruit juice can have the opposite effect for other drugs, such as the cancer drug etoposide. In this case, a cancer patient might take a dose of drug shown to have benefit but the amount of drug in their body may be too low.

Some differences between patients can be traced to their genes. Some individuals have subtle changes in their genetic codes that alter the way their body breaks down drugs. The most common of these differences is in a family of proteins called the cytochrome P450 enzymes (CYP450). The dose of certain drugs, such as the cancer drug tamoxifen, may be modified based on genetic testing to determine how a patient metabolizes (breaks down) such drugs.

For these reasons, understanding the relationship between a dose of a drug and the exposure of the patient to that drug is a key part of a successful drug development program.

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One comment on “Dose – Only a Piece of the Puzzle

  1. biotechbaumer
    February 24, 2012 at 7:01 pm #

    Another interesting caveat to the dose-exposure issue is with regards to developing ‘isoform-selective’ drugs. It’s tough but doable to do this…at least in vitro. But if your exposure is too high in vivo, you’ll lose all your selectivity!

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