'One Size Fits All' Drug Dosing Gives Suboptimal Results

Roxanne Nelson

April 30, 2013

WASHINGTON, DC — A number of drugs that show promise in early trials end up failing in late-stage studies. Is it possible that patients are just be receiving the wrong dose?

Steve Gullans, PhD, managing director at Excel Medical Ventures in Boston, Massachusetts, believes that could often be the case. In a presentation given here at TEDMED 2013, he pointed out that although drugs play a vital role in medical care, many patients receive inappropriate doses. As a result, they end up with less than optimal results.

In fact, outcomes can be quite detrimental if patients are overdosed or underdosed, he noted.

Dr. Steve Gullans

As an opening anecdote, Dr. Gullans recounted a story of his father calling the police at 3 AM to report the presence of a very large snake in the living room. It turned out that his father was hallucinating as a result of medication he was taking to treat Parkinson's disease.

"His dose was lowered, the snake disappeared, and he had significant relief of symptoms, but this is not always true for everyone," he explained.

Problems of Inappropriate Dosing

Millions of people take a variety of drugs every day, but not everyone benefits. In cancer, only about 30% of patients benefit from a specific drug; 70% are be deemed to be nonresponders.

"Why are so many of us nonresponders?" Dr. Gullans asked. Disease complexity is partially responsible, but it is also clear that many patients are not receiving sufficient doses, he explained.

The problem of inappropriate dosing, either too high or too low, is being increasingly reported in the medical literature. In one study (Clin Colorectal Cancer. 2012;11:263-267), researchers compared the efficacy and safety of a pharmacokinetic-guided 5-fluorouracil dose adjustment with the standard body-surface-area dosing in a FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin) regimen in patients with metastatic colorectal cancer.

With pharmacokinetic-guided dose adjustment, the objective response rate was 69.7%, median overall survival was 28 months, and median progression-free survival was 16 months. With standard dosing, the objective response rate was 46%, median overall survival was 22 months, and median progression-free survival was 10 months.

In another study, 85% of patients with rheumatoid arthritis had suboptimal blood levels of methotrexate, Dr. Gullans said. "There was a lot of pain for no reason."

"Drug levels can vary among patients — 5-, 10-, or even 30-fold — even after adjustment for body size," he continued. "Imatinib [Gleevec, Novartis] levels were found to vary 17-fold across patients, and outcomes correlated with dose."

A number of factors will cause a variation in blood levels, including genetics, metabolism, age, sex, diet, weight, liver function, time of day, and drug–drug interaction. "It is impossible to take all of these factors into account when dosing patients," said Dr. Gullans.

Goldilocks Window

The goal of optimal dosing is to find the right therapeutic window — with too much drug, there are adverse effects; with too little, the results are less than satisfactory. "Having it just right works out great; I call this the Goldilocks window," he noted. "Because of human variation, not everyone falls into this window. While drug levels are often adjusted to get into the right range, based on lack of response or high toxicity, most drug levels are never measured."

In the case of chemotherapeutic agents, where toxicity is a significant concern, "we tend to err on the side of safety; as result patients, may be underdosed," Dr. Gullans explained, and could become nonresponders.

The Goldilocks protocol for measuring and adjusting doses is not new. "It is already used for a handful of drugs, so why not for many more?" he asked. "We have the technology, we already use it on athletes for performance-enhancing drugs, so why not use it with cancer patients?"

Appropriate dosing could also play a major role in clinical trials, where drug levels that appear to be effective and cause the least toxicity are used, but this is not going to produce the desired results for all patients. "Is it any surprise that many drugs fail in late-stage trials if you're not measuring levels in patients?" he asked.

Dr. Gullans explained that although an effort is made to avoid toxicity, the clinical trial process is generally not geared to individualizing doses. "They prefer a simple protocol, and measuring up to toxicity is the usual way of doing it," he said. "The new targeted drugs are less toxic, so there is often no apparent toxicity, such as with imatinib."

He added that levels are routinely measured in certain classes of drugs, such as antibiotics, in phase 1 trials. "What is needed is an interest in measuring levels in patients to make sure they are getting the right dose."

"As a patient, wouldn't you prefer to have a truly personalized dosing? Wouldn't you like to be like Goldilocks and have it just right?" he concluded.

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