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New Cancer Drug Study Determines Dose Based on Genotype for Metabolizing Enzyme

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A new clinical study points to a use of pharmacogenomics that could increase in the future: tailoring the dose of a drug to a patient’s drug metabolism, based on the patients’ genotype for certain metabolizing enzymes.

“There is the ability now to optimize and personalize the dose based on an understanding of a patient’s genetic background,” said Dennis Brown, president and CEO of ChemGenex Therapeutics, a Menlo Park, Calif., cancer biopharma company involved in this study.

The study was a Phase I/II clinical trial of the drug, a topoisomerase II inhibitor called Quinamed (Amonafide), presented at last week’s Annual Meeting of the American Society of Clinical Oncology by researchers from the University of Texas Health Science Center in San Antonio; the Sarah Cannon Cancer Center in Nashville; the University of Louisville; and ChemGenex.

In the Phase I part of the study, patients with solid tumors — including ovarian, prostate, breast, and colon — received the drug at two different doses. The researchers also determined each patient’s genotype for the N-acetyltransferase 2 gene, or NAT2, which encodes an enzyme that converts Quinamed to a metabolite that is still active but also responsible for a toxic side effect.

Slow acetylators, where NAT2 is less active, tolerated a higher dose of the drug than intermediate or rapid acetylators, where the enzyme is more active.

David Hein, a professor of pharmacology and toxicology at the University of Louisville, and colleagues performed a genotyping analysis, to correlate patients’ NAT2 genotype with their Quinamed acetylation. They analyzed seven single nucleotide polymorphisms in the NAT2 gene using Applied Biosystems’ Taqman technology.

Based on these results, the researchers started adjusting the dose for further patients they enrolled in the study — a total of 32 — according to their genotype.

At present, the scientists are starting to enroll patients for the Phase II portion of the trial, which will focus on antitumor activity in a subset of tumor types using recommended doses based on their NAT2 genotype.

Although this is not the first study that correlates a genotype of a metabolizing enzyme and the effect of a drug, according to Hein, the study is “another good example” of how genotyping can be used to determine who should receive a drug at what dose.

Pharmaceutical companies have been trying to anticipate drug toxicity early in the research process, studying, for example, expression of signature genes in cell lines and animals.

However, many drugs still turn out to be toxic in a certain percentage of people, Hein said, which can compromise their further development. “That’s tragic for pharmaceutical companies … and it’s tragic for patients, since [the drug] is very effective in most people,” he said. Being able to identify ahead of time those patients where the drug is toxic — based on their individual drug metabolism — would solve this problem.

Makers of genotyping equipment agree that using pharmacogenomics studies in early stages of clinical trials, where a safe dose is determined, might become more important. “We think it’s an emerging trend and something that is going to make a huge difference in the ability to get labels correct on drugs,” said Jay Flatley, president and CEO of Illumina. “Up until now, everyone has taken a universal dose, which in some ways is responsible for adverse events in people who [received] too much … and lack of efficacy in people who have had too little.”

— JK

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