SAN DIEGO — With the Feb. 19 announcement by the US Food and Drug Administration that the drugs Celebrex and Bextra should remain on the market, data showing that higher doses of Celebrex are associated with increased cardiovascular risk may prove suddenly important to diagnostics companies with a CYP450 test capable of interrogating the 2C9 gene, which is involved in metabolizing both drugs.
The Merck drug Vioxx, which the company voluntarily withdrew from the market in September, is metabolized largely by cytosolic enzymes in the liver, with P450 enzymes playing only a minor role, according to the American Academy of Family Physicians.
In an interview with Pharmacogenomics Reporter at the Feb. 17 Clinical Genomics conference here last week, Walter Koch, senior director of pharmacogenomics at Roche Diagnostics, said the company is researching a 2C9 test for use on Applied Biosystems’ TaqMan platform, although he would not speculate as to whether the work would result in a product capable of identifying patients at risk for adverse reactions to some cox-2 inhibitors.
But no diagnostic companies contacted for this article expressed definite interest in pursuing development of a test specifically intended to provide dosing recommendations to doctors prescribing the popular painkillers. This despite the announcement by Pfizer on Dec. 17 that National Cancer Institute studies of its drug Celebrex showed a 2.5-fold increased risk of cardiovascular events at doses of 400 mg to 800 mg, while showing no increase in risk for patients taking 400 mg doses.
The 2C9 gene is also involved in the metabolism of warfarin, “one of the most litigated drugs,” said Koch. The gene associated with warfarin’s target, V-Kor, and 2C9 together account for two-thirds of the difference in dosing requirements of the drug, he said. “I would bundle those things,” he added.
An FDA panel ruled on Feb. 19 that Celebrex, Bextra, and Vioxx could remain on the market despite cardiovascular risks, but it called for further studies of the painkillers. While Pfizer did not pull the drugs Celebrex and Bextra from the market, it scaled back advertising for the drugs in December after studies found risks for both. Worldwide sales of Celebrex in 2004 were $3.3 billion, while Bextra sales reached approximately $1.3 billion, according to Pfizer financial statements. Worldwide sales of Vioxx were $2.5 billion in 2003, according to Merck.
What’s the Hold Up?
With that much money at stake, and with as much attention as cox-2 inhibitors have received in the press, it may be surprising that diagnostics companies do not seem to have focused their attention on supplementing the drugs with gene-based dosage guidelines. Few sources contacted for this article could provide details concerning cox-2 inhibitors and 2C9.
Calls to Merck and Pfizer were not returned by press time. GE Healthcare, whose CodeLink CYP450 chip covers 2C9, has no position on promoting or using its assay with cox-2 inhibitors. Third Wave Technologies, which sells a 2C9 Invader assay, was unable to comment on the impact of its products on cox-2 inhibitor prescriptions by press time.
An ABI spokesperson said that should a TaqMan product be produced with Roche Diagnostics, it would be intended for research use only, in keeping with ABI’s other products.
A customer service representative at Third Wave could not immediately confirm that the company still offered a 2C9 product for sale, although Adam Chazan, an analyst who covers the company for Pacific Growth, said Third Wave had agreed to work with a contract research organization to provide 2C9 tests for testing during clinical trials.
Quest Diagnostics was also unable to respond to calls before this issue went to press. The company lists a 2C9 test among a range of genetic tests that the laboratory giant offers, but a Quest customer service representative could not verify that the test was still for sale by press time.
Rheumatologist Scott Zashin, who operates a private practice in Dallas, Texas, and is author of the book Arthritis Without Pain, said many of his patients have continued to take Celebrex. Zashin said he would consider using a genetic diagnostic test to help determine individual dosages if the test was reliable, fast, reimbursable, and worked on patient blood samples.
Other Avenues for Pharmacogenomics in Cox-2 Inhibitors
Beyond CYP450 2C9, other genes and interactions related to cox-2 inhibitors may provide useful pharmacogenomics approaches. According to the American Academy of Family Physicians, Vioxx undergoes minimal metabolism by CYP450 3A4, but it inhibits the metabolism of warfarin, itself metabolized by 2C9. A long list of 2C9 inhibitors may increase the serum concentration of Celebrex, including selective serotonin reuptake inhibitors, tricyclic antidepressants, several antipsychotics, and beta blockers. Celebrex can directly inhibit 2D6, potentially leading to an increase in the concentration of drugs metabolized by this enzyme.
According to the Maryland Statewide Pharmacy and Therapeutics 2002 review of cox-2 inhibitors, Bextra is metabolized by 2C9 and 3A4, both of which it weakly inhibits. The drug is also a moderate inhibitor of 2C19.