MARION MERRELL DOW DEVELOPING NONCARDIOTOXIC SELDANE METABOLITE

MARION MERRELL DOW DEVELOPING NONCARDIOTOXIC SELDANE METABOLITE, terfenadine carboxylate, for which the company has a composition patent that runs through 1998. The terfenadine carboxylate isolated by Marion Merrell Dow is a "top priority" for the company, which said it is in active discussions with FDA about how rapidly the product can be developed. Marlborough, Mass.-based Sepracor is developing its own terfenadine carboxylate. The separations technology company, which focuses on developing new forms of existing drug compounds, filed use patent applications last summer for terfenadine carboxylate as an antihistamine and is seeking a marketing and development partner for the metabolite. The disclosure of new noncardiotoxic forms of terfenadine occurred with the publication of a study in the March 24 Journal of the American Medical Association showing that terfendaine carboxylate does not produce cardiac adverse events associated with its parent compound terfenadine (Seldane). The study was sponsored by Sepracor. Reports of deaths, cardiac arrest and arrhythmias led FDA to add boxed warnings to Seldane labeling and to labeling for the other currently marketed nonsedating antihistamine, Janssen's Hismanal (astemizole) last summer ("The Pink Sheet" July 27, 1992, p. 3). The JAMA study, by Raymond Woosley, MD, Georgetown University, et al., reviewed 25 cases of the rare ventricular arrhythmia torsades de pointes that had been reported to FDA as of April 1992 as being associated with Seldane therapy. The study further tested the hypothesis in in vitro cardiac electrophysiologic studies that terfenadine, and not its major metabolite, has quinidine-like activity in producing arrhythmias. Quinidine is thought to cause arrhythmias by inhibiting potassium currents across heart muscle cells. Terfenadine was found by Woosley et al. to cause quinidine-like inhibition of potassium currents when tested on cat ventricular myocytes. However, terfenadine carboxylate, which is produced when terfenadine is metabolized by a cytochrome P-450 liver enzyme called CYP3A4, failed to inhibit the potassium currents even at 30 times the terfenadine concentration needed to produce half a maximum effect. "The ability of terfenadine but not its metabolite to block potassium channels suggests that terfenadine carboxylate should be evaluated as an antihistamine with less potential than terfenadine for causing torsades de pointes," Woosley concluded. Physicians need to be more aware of the types of drugs that may interact with terfenadine to produce elevated levels of the parent compound and other factors that may affect the reaction to the drug, Woosley warned. He cited procainamide, disopyramide, sotalol, haloperidol, thioridazine, probucol and pentamidine as drugs that block potassium channels. There is also some evidence that flavenoids found in grapefruit juice and some nutritional supplements may inhibit the activity of the liver enzyme that metabolizes terfenadine, he said. The drug interaction potential for all pharmaceutical products should "optimally" be assessed prior to drug approval, FDA Center for Drug Evaluation and Research Director Carl Peck stated in an editorial accompanying the Woosley study. "The appreciation and understanding of such controllable sources of variability in drug action and potential injury to patients should be achieved prior to the marketing of new pharmaceutical products," Peck maintained. Through in vitro tests "it is now possible to determine which enzyme systems are involved in metabolizing particular drugs and which substances might interfere with metabolism," the FDAer noted. The editorial is co-signed by FDA Office of Drug Evaluation I Director Robert Temple, MD, and Office of Research Resources Director Jerry Collins, PhD. Another study appearing in the same issue of JAMA, conducted by Peter Honig, MD, Uniformed Services University of the Health Sciences, et al., treated six healthy volunteers with 60 mg terfenadine every 12 hours for seven days and concomitant oral ketoconazole (Janssen's Nizoral) 200 mg every 12 hours. The authors reported that all six subject had detectable plasma levels of unmetabolized terfenadine after the addition of ketoconazole, which was associated with QT interval prolongation of the patients' electrocardiogram. Four of the six patients were not able to complete ketoconazole therapy because of "significant electrocardiographic repolarization abnormalities." While the published studies and FDA editorial alert physicians to the potential side effects of Seldane therapy, allergy season has arrived without the appearance of the Seldane comprehensive patient program and direct-to-consumer ads promised by Marion Merrell Dow following the relabeling of the product. Reportedly, the company and FDA have disagreed on wording of the patient materials highlighting the risks associated with use of the antihistamine.