A DRUG-INTERACTION BETWEEN ZAFIRLUKAST AND THEOPHYLLINE

The apparent low adverse effect profile of the new drug zafirlukast ha s made it an attractive choice in the treatment of asthma. We present the first case (to our knowledge) of a potentially serious drug-drug i nteraction between zafirlukast and theophylline. A 15-year-old white g irl with asthma had been taking theophylline (Slo-bid, Rhone-Poulenc R orer Pharmaceuticals Inc, Collegeville, Pa) (300 mg twice daily), with drug levels of approximately 61 mu mol/L (11.0 mu g/mL) for several y ears. Recently, her serum theophylline levels had increased to the tox ic range (133.2 mu mol/L [24 mu g/mL]) shortly after the addition of z afirlukast (Accolate, Zeneca Pharmaceuticals, Wilmington, Del) to her regimen. Attempts were made to stop and then restart the theophylline therapy at progressively lower doses; however, with each attempt, the patient's reaction to the drug became more toxic, with serum theophyll ine levels ranging between 99.9 and 149.9 mu mol/L (18 and 27 mu g/mL) . So this potential drug-drug interaction could be investigated, the p atient stopped taking both drugs for 1 week. Then, she again started t aking theophylline (75 mg twice daily), and over 2 days reached a stea dy state serum theophylline level of 12.8 to 14.4 mu mol/L (2.3-2.6 mu g/mL). On the third day, zafirlukast (20 mg twice daily) was reintrod uced to the regimen, and the theophylline therapy was continued. By th e fifth day, a dramatic 7-fold increase was seen in the serum theophyl line level (101.6 mu mol/L [18.3 mu g/mL]). The areas under the curve for theophylline alone and theophylline with zafirlukast were 29.3 and 197 (mg.h)/L, respectively. One explanation for the noted increase in the theophylline level is that metabolism occurs mainly by cytochrome P450 (CYP 1A2), an enzyme that is known to be inhibited with high con centrations of zafirlukast. Although-the current metabolism of the 2 d rugs in combination is poorly understood, the potential for serious in teractions seems to exist in the rapidly growing population of persons with asthma, for whom they may be prescribed. The noted increase in t he theophylline level after zafirlukast administration is in contrast to the original reports by the manufacturer. Therefore, we recommend t hat physicians evaluate serum theophylline levels closely when prescri bing the 2 drugs in combination.