Dose selection and dosing interval determination for LTRA use in asthma

The dose and dosing interval for leukotriene receptor antagonists montelukast and zafirlukast in adult asthmatic patients were determined by bronchoprovocation with exercise or leukotriene D4 inhalation. Subsequent dose-ranging studies confirmed that once-daily ingestion of a 10-mg dose of montelukast was effective and safe; higher doses did not improve efficacy or increase the risk of adverse effects. In contrast, zafirlukast doses that exceeded the approved dose of 20 mg ingested twice daily during fasting improved efficacy but increased the risk of elevated liver enzymes. Pharmacokinetic studies showed that montelukast bioavailability is not affected by food and did not interact with other drugs. Zafirlukast inhibited warfarin metabolism while food intake and concurrent therapy with theophylline or aspirin decreased zafirlukast levels. Pharmacokinetic and subsequent efficacy or safety studies revealed that a 5-mg and a 4-mg chewable tablet of montelukast ingested once daily were effective in and well tolerated by patients in the 6- to 14-year and 2- to 5-year age-groups, respectively. Both pediatric montelukast doses produced the same magnitude of tissue exposure as did the 10-mg adult dose. The Food and Drug Administration approved a 10-mg film-coated tablet of zafirlukast for children 7 to 11 years of age. It must be administered twice daily fasting.