The ability of drugs to inhibit histamine-induced wheals has been used frequently as a pharmacodynamic index of clinical efficacy. Host response using this model can be predictive of clinical response in atopic diseases such as allergic rhinitis and urticaria. Terfenadine is a widely used nonsedating antihistamine currently approved for use at a dosage of 60 mg every 12 hours. Our clinical trial was designed to determine whether higher dosages of this agent were associated with amplified efficacy in suppressing the wheal response to intradermal histamine phosphate. Twenty-six healthy male Caucasian volunteers were randomized in a double-blind crossover fashion to receive terfenadine 60 mg every 12 hours, 120 mg each day, 120 mg every 12 hours, and placebo. Each dose was given orally for three days followed by a 6-day washout period. Histamine was administered intradermally one hour prior to dosing for baseline measurements. Histamine was given at defined intervals after treatment or placebo on days 1 (acute dosing) and 3 (steady state), and the percent inhibition of histamine-induced wheal area as compared with baseline was determined. Subjects receiving all three active doses exhibited significant wheal inhibition compared with placebo on days 1 and 3 (P less than or equal to .01). Subjects receiving the 60 mg every 12 hours and the 120 mg each day dosages exhibited roughly equivalent mean wheal suppression over the 24-hour period of each testing day (54% versus 60%, respectively, on day 1 and 62% versus 63%, respectively, on day 3, no significant differences).(ABSTRACT TRUNCATED AT 250 WORDS)