Population pharmacokinetics of terfenadine

After oral administration of terfenadine, plasma concentrations of the parent drug are usually below the limits of quantitation of conventional analytical methods because of extensive first-pass metabolism. Data are usually reported on the carboxylic acid metabolite (M1) but there are no published reports of pharmacokinetic parameters for terfenadine itself. The present study was undertaken to evaluate the population pharmacokinetics of terfenadine.

Data from 132 healthy male subjects who participated in several different studies were included in this analysis. After an overnight fast, each subject received a single 120 mg oral dose of terfenadine; blood samples were collected for 72 hours. Terfenadine plasma concentrations were measured using HPLC with mass spectrometry detection and M1 plasma concentrations were measured using HPLC with fluorescence detection. A 2-compartment model was fitted to the terfenadine data using NONMEM; terfenadine and M1 data were also analyzed by noncompartmental methods.

Population mean Ka was 2.80 hr-1, Tlag was 0.33 hr, Cl/F was 4.42 x 10(3) 1/hr, Vc/F was 89.8 x 10(3) 1. Q/F was 1.85 x 10(3) 1/hr and Vp/F was 29.1 x 10(3) 1. Intersubject CV ranged from 66 to 244% and the residual intrasubject CV was 21%. Based on noncompartmental methods, mean terfenadine Cmax was 1.54 ng/ml, Tmax was 1.3 hr, t1/2 lambda Z was 15.1 hr, Cl/F was 5.48 x 10(3) 1/hr and V lambda Z/F was 119.2 x 10(3) 1. M1 concentrations exceeded terfenadine concentrations by more than 100 fold and showed less intersubject variability.

Terfenadine disposition was characterized by a 2-compartment model with large intersubject variability, consistent with its significant first-pass effect.