Effect of itraconazole on the pharmacokinetics and pharmacodynamics of fexofenadine in relation to the MDR1 genetic polymorphism

Objective: Our objective was to evaluate the effect of itraconazole, a P-glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of fexofenadine, a P-glycoprotein substrate, in relation to the multidrug resistance 1 gene (MDR1) G2677T/C3435T haplotype. Methods: A single oral dose of 180 mg fexofenadine was administered to 7 healthy subjects with the 2677GG/3435CC (G/C) haplotype and 7 with the 2677TT/3435TT (T/T) haplotype. One hour before the fexofenadine dose, either 200 mg itraconazole or placebo was administered to the subjects in a double-blinded, randomized, crossover manner with a 2-week washout period. Histamine-induced wheal and flare reactions were measured to assess the effects on the antihistamine response. Results: In the placebo phase, pharmacokinetic parameters of fexofenadine showed no statistically significant difference between 2 MDR1 haplotypes; the area under the curve from time 0 to infinity (AUC_0-∞) of fexofenadine in the T/T and G/C groups was 5194.0 ± 1910.8 and 4040.4 ± 1832.2 ng·mL^-1·h^-1, respectively (P = .271), and the oral clearance (CL/F) was 530.9 ± 191.1 and 806.0 ± 355.3 mL·h^-1·kg^-1, respectively (P = .096). The disposition of itraconazole, a substrate of P-glycoprotein, was not significantly different between the 2 haplotypes. After itraconazole pretreatment, however, the differences in fexofenadine pharmacokinetics became statistically significant; the mean fexofenadine AUC_0-∞ in the T/T group was significantly higher than that in the G/C group (15,630.6 ± 5070.0 and 9252.9 ± 2044.1 ng/mL·h, respectively; P = .007), and CL/F of the T/T subjects was lower than that of the G/C subjects (167.0 ± 33.3 and 292.3 ± 42.2 mL·h^-1·kg^-1, respectively; P < .001). Itraconazole pretreatment caused more than a 3-fold increase in the peak concentration of fexofenadine and the area under the curve to 6 hours compared with the placebo phase. This resulted in a significantly higher suppression of the histamine-induced wheal and flare reactions in the itraconazole pretreatment phase compared with those in the placebo phase. Conclusion: The effect of MDR1 G2677T/C3435T haplotypes on fexofenadine disposition are magnified in the presence of itraconazole. Itraconazole pretreatment significantly altered the disposition of fexofenadine and thus its peripheral antihistamine effects.