Loratadine and terfenadine interaction with nefazodone: Both antihistamines are associated with QTc prolongation

Background and Objective: Nefazodone inhibits CYP3A; therefore coadministra tion with CYP3A substrates such as terfenadine or loratadine may result in increased exposure to these drugs. A potential pharmacodynamic consequence is electrocardiographic QTc prolongation, which has been associated with to rsade de pointes cardiac arrhythmia. Therefore a clinical pharmacokinetic-p harmacodynamic evaluation of this potential interaction was conducted. Methods: A randomized, double-blind, double-dummy, parallel group, multiple -dose design was used. Healthy men and women who were given doses of 60 mg of terfenadine every 12 hours, 20 mg of loratadine once daily, and 300 mg o f nefazodone every 12 hours were studied. Descriptive pharmacokinetics (tim e to maximum concentration, maximum concentration, and area under the plasm a concentration-time curve) were used for the examination of interactions a mong the respective parent drugs and metabolites. QTc prolongation (mean va lue over the dosing interval) was the pharmacodynamic parameter measured. K inetic and dynamic analysis was used for the examination of pooled concentr ation and QTc data with the use of a linear model. Results: Concomitant nefazodone treatment markedly increased the dose inter val area under the plasma concentration-time curve of both terfenadine (mea n value, 17.3 +/- 8.5 ng (.) mL/h versus 97.4 + 48.9 ng (.) mL/h; P < .001) and carboxyterfenadine (mean value, 1.69 <plus/minus> 0.48 mug (.) h/mL ve rsus 2.88 +/- 0.53 mug h/mL; P < .001) and moderately increased the dose in terval area under the plasma concentration-time curve of both loratadine (m ean value, 31.5 <plus/minus> 27.9 ng (.) h/mL versus 43.7 +/- 25.9 ng (.) h /mL; P < .014) and descarboethoxyloratadine (mean value, 73.4 <plus/minus> 54.9 ng (.) h/mL versus 81.9 +/- 26.2 ng (.) h/mL; P < .002). The mean QTc was unchanged with terfenadine alone; however, it was markedly prolonged wi th concomitant nefazodone and terfenadine (mean [90% confidence interval] p rolongation 42.4 ms [34.2, 50.6 ms]; P < .05). Similarly, the mean QTc was unchanged with loratadine alone; however, it was prolonged with concomitant nefazodone and loratadine (21.6 ms [13.7, 29.4 ms]; P < .05). Nefazodone a lone did not change mean QTc. QTc was positively correlated with terfenadin e plasma concentration (r(2) = 0.21; P = .0001). Similarly, QTc was positiv ely correlated with loratadine plasma concentration (r(2) = 0.056; P = .000 8) but with a flatter slope. There was no relationship between QTc and nefa zodone plasma concentration during treatment with nefazodone alone(r(2) = 0 .002, not significant). Conclusions: In healthy men and women, concomitant nefazodone treatment at a therapeutic dose increases exposure to both terfenadine and carboxyterfen adine. This increased exposure is associated with marked QTc prolongation, which is correlated with terfenadine plasma concentration. A similar intera ction occurs with loratadine, although it is of lesser magnitude. Concomita nt administration of nefazodone with terfenadine may have predisposed indiv iduals to the arrhythmia associated with QTc prolongation, torsade de point es, when terfenadine was available for clinical use. However, a new finding is that in the context of higher than clinically recommended daily doses ( 20 mg) of loratadine concomitant administration with a metabolic inhibitor such as nefazodone can also result in QTc prolongation.