Pharmacokinetic (PK) and pharmacodynamic (PD) interaction between nefazadone (NEF) and terfenadine (TER) but not NEF and loratidine (LOR)

Sixty-seven healthy volunteers received NEF + placebo (PBO) (n=13), NEF + TER (n=14), NEF + LOR (n=14), TER + PBO (n=13) in a multiple dose study. PK: NEF increased TER AUC (ng·hr/ml) markedly and increased LOR AUC (ng·hr/ml) to a lesser extent. PBO (mean±SD) NEF p-value TER AUC 17.3±8.5 97.4±48.9 <.001 LOR AUC 31.5±27.9 43.7·25.9 .014 PD: NEF + TER markedly increased mean QTc prolongation associated with TER and NEF + LOR had little mean QTc prolongation, as did NEF + PBO and LOR + PBO. Mean QTc Prolongation (msec) 95% C.I. TER+NEF 42.4 (34.2,50.6) TER+PBO 8.0 (-0.6,16.6) LOR+NEF 21.6 (13.7,29.4) LOR+PBO 9.1 (1.1,17.1) NEF+PBO 10.8 (2.6,19.0) Conclusion: Coadministration of NEF with TER results in markedly increased exposure to TER and this is associated with increased QTc prolongation. Coadministration of NEF with LOR results in a limited increase in LOR exposure and this has a limited effect on QTc prolongation.