DOSE-DEPENDENT TIRACIZINE DISPOSITION IN HEALTHY-VOLUNTEERS - SERUM AND URINE KINETICS AND DOSE-RELATED ECG-CHANGES

The pharmacokinetics of tiracizine, a new class I antiarrhythmic agent , and 3 of its metabolites were assessed in serum and urine of 8 healt hy extensive metabolisers after single oral administration of 50, 100, and 200 mg tiracizine hydrochloride. Additionally, tiracizine induced EGG-changes were compared between the different doses. With increasin g doses enhancement of AUC and C-max of tiracizine and its metabolites revealed a slight deviation from linearity indicated by exceeding the upper limits of the 95% nonparametric confidence interval set by 0.8- 1.2 for the ratio (dose corrected parameters after the 100 and 200 mg dose, respectively)/(parameters after 50 mg). The increase of the dose corrected parameters after the 200 mg dose was about 1.3-fold compare d with the 50 mg parameters for the parent compound as well as its met abolites. The significant decrease of the renal clearance of all 4 sub stances with increasing doses indicates that saturable tubular secreti on mainly accounts for non-linearity Due to the occurrence of non-line ar (tubular secretion) as well as linear (glomerular filtration, hepat ic metabolism) elimination in parallel, however, it is concluded that saturable tubular secretion is of minor importance at higher doses and should not be overestimated. However, there was some evidence for sat urable hepatic tiracizine metabolism in 4 of the 8 participants. There fore, a fall of apparent intrinsic clearance has also to be taken into consideration, especially at higher doses. PQ- and QRS-intervals were prolonged in a dose dependent manner and culminated at 1 h after drug intake, QT(c)-time, however, remained unchanged. A log-linear relatio nship between serum concentrations of the parent compound and PQ- as w ell as QRS-time is suspected for serum levels about 80 ng/ml, but has to be confirmed by individual pharmacokinetic-pharmacodynamic modellin g. PQ- and QRS-intervals might be suitable for tiracizine therapeutic monitoring.