Pharmacokinetic-pharmacodynamic modelling of the effect of Moxifloxacin on QT sub(c prolongation in telemetered cynomolgus monkeys)

Delayed ventricular repolarisation is manifested electrocardiographically in a prolongation of the QT interval. Such prolongation can lead to potentially fatal Torsades de Pointes. Moxifloxacin is a fluoroquinolone antibiotic which has been associated with QT prolongation and, as a result, is recommended by the regulatory authorities as a positive control in thorough QT studies performed to evaluate the potential of new chemical entities to induce QT prolongation in humans. The sensitivity of the cynomolgus monkey as a quantitative preclinical predictor of the PK-QT sub(c relationship is discussed. Methods: Cardiovascular monitoring was performed in the telemetered cynomolgus monkey for 22 h following oral administration of Moxifloxacin (10, 30 and 90 mg/kg) or placebo. QT) sub(c) was derived using an individual animal correction factor (ICAF): RR-I = QT-I - (RR-550) [inline image] (IACF). A PKPD analysis was performed to quantify the increase in placebo-adjusted QT sub(c elicited by administration of Moxifloxacin. In addition, the rate of onset of hERG channel blockade of Moxifloxacin was compared to Dofetilide by whole cell patch clamp technique in HEK-293 cells stably expressing the hERG channels. Results: Moxifloxacin induced a dose dependent increase in QT) sub(c). A maximum increase of 28 ms was observed following administration of 90 mg/kg Moxifloxacin. The corresponding maximum free systemic exposure was 18 [micro]M. Interrogation of the PK-QT sub(c relationship indicated a direct relationship between the systemic exposure of Moxifloxacin and increased QT) sub(c). A linear PKPD model was found to describe this relationship whereby a 1.5 ms increase in QT sub(c was observed for every 1 [micro]M increase in free systemic exposure. Discussion: The exposure dependent increases in QT) sub(c) observed following oral administration of Moxifloxacin to the cynomolgus monkey are in close agreement with those previously reported in human subjects. A direct effect linear relationship was found to be conserved in both species. As a result of the quantitative agreement in both species, the utility of the telemetered cynomolgus monkey as a preclinical predictor of QT sub(c prolongation is exemplified. Furthermore, the rate of onset of hERG channel blockade observed in patch clamp offers a mechanistic insight into the relative rates of channel blockade observed in vivo with both Moxifloxacin and Dofetilide.)