2011 - Athens - Greece

PAGE 2011: Cardiovascular, QT-prolongation
Piet van der Graaf

Towards a Thorough Preclinical QT (TpQT) study paradigm: Pharmacokinetic-Pharmacodynamic (PKPD) Modelling of QTc Effects of Moxifloxacin in Cynomolgus Monkeys

Piet H. van der Graaf, Kenny J. Watson, William P. Gorczyca, John Umland, Ying Zhang, Xian Chen, Sunny Z. Sun, Bernard Fermini, Mark Holbrook


Objectives:  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-QTc relationship is discussed.

Methods:  Cardiovascular monitoring was performed in the telemetered cynomolgus monkey for 22 hours following oral administration of Moxifloxacin (10, 30 and 90mg/kg) or placebo. QTc was derived using an individual animal correction factor (ICAF) : RR-I = QT-I-(RR-550)*(IACF). A PKPD analysis was performed to quantify the increase in placebo-adjusted QTc 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 QTc. A maximum increase of 28msec was observed following administration of 90mg/kg Moxifloxacin. The corresponding maximum free systemic exposure was 18µM. Interrogation of the PK-QTc relationship indicted a direct relationship between the systemic exposure of Moxifloxacin and increased QTc. A linear PKPD model was found to describe this relationship whereby a 1.5msec increase in QTc was observed for every 1µM increase in free systemic exposure.

Conclusions:  The exposure dependent increases in QTc  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 QTc 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.  This work builds on that of Jonker et al. [1] and adds to the growing body of evidence that thorough preclinical PKPD evaluation could provide an effective and efficient quantitative decision framework for derisking of QT liability in man.

[1] Jonker, D. M., Kenna, L. A., Leishman, D., Wallis, R., Milligan, P. A., & Jonsson, E. N. (2005). A pharmacokinetic-pharmacodynamic model for the quantitative prediction of Dofetilide clinical QT prolongation from human ether-a-go-go-related gene current inhibition data. Clinical Pharmacology and Therapeutics, 77, 572-582.

Reference: PAGE 20 (2011) Abstr 1961 [www.page-meeting.org/?abstract=1961]
Poster: Cardiovascular, QT-prolongation