title: Pharmacokinetic-pharmacodynamic modelling of the effect of Moxifloxacin on QTc prolongation in telemetered cynomolgus monkeys.
abstract: BACKGROUND
  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 h following oral administration of Moxifloxacin (10, 30 and 90 mg/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 28 ms was observed following administration of 90 mg/kg Moxifloxacin. The corresponding maximum free systemic exposure was 18μM. Interrogation of the PK-QTc relationship indicated a direct relationship between the systemic exposure of Moxifloxacin and increased QTc. A linear PKPD model was found to describe this relationship whereby a 1.5 ms increase in QTc was observed for every 1 μM 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.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Global R&D, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK.
authors.forename: Kenny J
authors.initials: KJ
authors.lastname: Watson
authors.forename: William P
authors.initials: WP
authors.lastname: Gorczyca
authors.forename: John
authors.initials: J
authors.lastname: Umland
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xian
authors.initials: X
authors.lastname: Chen
authors.forename: Sunny Z
authors.initials: SZ
authors.lastname: Sun
authors.forename: Bernard
authors.initials: B
authors.lastname: Fermini
authors.forename: Mark
authors.initials: M
authors.lastname: Holbrook
authors.forename: Piet H
authors.initials: PH
authors.lastname: Van Der Graaf
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D001372:Aza Compounds / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics; D024841:Fluoroquinolones; D006801:Humans; D008133:Long QT Syndrome / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism; D008252:Macaca fascicularis; D000077266:Moxifloxacin; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D011804:Quinolines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013686:Telemetry; D014162:Transfection
chemical_list: D001372:Aza Compounds; D001798:Blood Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; C000606913:KCNH2 protein, human; D011804:Quinolines; D000077266:Moxifloxacin