PMID- 21419854
OWN - NLM
STAT- MEDLINE
DCOM- 20110822
LR  - 20181201
IS  - 1873-488X (Electronic)
IS  - 1056-8719 (Linking)
VI  - 63
IP  - 3
DP  - 2011 May-Jun
TI  - Pharmacokinetic-pharmacodynamic modelling of the effect of Moxifloxacin on QTc 
      prolongation in telemetered cynomolgus monkeys.
PG  - 304-13
LID - 10.1016/j.vascn.2011.03.002 [doi]
AB  - INTRODUCTION: 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 18muM. 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 muM increase in free systemic exposure. 
      DISCUSSION: 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.
CI  - Copyright (c) 2011 Elsevier Inc. All rights reserved.
FAU - Watson, Kenny J
AU  - Watson KJ
AD  - Pharmacokinetics, Dynamics and Metabolism, Pfizer Global R&D, Ramsgate Road, 
      Sandwich, Kent, CT13 9NJ, UK.
FAU - Gorczyca, William P
AU  - Gorczyca WP
FAU - Umland, John
AU  - Umland J
FAU - Zhang, Ying
AU  - Zhang Y
FAU - Chen, Xian
AU  - Chen X
FAU - Sun, Sunny Z
AU  - Sun SZ
FAU - Fermini, Bernard
AU  - Fermini B
FAU - Holbrook, Mark
AU  - Holbrook M
FAU - Van Der Graaf, Piet H
AU  - Van Der Graaf PH
LA  - eng
PT  - Journal Article
DEP - 20110317
PL  - United States
TA  - J Pharmacol Toxicol Methods
JT  - Journal of pharmacological and toxicological methods
JID - 9206091
RN  - 0 (Aza Compounds)
RN  - 0 (Blood Proteins)
RN  - 0 (ERG1 Potassium Channel)
RN  - 0 (Ether-A-Go-Go Potassium Channels)
RN  - 0 (Fluoroquinolones)
RN  - 0 (KCNH2 protein, human)
RN  - 0 (Quinolines)
RN  - U188XYD42P (Moxifloxacin)
SB  - IM
MH  - Action Potentials/drug effects
MH  - Administration, Oral
MH  - Animals
MH  - Aza Compounds/blood/*pharmacokinetics/*pharmacology
MH  - Blood Proteins/metabolism
MH  - Cell Line
MH  - *Disease Models, Animal
MH  - ERG1 Potassium Channel
MH  - Electrocardiography
MH  - Ether-A-Go-Go Potassium Channels/antagonists & inhibitors/genetics
MH  - Fluoroquinolones
MH  - Humans
MH  - Long QT Syndrome/blood/*chemically induced/metabolism
MH  - *Macaca fascicularis
MH  - Moxifloxacin
MH  - Patch-Clamp Techniques
MH  - Protein Binding
MH  - Quinolines/blood/*pharmacokinetics/*pharmacology
MH  - Telemetry
MH  - Transfection
EDAT- 2011/03/23 06:00
MHDA- 2011/08/23 06:00
CRDT- 2011/03/23 06:00
PHST- 2010/10/11 00:00 [received]
PHST- 2011/02/22 00:00 [revised]
PHST- 2011/03/03 00:00 [accepted]
PHST- 2011/03/23 06:00 [entrez]
PHST- 2011/03/23 06:00 [pubmed]
PHST- 2011/08/23 06:00 [medline]
AID - S1056-8719(11)00021-9 [pii]
AID - 10.1016/j.vascn.2011.03.002 [doi]
PST - ppublish
SO  - J Pharmacol Toxicol Methods. 2011 May-Jun;63(3):304-13. doi: 
      10.1016/j.vascn.2011.03.002. Epub 2011 Mar 17.