Application of a probabilistic method for the determination of drug-induced QT prolongation in telemetered cynomolgus monkeys: effects of moxifloxacin.
BACKGROUND
Moxifloxacin is the most widely used positive reference agent in clinical cardiac repolarization safety studies, but it has not been characterized in the cynomolgus monkey. This important experimental animal species exhibits pronounced heart rate variability, complicating the temporal evaluation of QT interval data.


METHODS
Digitized epicardial ECGs and aortic blood pressures were collected for 20 h in telemetered cynomolgus monkeys (n=6) following the administration of either vehicle or moxifloxacin (10 or 50 mg/kg, p.o.). Moxifloxacin plasma concentrations were determined 4 h postdose. ECG intervals were analyzed by computerized algorithms. Individual probabilistic QT rate-corrections (QTc) were derived from the slopes of predose log-transformed QT-RR data where each QT value was the mean of >250 beats/RR increment. The resulting QTc was used to determine the repolarization effects of moxifloxacin, expressed as the placebo-adjusted change in QTc (DeltaQTc), and as the integrated response from 0 to 12 h (AUC(0-->12)) postdose.


RESULTS
No DeltaQTc effect was produced by 10 mg/kg moxifloxacin. However, moxifloxacin (50 mg/kg; 5.86+/-0.5 microg/mL C(max)) significantly prolonged the RR interval by 50 to 112 ms from 3.5 to 7.5 h postdose and DeltaQTc by >or=7.2 ms from 1.83 to 9.17 h, with a maximal DeltaQTc effect of +26.4 ms. No notable effects on either systemic blood pressure or body temperature occurred with either dose.


CONCLUSIONS
Probabilistic QT rate-corrections appear to have eliminated the confounding effects of heart rate, provided for a stable QTc baseline, and enabled the demonstration of an exposure-dependent QTc prolongation by moxifloxacin. The duration and magnitude of the QTc effect paralleled moxifloxacin pharmacokinetics, and C(max) values were similar to those achieved clinically in thorough QT/QTc studies. Thus, novel probabilistic QT rate-corrections may offer highly robust assessments of repolarization risk in both nonclinical and clinical investigations.
Holzgrefe
Henry H
HH
Bristol-Myers Squibb Pharmaceutical Research Institute, Syracuse, NY 13221-4755, USA. HenryHolzgrefe@Hotmail.com
Cavero
Icilio
I
Buchanan
Lewis V
LV
Gill
Michael W
MW
Durham
Stephen K
SK
D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001011:Aorta; D001372:Aza Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature; D003627:Data Interpretation, Statistical; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D024841:Fluoroquinolones; D006329:Heart Conduction System / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D008133:Long QT Syndrome / Q000139:chemically induced / Q000188:drug therapy*; D008252:Macaca fascicularis; D008297:Male; D015233:Models, Statistical; D000077266:Moxifloxacin; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013686:Telemetry
D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin