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Drug Saf. 2014 Mar;37(3):183-9. doi: 10.1007/s40264-014-0142-2.

Impact of electrocardiographic data quality on moxifloxacin response in thorough QT/QTc studies.

Author information

1
Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA, lars.johannesen@fda.hhs.gov.

Abstract

BACKGROUND:

Thorough QT studies are typically conducted for drugs with systemic bioavailability and include a positive control, typically moxifloxacin, with a well-described QTc effect.

OBJECTIVE:

This study tested two hypotheses: that (i) re-measuring the QT intervals based on electrocardiogram (ECG) pattern similarity improves the moxifloxacin time profile, and (ii) that study conduct influences the ability to detect a typical moxifloxacin time profile.

METHODS:

ECGs from 65 studies with available moxifloxacin plasma concentrations were obtained, including four studies with an unexpected moxifloxacin response. Residual error of a concentration-QT model was evaluated before and after re-measuring the QT interval based on ECG pattern similarity. Intra-replicate heart rate differences were calculated using the original heart rate measurements and the 10-s average heart rates.

RESULTS:

Similarity re-measurements reduced the residual error of the model (before vs. after of 8.43 ± 2.00 vs. 7.55 ± 1.86 ms; p < 0.001). For both original and averaged 10-s heart rate, intra-replicate heart rate differences were significantly lower (p < 0.001) in studies with the expected response than in those with an unexpected time profile.

DISCUSSION:

The pattern similarity measurement methodology reduces the residual error of the model, which influences the time profile of the moxifloxacin response. Accuracy of study conduct, represented by intra-replicate heart rate differences, separated studies with and without the expected moxifloxacin time profile.

PMID:
24554350
DOI:
10.1007/s40264-014-0142-2
[Indexed for MEDLINE]

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