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Sensitivity of common marmosets to detect drug-induced QT interval prolongation: moxifloxacin case study
Ryuichi Komatsu1, Masaki Honda, Henry H Holzgrefe
1Fuji Gotemba Laboratory, Chugai Pharmaceutical Co., Ltd., Shizuoka 412-8513, Japan.
Introduction:
Moxifloxacin is the most widely used positive reference agent in clinical cardiac repolarization studies, but it has not been characterized in common marmosets which are uniquely suited to studies in early-stage development due to their small size and minimal test article requirements. The purpose of this study was to evaluate the sensitivity of the common marmoset to detect moxifloxacin-associated QT interval prolongation.
Methods:
Eight telemetered common marmosets were monitored for 24 h following oral administration of moxifloxacin by gavage at 0, 10, 30, and 100 mg/kg using a Latin square design. Concurrently, a pharmacokinetic evaluation in 8 non-telemetered animals was conducted. A rate-corrected QT (QTc) interval was derived using an individual probabilistic QT rate-correction. QTc (placebo-adjusted QTc change from the individual baseline) was calculated and the relationship between pharmacokinetics (PK) and pharmacodynamics (PD) was analyzed.
Results:
A slight, but not significant, increase in QTc was detected with 10 mg/kg of moxifloxacin. Moxifloxacin at 30 and 100 mg/kg elicited dose-dependent increases in QTc of 14.0+/-3.6 and 35.0+/-6.2 ms, respectively, with associated total moxifloxacin C(max) values of 6.5+/-0.5 and 16.5+/-1.6 microg/mL, respectively. From the PK/PD relationship, the plasma concentration which would attain QTc of 5 to 10 ms was estimated to be 1.67-3.73 microg/mL. The results were consistent with typical clinical trial results (QTc of 6.6-14.8 ms at 2.5-3.5 microg/mL).
Conclusions:
The present study demonstrates that the common marmoset is highly sensitive to moxifloxacin-associated changes in cardiac repolarization, assessed as QTc. As such, this species is suitable for precise and reliable detection of small, but significant, drug-associated increases in QTc interval. Thus, the common marmoset should be regarded as a validated animal model for the detection of QT risk in early-stage drug development and represents an important addition to the current in vivo armamentarium.
Insights
Common marmosets are highly sensitive to moxifloxacin, showing dose-dependent QT interval prolongation. This validates the marmoset as a reliable animal model for detecting drug-induced QT risk in early development.
Area of Science:
- Pharmacology
- Cardiovascular Research
- Preclinical Drug Development
Background:
- Moxifloxacin is a standard reference drug for cardiac repolarization studies.
- Common marmosets are suitable for early-stage drug development due to their size and minimal requirements.
- Moxifloxacin's effect on QT interval in marmosets was previously uncharacterized.
Purpose of the Study:
- To evaluate the sensitivity of common marmosets to moxifloxacin-induced QT interval prolongation.
- To establish the common marmoset as a model for assessing cardiac repolarization risks.
Main Methods:
- Eight telemetered marmosets received oral moxifloxacin (0, 10, 30, 100 mg/kg) in a Latin square design.
- Pharmacokinetic and pharmacodynamic analyses were performed, including rate-corrected QT (QTc) interval.
- Individual probabilistic QT rate-correction was used for QTc derivation.
Main Results:
- Moxifloxacin induced dose-dependent increases in QTc at 30 and 100 mg/kg (14.0±3.6 ms and 35.0±6.2 ms, respectively).
- Pharmacokinetic/pharmacodynamic modeling estimated concentrations for 5-10 ms QTc prolongation (1.67-3.73 µg/mL).
- Results aligned with human clinical trial findings for moxifloxacin.
Conclusions:
- Common marmosets demonstrate high sensitivity to moxifloxacin-associated QT prolongation.
- The marmoset is a suitable model for precise detection of small, significant drug-associated QTc changes.
- This species is validated for early-stage drug development to assess QT risk.
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