Abstract | PURPOSE: To evaluate the pharmacokinetics and cardiac repolarization effect (measured by QT/QTc interval) of amrubicin and its active metabolite amrubicinol in non-Japanese patients with advanced solid tumors. METHODS: Patients received amrubicin 40 mg/m(2)/day as a 5-min infusion on days 1-3 of a 21-day cycle. During cycle 1, serial blood and plasma samples were collected on days 1-9 and time-matched triplicate electrocardiograms on the "off- drug" visit (1-5 days prior to start of treatment) and days 1-9. RESULTS: Twenty-four patients were treated. Amrubicinol reached peak concentration 2-4 h after amrubicin administration and had a terminal half-life of 53 h. Distribution of amrubicinol into erythrocytes was fivefold greater than into plasma. The molar ratio of amrubicinol to amrubicin in blood was 0.67 on day 3. The presence of an NQO1 polymorphism did not alter drug exposure. The upper bound of the one-sided 95 % confidence interval for the time-matched, baseline-adjusted change from the off- drug day in QTcI (individual correction) was <10 ms at all times and was only >10 ms (10.20 ms) at a single time point for QTcF (Fridericia correction). No relationship was observed between blood amrubicin or amrubicinol concentrations and QTcF changes. All QTcF measurements were <480 ms, and none increased by >60 ms from baseline. CONCLUSIONS: Data suggest that amrubicinol is an important active metabolite in humans and that both compounds were not associated with clinically relevant QTc interval prolongation at the dose regimen studied.
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Authors | Nianhang Chen, Sant P Chawla, Elena Gabriela Chiorean, William L Read, Mayer Gorbaty, Alain C Mita, Lotus Yung, Peter Bryan, Richard McNally, Markus F Renschler, Sunil Sharma |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 71
Issue 4
Pg. 1083-94
(Apr 2013)
ISSN: 1432-0843 [Electronic] Germany |
PMID | 23400695
(Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anthracyclines
- Antineoplastic Agents
- amrubicinol
- amrubicin
- NAD(P)H Dehydrogenase (Quinone)
- NQO1 protein, human
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Topics |
- Adult
- Aged
- Anthracyclines
(adverse effects, pharmacokinetics, pharmacology)
- Antineoplastic Agents
(pharmacokinetics)
- Electrocardiography
(drug effects)
- Female
- Heart
(drug effects, physiology)
- Heart Rate
(drug effects)
- Humans
- Male
- Middle Aged
- NAD(P)H Dehydrogenase (Quinone)
(genetics)
- Neoplasms
(drug therapy)
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