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Plasma pharmacokinetics of the indenoisoquinoline topoisomerase I inhibitor, NSC 743400, in rats and dogs.
- Source :
-
Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2015 May; Vol. 75 (5), pp. 1015-23. Date of Electronic Publication: 2015 Mar 17. - Publication Year :
- 2015
-
Abstract
- Purpose: NSC 743400 is a novel synthetic indenoisoquinoline analog under development as an anticancer agent. It is a potent topoisomerase I inhibitor with potential therapeutic advantages over FDA-approved camptothecin derivatives. In preparation for clinical development of NSC 743400, we determined the pharmacokinetics after administration to rats and dogs.<br />Methods: NSC 743400 was administered intravenously at a dose of 12 or 24 mg/m(2) to rats (single bolus) or 10, 50, 100, 215, 430, or 646 mg/m(2) (intravenous infusion) or 860 or 1720 mg/m(2) (orally) to dogs.<br />Results: Intravenously administered NSC 743400 was eliminated from both species with an estimated t 1/2 of 2-5 h in rat and 6-14 h in dog. Elimination t 1/2 increased with dose in dog. Area under the plasma concentration-versus-time curve (AUC) was comparable in both species, at about 300-400 h ng/mL for the approximately 10 mg/m(2) dose groups. Overall, AUC values increased proportionally with dose for both species but had evidence of more than proportional exposure at the highest doses. Oral dosing resulted in variable drug absorption.<br />Conclusions: The pharmacokinetic data were used to plan first-in-human clinical trials.
- Subjects :
- Animals
Benzodioxoles administration & dosage
Benzodioxoles pharmacokinetics
Dogs
Dose-Response Relationship, Drug
Female
Infusions, Intravenous
Injections, Intravenous
Isoquinolines administration & dosage
Isoquinolines pharmacokinetics
Male
Random Allocation
Rats
Rats, Inbred F344
Topoisomerase I Inhibitors administration & dosage
Topoisomerase I Inhibitors pharmacokinetics
Benzodioxoles blood
Isoquinolines blood
Topoisomerase I Inhibitors blood
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0843
- Volume :
- 75
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cancer chemotherapy and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 25776905
- Full Text :
- https://doi.org/10.1007/s00280-015-2722-y