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.
Methods
NSC 743400 was administered intravenously at a dose of 12 or 24 mg/m2 to rats (single bolus) or 10, 50, 100, 215, 430, or 646 mg/m2 (intravenous infusion) or 860 or 1720 mg/m2 (orally) to dogs.
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/m2 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.
Conclusions
The pharmacokinetic data were used to plan first-in-human clinical trials.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Pommier Y (2006) Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer 6(10):789–802. doi:10.1038/nrc1977
Antony S, Agama KK, Miao ZH, Takagi K, Wright MH, Robles AI, Varticovski L, Nagarajan M, Morrell A, Cushman M, Pommier Y (2007) Novel indenoisoquinolines NSC 725776 and NSC 724998 produce persistent topoisomerase I cleavage complexes and overcome multidrug resistance. Cancer Res 67(21):10397–10405. doi:10.1158/0008-5472.CAN-07-0938
Kaur G, Frary S, Thillainathan J, Hollingshead M, Pommier Y, Parchment R, Tomaszewski J, Doroshow J, NCI Phase 0 Preclinical Team (2008) Indenoisoquinolines NSC 725776 and NSC 724998 inhibit angiogenesis: {gamma}H2AX is potential pharmacologic biomarker. AACR Meeting Abstracts 2008 (1_Annual_Meeting):1101
U.S. Department of Health and Human Services Food and Drug Administration (2001) Guidance for industry-bioanalytical method validation. U.S. Department of Health and Human Services; Food and Drug Administration; Center for Drug Evaluation; and Research Center for Veterinary Medicine
Holleran JL, Parise RA, Yellow-Duke AE, Egorin MJ, Eiseman JL, Covey JM, Beumer JH (2010) Liquid chromatography-tandem mass spectrometric assay for the quantitation in human plasma of the novel indenoisoquinoline topoisomerase I inhibitors, NSC 743400 and NSC 725776. J Pharm Biomed Anal 52(5):714–720. doi:10.1016/j.jpba.2010.02.020
Wiwi CA, Waxman DJ (2004) Role of hepatocyte nuclear factors in growth hormone-regulated, sexually dimorphic expression of liver cytochromes P450. Growth Factors 22(2):79–88
Waxman DJ, O’Connor C (2006) Growth hormone regulation of sex-dependent liver gene expression. Mol Endocrinol 20(11):2613–2629. doi:10.1210/me.2006-0007
Beumer JH, Holleran JL, Doroshow JH, Chen A, Allen D, Covey JM, Tomaszewski JE, Pommier Y, Kummar S, Eiseman JL (2014) Phase I pharmacokinetics and pharmacodynamics of a novel indenoisoquinoline topoisomerase 1 (TOP1) inhibitor, LMP400, administered on a daily × 5 schedule. In: Annual Meeting of the American Association for Cancer Research San Diego, p 4643
Cinelli MA, Reddy PV, Lv PC, Liang JH, Chen L, Agama K, Pommier Y, van Breemen RB, Cushman M (2012) Identification, synthesis, and biological evaluation of metabolites of the experimental cancer treatment drugs indotecan (LMP400) and indimitecan (LMP776) and investigation of isomerically hydroxylated indenoisoquinoline analogues as topoisomerase I poisons. J Med Chem 55(24):10844–10862. doi:10.1021/jm300519w
U.S. Department of Health and Human Services Food and Drug Administration (2007) Topotecan pharmacology/toxicology review and evaluation. U.S. Department of Health and Human Services; Food and Drug Administration; Center for Drug Evaluation and Research
Giovanella BC, Stehlin JS, Hinz HR, Kozielski AJ, Harris NJ, Vardeman DM (2002) Preclinical evaluation of the anticancer activity and toxicity of 9-nitro-20(S)-camptothecin (Rubitecan). Int J Oncol 20(1):81–88
Zahalka E, Seung H, Glaze E, Tomaszewski J, Cushman M, Pommier Y (2007) Pilot toxicity study of indenoisoquinoline analogs (NSC-725776 and NSC-724998) in beagle dogs. In: Annual Meeting of the American Association for Cancer Research, April 14, 2007, p 1562
Acknowledgments
This research was supported by NCI contracts N01-CM-42202 (IITRI), N01-CM-52202, HHSN261201100015C (University of Pittsburgh), and N01-CM-42204 (Bridge), and this project used the UPCI Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) and was supported in part by award P30CA047904.
Ethical standard
All human and animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Merrill J. Egorin: Deceased.
Rights and permissions
About this article
Cite this article
Muzzio, M., Hu, SC., Holleran, J.L. et al. Plasma pharmacokinetics of the indenoisoquinoline topoisomerase I inhibitor, NSC 743400, in rats and dogs. Cancer Chemother Pharmacol 75, 1015–1023 (2015). https://doi.org/10.1007/s00280-015-2722-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-015-2722-y