Evaluation of Satraplatin in Dogs with Spontaneously Occurring Malignant Tumors

Journal of Veterinary Internal Medicine

K.A. Selting²  X. Wang³  D.L. Gustafson¹  C.J. Henry²  J.A. Villamil²  D.L. McCaw²  D. Tate²  M. Beittenmiller²  C. Garnett² 

[1] Animal Cancer Center, Colorado State University, Fort Collins, CO.;Departments of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO;Department of Chemistry, and MU Research Reactor, University of Missouri, Columbia, MO

关键词: Canine;    Chemotherapy;    Clinical pharmacology;    Pharmacokinetics;    Pharmacology;   

DOI  :  10.1111/j.1939-1676.2011.0727.x

来源: Wiley

【 摘 要 】

Abstract

Background: Satraplatin is the 1st orally bioavailable platinum anticancer drug.

Objective: Our objectives were to evaluate efficacy in vitro against a canine cancer cell line, to determine the maximally tolerated dose (MTD) of satraplatin in tumor-bearing dogs, to identify the dose-limiting and other toxicities in dogs, and to record pharmacokinetics (PK).

Animals: Dogs with macro- or microscopic malignant neoplasia.

Methods: D17 canine osteosarcoma cells first were evaluated in a clonogenic survival assay. Then, dogs with a diagnosis of malignant neoplasia were prospectively entered in standard 3 + 3 cohorts. Additional patients were entered at the MTD to assess efficacy. Total and free platinum (by ultrafiltrate) concentrations were determined with inductively coupled plasma mass spectroscopy.

Results: Satraplatin inhibited clonogenic survival in vitro at clinically relevant and achievable concentrations. Twenty-three dogs were treated, 14 with PK evaluation. The MTD was 35 mg/m²/d for 5 days, repeated every 3–4 weeks. Bioavailability was 41%. PK variables (mean ± SD) at the MTD included T_max 1.8 (± 0.7) hours, C_max 72 (± 26) ng/mL, area under concentration (AUC)_{0–24 h} 316 (± 63) h × ng/mL, and MRT 7 (± 1.3) hours. Higher AUC after the 5th versus the 1st dose suggested drug accumulation. Interestingly, platelets consistently reached nadir sooner than did neutrophils (day 14 versus 19). Myelosuppression was dose-limiting and gastrointestinal toxicity was mild.

Conclusions and Clinical Importance: Satraplatin was well tolerated in tumor-bearing dogs, thus warranting further investigation in a phase II trial.

【 授权许可】

Unknown   
Copyright © 2011 by the American College of Veterinary Internal Medicine