Pharmacokinetic study and evaluation of the safety of taurolidine for dogs with osteosarcoma

Journal of Experimental & Clinical Cancer Research

Bernard Séguin¹  Shay Bracha⁵  Lisa Brownlee¹  William G Tracewell³  John E Mata²  Jennifer Simpson⁴  Stuart C Helfand⁵  Kevin Marley⁵ 

[1] Animal Cancer Center, 300 W Drake Rd, Fort Collins, CO 80523, USA;College of Osteopathic Medicine of the Pacific-Northwest, Western University of Health Sciences, 200 Mullins Drive, Lebanon, OR 97355, USA;Teva Pharmaceuticals, 145 Brandywine Parkway, West Chester, PA 19380, USA;Veterinary Medical and Surgical Group, 2199 Sperry Ave, Ventura, CA 93003, USA;Department of Clinical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA

关键词: Dog;    Osteosarcoma;    Carboplatin;    Doxorubicin;    Taurolidine;   

Others  :  815079
DOI  :  10.1186/1756-9966-32-74

 received in 2013-08-19, accepted in 2013-09-18,  发布年份 2013

【 摘 要 】

Background

Osteosarcoma in dogs and humans share many similarities and the dog has been described as an excellent model to study this disease. The median survival in dogs has not improved in the last 25 years. Taurolidine has been shown to be cytotoxic to canine and human osteosarcoma in vitro. The goals of this study were to determine the pharmacokinetics and safety of taurolidine in healthy dogs and the safety of taurolidine in combination with doxorubicin or carboplatin in dogs with osteosarcoma.

Methods

Two percent taurolidine was infused into six healthy dogs (150 mg/kg) over a period of two hours and blood samples were taken periodically. One dog received taurolidine with polyvinylpyrrolidone (PVP) as its carrier and later received PVP-free taurolidine as did all other dogs in this study. Serum taurolidine concentrations were determined using high-performance liquid chromatography (HPLC) online coupled to ESI-MS/MS in the multiple reaction monitoring mode. Subsequently, the same dose of taurolidine was infused to seven dogs with osteosarcoma also treated with doxorubicin or carboplatin.

Results

Taurolidine infusion was safe in 6 healthy dogs and there were no significant side effects. Maximum taurolidine serum concentrations ranged between 229 to 646 μM. The dog that received taurolidine with PVP had an immediate allergic reaction but recovered fully after the infusion was stopped. Three additional dogs with osteosarcoma received doxorubicin and taurolidine without PVP. Toxicities included dilated cardiomyopathy, protein-losing nephropathy, renal insufficiency and vasculopathy at the injection site. One dog was switched to carboplatin instead of doxorubicin and an additional 4 dogs with osteosarcoma received taurolidine-carboplatin combination. One incidence of ototoxicity occurred with the taurolidine- carboplatin combination. Bone marrow and gastro-intestinal toxicity did not appear increased with taurolidine over doxorubicin or carboplatin alone.

Conclusions

Taurolidine did not substantially exacerbate bone marrow or gastro-intestinal toxicity however, it is possible that taurolidine increased other toxicities of doxorubicin and carboplatin. Administering taurolidine in combination with 30 mg/m² doxorubicin in dogs is not recommended but taurolidine in combination with carboplatin (300 mg/m²) appears safe.

【 授权许可】

   
2013 Marley et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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