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

Abstract

BackgroundOsteosarcoma 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.MethodsTwo 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.ResultsTaurolidine 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.ConclusionsTaurolidine 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.

The autophagy inhibitor spautin-1, either alone or combined with doxorubicin, decreases cell survival and colony formation in canine appendicular osteosarcoma cells

“…Despite being the most common and aggressive bone neoplasm of dogs, the treatment used for canine appendicular osteosarcoma has been largely unchanged for decades [ 1 ]. The addition of adjuvant chemotherapy post-amputation was investigated in the late 1980s [ 2 – 6 ], was further evaluated and made common practice in the 1990s [ 3 , 7 – 10 ], and remains the standard of care for curative intent today.…”

“…The use of these two chemotherapeutics has also been compared retrospectively with no significant difference in outcome [ 19 ]. New or alternative therapeutic agents, including other platinum compounds, different classes of chemotherapeutics, bisphosphonates and other palliative therapies, liposome-encapsulated drugs, matrix metalloproteinase inhibitors, mTOR inhibitors, tyrosine kinase inhibitors, human cytotoxic T-cells, immunotherapies, drugs that target multi-drug resistance, and even personalized strategies have not proved superior to the current regimen [ 1 , 20 – 32 ]. There is however, a new vaccine with promising phase I results [ 33 ].…”

Lateral manus translation for limb‐sparing surgery in 18 dogs with distal radial osteosarcoma in dogs

“…Chemotherapy protocols included carboplatin alone, doxorubicin alone, and a combination of doxorubicin and carboplatin. Three dogs were also administered taurolidine as part of a clinical trial . One dog received metronomic chemotherapy with cyclophosphamide and carprofen, followed by toceranib after metastatic disease was detected.…”

Evaluation of the safety and efficacy of TRAIL and taurolidine use on human fibrosarcoma xenografts in vivo

“…Although taurolidine has been assumed to be well-tolerated, severe side effects have been observed in preclinical studies (39)(40)(41). In a recent study evaluating the antineoplastic effects of taurolidine in immunocompetent mice with osteosarcoma, taurolidine was associated with severe liver toxicity, with a notable increase of liver enzymes, and led to pathological alterations of hepatocytes as detected by electron microscopy (39).…”

“…In a recent study evaluating the antineoplastic effects of taurolidine in immunocompetent mice with osteosarcoma, taurolidine was associated with severe liver toxicity, with a notable increase of liver enzymes, and led to pathological alterations of hepatocytes as detected by electron microscopy (39). Further studies assessing the safety of taurolidine in dogs and canines with osteosarcoma demonstrated that taurolidine enhanced the systemic toxicity of chemotherapeutics like doxorubicin and carboplatin (40,41). Although initial clinical tests in humans reported low toxicity (42)(43)(44)(45), the present findings suggest that cautious use is advisable, and raise concern with regard to the therapeutic index of taurolidine, which must be analysed by forthcoming studies with detailed toxicity tests.…”