Serum Symmetric Dimethylarginine as a Predictor of Toxicity of Carboplatin in Dogs.

Abstract

Glomerular filtration rate (GFR) predicts carboplatin clearance and myelotoxicity in humans and cats. This relationship is unknown in dogs. In canines, elevated serum symmetric dimethylarginine (SDMA) correlates with reduced GFR. This study prospectively evaluated whether dogs with elevated SDMA (>&#x2009;14&#x2009;&#x3bc;g/dL) are at increased risk of hematologic and gastrointestinal toxicity following carboplatin chemotherapy. Plasma samples were collected to determine if SDMA or other factors are significant determinants of carboplatin pharmacokinetics. Thirty client-owned dogs weighing >&#x2009;15&#x2009;kg with confirmed neoplasia were enrolled. Dogs received carboplatin intravenously (300&#x2009;mg/m). SDMA was measured on the day of treatment. Nonlinear mixed effects modelling was done to identify possible covariates affecting pharmacokinetic parameters. Adverse effects were monitored with weekly complete blood counts and owner assessment forms. Five dogs had elevated SDMA; four had significantly reduced carboplatin clearance (mean 93.9, range 76.1-116.8&#x2009;mL/h/kg) compared with dogs with SDMA &#x2264;&#x2009;14&#x2009;&#x3bc;g/dL (mean 185.4, range 114.3-268.3&#x2009;mL/h/kg, p&#x2009;<&#x2009;0.001). Three dogs with elevated SDMA experienced grade 4 neutropenia; one was euthanized due to sepsis. Two additional dogs with elevated SDMA were euthanized 5- and 13-days post treatment due to severe gastrointestinal signs. Twenty-five dogs had SDMA &#x2264;&#x2009;14&#x2009;&#x3bc;g/dL: 10 had asymptomatic grade 3 or 4 neutropenia, 3 had grade 3 or 4 GI toxicity, and none died. Elevated SDMA was associated with decreased carboplatin clearance in dogs and predicted risk for treatment-related toxicity and death in our study population.