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Vet Comp Oncol. 2019 Jan 14. doi: 10.1111/vco.12455. [Epub ahead of print]

Doxorubicin area under the curve is an important predictor of neutropenia in dogs with naturally occurring cancers.

Author information

1
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, California.
2
Flint Animal Cancer Center, College of Veterinary Medicine and Biological Sciences, Colorado State University, Fort Collins, Colorado.
3
Comprehensive Cancer Center, University of Colorado Comprehensive Cancer Center, Aurora, Colorado.

Abstract

Doxorubicin (DOX) area-under-the-curve (AUC) was calculated for 40 dogs with spontaneously occurring cancers using a previously validated limited-sampling approach. All dogs were administered a dose of 30 mg/m2 by intravenous infusion and serum samples were collected at 5, 45 and 60 minutes post-infusion. DOX and its major metabolite, doxorubicinol (doxol), were quantified in serum samples using high-performance liquid chromatography tandem-mass spectrometry. Wide interpatient variability was observed in the predicted DOX AUC with a coefficient of variation of 34%. A significant relationship was found between DOX AUC and absolute white blood cell count (P = 0.003), absolute neutrophil count (ANC; P = 0.002) and surviving fraction of neutrophils (P = 0.03) approximately 1 week after dosing (nadir). No changes in other hematologic parameters (red blood cells, platelets, lymphocytes, haemoglobin) were found to correlate with DOX AUC. The absolute dose (mg) and the dose per unit body weight (mg/kg) were not significantly correlated with nadir ANC. No relationships were found between maximum serum doxol concentration and myelosuppression. Baseline ANC was also significantly correlated to nadir ANC and a model was constructed using baseline ANC and DOX AUC that significantly described the nadir ANC. These findings demonstrate the important relationship between systemic DOX exposure and degree of neutropenia in dogs, and suggest a potential for individualized, pharmacokinetically-guided DOX dosing in dogs.

KEYWORDS:

canine cancer; doxorubicin; limited-sampling model; pharmacokinetic-pharmacodynamic relationship

PMID:
30638304
DOI:
10.1111/vco.12455

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