Pharmacokinetics of Carboplatin in Combination with Low-Dose Cyclophosphamide in Female Dogs with Mammary Carcinoma

SIMPLE SUMMARY: This study was designed to assess the effect of metronomic cyclophosphamide on carboplatin’s tolerability, efficacy, and pharmacokinetics in female dogs with mammary carcinoma. Sixteen female dogs with mammary carcinoma were treated with 300 mg/m(2) intravenous (i.v.) carboplatin therapy (n = 8) or 300 mg/m(2) i.v. carboplatin which was associated with 12.5 mg/m(2)/day oral cyclophosphamide (n = 8). A non-compartmental analysis was applied to calculate the PK parameters of carboplatin in the second and fourth chemotherapy cycles. The carboplatin pharmacokinetics showed high interindividual variability with 10-fold variation in the area under the plasma concentration–time curve (AUC) in the animals receiving carboplatin only. The systemic plasma exposure (AUC and C(max)) to carboplatin was equivalent in both of the treatments (carboplatin alone and carboplatin + cyclophosphamide). Carboplatin + metronomic cyclophosphamide was well-tolerated by all of the animals. Our results demonstrated that adding low daily doses of cyclophosphamide to the carboplatin therapy increased the survival rate of the female dogs with mammary cancer. ABSTRACT: This prospective study aimed to evaluate the effect of metronomic cyclophosphamide on carboplatin’s tolerability, efficacy, and pharmacokinetics in dogs with mammary carcinoma. Sixteen female dogs with mammary carcinoma were divided into groups: 300 mg/m(2) intravenous (i.v.) carboplatin therapy (G1 = 8) or 300 mg/m(2) i.v. carboplatin which was associated with 12.5 mg/m(2) oral cyclophosphamide in a metronomic regimen (G2 = 8). The investigated animals underwent a clinical evaluation, a mastectomy, a carboplatin chemotherapy, and serial blood sampling for the pharmacokinetic analysis. The adverse events and survival rates were monitored. A non-compartmental analysis was applied to calculate the pharmacokinetic parameters of carboplatin in the 2nd and 4th chemotherapy cycles. Carboplatin PK showed high interindividual variability with a 10-fold variation in the area under the plasma concentration–time curve (AUC) in G1. The systemic plasma exposure to carboplatin was equivalent in both of the treatments considering the AUC and maximum plasma concentration (C(max)) values. Although the red blood cells (p < 0.0001), platelets (p = 0.0005), total leukocytes (p = 0.0002), and segmented neutrophils (p = 0.0007) were reduced in G2, the survival rate increased (p = 0.0044) when it was compared to G1. In conclusion, adding low daily doses of cyclophosphamide to a carboplatin therapy showed promising outcomes in female dogs with mammary tumors.