Introduction

Cyclophosphamide (CP) is an alkylating chemotherapeutic included in many treatment protocols for canine cancer. CP requires hepatic metabolism for activation to the intermediate compound 4-hydroxycyclophosphamide (4-OHCP) which then spontaneously forms alkylating phosphoramide mustard. The total dose of CP is frequently fractionated and given over multiple days. CP is reported to cause auto-induction of metabolism in humans, with faster CP clearance and relatively increased 4-OHCP formation following fractionated versus bolus dosing, however, canine pharmacokinetic studies of CP dose fractionation are lacking.

Methods

The study objective was to evaluate the pharmacokinetics of fractionated oral CP at the standard dose of 200–250 mg/m2 over multiple days in a prospectively identified population of cancer-bearing dogs. Plasma concentrations of CP and 4-OHCP were measured by ultra-high performance liquid chromatography tandem-mass spectrometry in seven dogs following the first and last pills to assess for auto-induction of CP metabolism.

Results

A non-parametric, paired T-test of elimination rate values showed no significant difference in the rate of CP elimination between first and last doses (0.73±0.46 h-1 versus 1.22±0.5 h-1; p=0.125). Additionally, no significant difference in dose-normalized 4-OHCP exposure was identified between first and last doses (5.9±2.1 h*ng/mL versus 7.9±6.4 h*ng/mL; p=0.936).

Conclusion

These results suggest that fractionated dosing may not increase exposure to the active metabolite of CP in dogs as it does in humans. As such, oral bolus and fractionated dosing may be equivalent in terms of bio-activation of CP in dogs administered standard dosing of 200–250 mg/m2.

Funding Information

Supported by the Center for Companion Animal Health, School of Veterinary Medicine, University of California-Davis, Davis, CA, USA.