Pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide in cats after oral, intravenous, and intraperitoneal administration of cyclophosphamide

Abstract

OBJECTIVE To characterize pharmacokinetics of cyclophosphamide and 4-hydoxycyclophosphamide (4-OHCP) in the plasma of healthy cats after oral, intravenously, or intraperitoneal administration of cyclophosphamide. ANIMALS 6 healthy adult cats. PROCEDURES Cats were randomly assigned to receive 200 mg/m2 of cyclophosphamide via each of 3 routes of administration (oral, IV, and IP); there was a 30-day washout period between successive treatments. Plasma samples were obtained at various time points for up to 8 hours after administration. Samples were treated with semicarbazide hydrochloride to trap the 4-OHCP in stable form, which allowed for cyclophosphamide and trapped 4-OHCP to be simultaneously measured by use of tandem mass spectrometry. Pharmacokinetic parameters were determined from drug concentration–versus-time data for both cyclophosphamide and 4-OHCP. RESULTS Cyclophosphamide was tolerated well regardless of route of administration. Pharmacokinetic parameters for 4-OHCP were similar after oral, IV, and IP administration. Area under the concentration-time curve for cyclophosphamide was lower after oral administration than after IV or IP administration. CONCLUSIONS AND CLINICAL RELEVANCE Cyclophosphamide can be administered interchangeably to cats as oral, IV, and IP, formulations, which should provide benefits with regard to cost and ease of administration to certain feline patients. (Am J Vet Res 2017;78:862–866)

Kinetics of Cyclophosphamide Metabolism in Humans, Dogs, Cats, and Mice and Relationship to Cytotoxic Activity and Pharmacokinetics

“…A semiphysiologic model describing the metabolism of CP was generated and used to simulate CP PK using each of the listed microsome's kinetics parameters. Simulation output, in colored lines, is compared with published PK data for (A) dogs (Warry et al, 2011), (B) cats (Stroda et al, 2017), and (C) mice (Supplemental Fig. 4), where each symbol represents plasma CP concentrations from one animal subject.…”

“…For the cytotoxicity assay, we treated cells with microsomes and CP at a range from 3.8 to 3831 mM for 2 hours, then monitored cytotoxicity and quantified cell death after 72 hours via IncuCyte imaging. These concentrations were chosen to encompass a wide range of pharmacologic CP concentrations observed at clinically relevant doses, which includes the following: cat C max = 35.2 mM (Stroda et al, 2017), dog C max = 78.5 mM (Warry et al, 2011), mouse C max = 204.1 mM, and human C max = 700 mM . Nonpharmacologic concentrations of CP were also included to capture fully the cytotoxic phenomena.…”

“…4). Plasma PK data from canine (Warry et al, 2011), feline (Stroda et al, 2017), and human (Struck et al, 1987; subjects were also used in the model. Simulated PK data from the model were compared against the intravenous dosing scheme (bolus or infusion) and clinical PK data.…”

“…Typical chemotherapeutic doses in humans are 500-1200 mg/m 2 cumulatively when administered every 21 days either as a single dose or fractionated over multiple doses (de Jonge et al, 2005;Penel et al, 2012). Chemotherapeutic doses of CP in dogs and cats range from 200 to 250 mg/m 2 (Garrett et al, 2002;Warry et al, 2011) and from 200 to 300 mg/m 2 (Teske et al, 2002;Stroda et al, 2017), respectively, and are reflective of the University of Wisconsin-Madison protocol and its variations. The doses used in humans, dogs, and cats are empirically determined from the maximum tolerated dose in each of the species with sparse historical pharmacokinetic data available for comparison owing to the complex nature of CP pharmacology.…”

Determination of O6-Methylguanine in dried blood spot of breast cancer patients after cyclophosphamide administration

“…Then, 4-OHCP and Aldophosphamide enter the cells. Aldophosphamide is decomposed into active alkylating metabolites, namely Phosphoramide mustard and acrolein (a by-product with less activity) [12]. This [13].…”