**Background:** Capecitabine is an oral prodrug of 5-fluorouracil used in humans for colorectal, head and neck, and mammary carcinomas. It is relatively inexpensive, has a short half-life, and is thought to preferentially target cancer cells due to differential thymidine phosphorylase expression. However, its use in dogs with carcinomas had not been widely explored. This pilot study aimed to determine the plasma disposition of capecitabine after a single oral dose and document adverse events over 5 weeks in carcinoma-bearing dogs.
**Methods:** Five client-owned dogs with naturally occurring carcinomas (squamous cell carcinoma, thyroid carcinoma, anal sac adenocarcinoma, perianal carcinoma, urothelial carcinoma) were enrolled. Dogs were fasted for at least 8 hours, then received a single oral dose of capecitabine at 750 mg/m² (rounded to nearest tablet size, within 10% variation). Blood samples were collected at 0, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, and 24 hours post-dose. Plasma capecitabine concentrations were measured via UPLC-MS/MS (limit of quantification 0.25 ng/ml). Dogs then received 14 daily doses of capecitabine at 750 mg/m² in a 3-week cycle, with rechecks at 2 and 5 weeks including CBC, chemistry, fluorescein eye stain, and tumor imaging. Adverse events were graded using VCOG criteria. Pharmacokinetic parameters were determined via noncompartmental analysis.
**Key Results:** All five dogs completed the study. No dogs withdrew due to adverse events. The median AUC₀₋ₗₐₛₜ was 890 h·ng/ml (range 750-1100 h·ng/ml), and median AUC₀₋₆ₕᵣₛ was 1000 h·ng/ml (range 790-1100 h·ng/ml) for those with peaks before 6 hours. Maximum plasma concentration (Cmax) was highly variable: median 370 ng/ml (range 190-2600 ng/ml). Time to Cmax (Tmax) ranged from 0.25 to 6 hours (median 3 hours). No dog had detectable capecitabine at 24 hours; only 3 dogs had detectable levels at 10 hours (median 3.8 ng/ml, range 0.43-17 ng/ml). Adverse events were generally low grade: one dog had grade 1 constipation, one had grade 1 lethargy, one had a possible grade 3 syncopal episode (resolved spontaneously, no recurrence), one had grade 1 vomiting if NSAID given concurrently, and one had grade 2 lethargy/inappetence and grade 1 neutropenia (likely due to tumor progression). No ocular changes or cutaneous lesions were observed. Tumor response at 5 weeks: 3 dogs had progressive disease, 2 had stable disease (one perianal carcinoma, one anal sac adenocarcinoma; both continued capecitabine off-study with tumor control at 150 and 73 days post-first dose, respectively).
**Clinical Implications:** This pilot study suggests that oral capecitabine at 750 mg/m² once daily is well tolerated in dogs with carcinomas, with only mild adverse events and no neurotoxicity or ocular toxicity observed (contrasting with prior studies using capecitabine in immunosuppressive regimens). The high inter-individual variability in Cmax and Tmax indicates that individualized dosing may be necessary. The AUC values in dogs (750-1100 h·ng/ml) are lower than those reported in humans (5500-7300 h·ng/ml), suggesting a higher dose may be needed for therapeutic efficacy. The rapid clearance (no detectable drug by 24 hours) supports evaluation of twice-daily dosing or shorter intervals. Limitations include small sample size, short follow-up (5 weeks), concurrent medications, and inability to quantify the active metabolite 5-fluorouracil. Larger phase 1 dose-finding studies are warranted to establish optimal dosing and efficacy.