Pharmacokinetic and Safety Comparison of Two Capecitabine Tablets in Patients With Colorectal or Breast Cancer

This was a multicenter, open, random, balanced, three-period, three-sequence and semi-repetitive cross study with 48 subjects. Eligible subjects were randomly assigned in a 1:1:1 ratio to receive one period of test formulation or two period of reference formulation, followed by a 1-day washout period and administration of the alternate formulation. Serial blood samples for pharmacokinetic assessment were collected at 0 hours (predose) up to 8 hours postdose. The plasma concentrations of capecitabine were analyzed by LC/MS-MS. Pharmacokinetic parameters (non-compartmental model) were assessed with WinNonlin software. The pharmacokinetic parameters assessed were area under the plasma concentration-time curve from time 0 to the time of last measurable concentration (AUC0-t), AUC from time zero to infinity (AUC0-∞), the peak plasma concentration of the drug (C max ), time needed to reach maximum concentration (Tmax), the elimination half-life (t1/2), and terminal elimination rate (λz). All were analyzed using an ANOVA model after logarithmic transformation of the data. For establishing bioequivalence (BE) for capecitabine， reference-scaled average bioequivalence (RSABE) acceptance criteria and average bioequivalence (ABE) acceptance criteria were used. Safety and tolerability was assessed during the entire study period.

Inclusion criteria

• Patients with histologically or cytologically confirmed colorectal or breast cancer receiving capecitabine monotherapy or combination chemotherapy.
• Eligible patients were within 18-70 years of age.
• ECOG score was 0-2.
• Left ventricular ejection fraction (LVEF) > 50%.
• There was no serious persistent toxicity to capecitabine treatment before screening (laboratory tests ≤ grade 1 (NCI CTCAE 5.0 standard)
• Hand-foot syndrome ≤ grade 2 after recovery from the previous treatment period).

Exclusion criteria

• Patients were known allergy to fluorouracil or 5-fluorouracil.
• Patients with complete lack of known dihydropyrimidine dehydrogenase (DPD) activity.
• Patients with abnormal hepatic and renal function (serum creatinine≤ 1.5 ×ULN; CLcr ≥ 51 mL/min; bilirubin≤ 1.5 ×ULN; AST, ALT≤2.5×ULN)
• Needed to accept phenytoin, warfarin, other coumarin derivatives anticoagulants, folic acid, and CYP2C9 substrates during the research.
• Patients with brain metastases or other metastases of the central nervous system (except those who were treated at least 6 months prior to the start of the study and were stable and asymptomatic).