Abstract
Capecitabine is a prodrug, is selectively activated by tumor cells to its cytotoxic moiety, 5-fluorouracil, by thymidine phosphorylase, which is generally expressed at high levels in tumors. Clinical and pharmacokinetics studies for capecitabine are perfomed in patients with cancer. The objective of the study was to evaluate the safety of a bioequivalence study (150 mg tablet) using healthy male volunteers under fasting and non-fasting conditions. The study was conducted with an open, randomized, two-period crossover design in a 2-week washout interval without food. After the study without food was completed, a new protocol was submitted to the Ethics Committee to evaluate the study with food. The volunteers were selected for the study after having their health status previously assessed by a clinical evaluation and laboratory tests (biochemical and hematological parameters, and urinalysis). A single capecitabine tablet (150mg) was given in each interment. An extra laboratory analysis was performed one week after the first administration of the drug for the safety of the subjects. Plasma capecitabine concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (HPLC/MS/MS) with positive ion electrospray ionization using multiple reactions monitoring (MRM). The pharmacokinetic parameters were 529.38 (±265.22) and 462.88 (±425.85) ng.mL -1 for C max , 262.31 (±75.34) and 300.49 (±91.51) ng.hr.mL -1 for AUC last , and 0.66 (range 0.5 – 1.25) hr and 1.0 (range 0.33 – 1.33) hr for T max , without and with food, respectively, for the reference formulation. The intra-subject CV were 42.6% and 76.3% for C max and 9.64% and 20.3% for AUC last without and with food, respectively. The drug was well tolerated by the volunteers, and they presented no adverse reactions. The biochemical and hematological parameters presented no clinically relevant alterations. Our results indicate that it is safe to perform capecitabine bioequivalence studies in healthy male volunteers.
Highlights
Capecitabine is an adjuvant treatment for colon cancer and for the treatment of metastatic breast cancer in particular patients whose pathology did not improve during treatment with other therapeutic agents [6,7,8,9,10,11]
Capecitabine is a prodrug is selectively activated by tumor cells to its cytotoxic moiety, 5-fluorouracil, by thymidine phosphorylase, which is generally expressed at high levels in tumors [6,7,8,9,10,11]
Maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) values are decreased after the ingestion of food [4,5]
Summary
Capecitabine is an adjuvant treatment for colon cancer and for the treatment of metastatic breast cancer in particular patients whose pathology did not improve during treatment with other therapeutic agents [6,7,8,9,10,11]. Clinical and pharmacokinetics studies for capecitabine are performed in both healthy volunteers and patients with cancer [18]. The capecitabine is administrated orally, morning and evening, for 14 consecutive days followed by 1 week of no drug (3-week cycles) [4,5,6]. The incidence of adverse reactions observed in breast and colorectal cancer patients after 2500 mg/m2 per day (the average therapy was 127 days) was as follows: 1-10%: taste disturbance, chest pain, alopecia, gastrointestinal hemorrhage, thrombocytopenia, cough, venous thrombosis, dehydration, skin/nail discoloration, insomnia, back pain, oral discomfort, gastrointestinal motility disorder, dizziness, arthralgia/myalgia, headache; 11-20%: dyspnea, neuropathy/ paresthesia, eye irritation, edema, constipation, neutropenia, pyrexia; 21-30%: lymphopenia, stomatitis, anorexia, dermatitis, vomiting; 31%40%: abdominal pain; 41-50%: fatigue/weakness, hyperbilirubenemia, nausea; > 50%: hand-foot syndrome, diarrhea, anemia [5,6]
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