Pharmacokinetic Optimisation of the Treatment of Cancer with High Dose Zidovudine

摘要: The thymidine analogue zidovudine is currently used for the treatment of HIV-infected patients, as early development drug an anticancer agent yielded modest results. A comprehensive preclinical analysis, however, showed that inhibitors de novo thymidylate synthesis, including fluorouracil and methotrexate, enhanced antiproliferative activity in cancer cells. Significant inhibition tumour growth was obtained mice bearing human colon xenografts given intraperitoneal 300 to 600 mg/kg weekly combination with methotrexate 87.5 or 85 mg/kg, pharmacokinetic studies high peak plasma concentrations (Cmax) were obtained, ranging from 610.3 1698.8 μmol/L. In order exploit therapeutic zidovudine, phase I II clinical designed pharmacokinetic-pharmacodynamic profile investigated. Clinical responses patients treated intravenously bolus 500 mg/m2, leucovorin short (90 120 minutes) infusions dose (up 10 g/m2), generating Cmax similar those models. However, chemotherapy-pretreated receiving by oral route (1 9 g/m2/day) 48-hourly continuous intravenous infusion (2 20 leucovorin, failures observed despite systemic exposure, described area under concentration-time curve occurrence DNA strand breaks peripheral blood mononucleated cells, biological expression activity. conclusion, evidence suggest schedule administration a requisite its activity, indicating importance concentration-monitored trials optimise chemotherapy patients. likelihood response appears be related achievement constant appear less likely produce