Models of schedule dependent haematological toxicity of 2'-deoxy-2'-methylidenecytidine (DMDC).

摘要: Objective: DMDC (2'-deoxy-2'-methylidenecytidine) is a potential antitumour deoxycytidine analogue of cytosine arabinoside. The major dose-limiting toxicity haematological depression, particularly neutropenia, and therefore quantitative exposure–toxicity relationships for are warranted. Methods: Data on the survival fraction at nadir leukocytes, neutrophils platelets from 66 patients receiving once-daily regimen 85 twice-daily were related to concentration–time profiles using area under plasma curve (AUC), threshold general models. A semiphysiological model versus time after administration included transient compartments imitate differentiation stages in bone marrow. Results: relationship between was best described an AUC-dependent with separate functions once- dosing, indicating schedule dependence effects, even if differences treatment duration had similar explanatory value. Twice-daily dosing associated greater toxic effects than dosing. AUC required 70% reduction 16 mgh/l 4.2 mg·h/l regimens, respectively. nine proliferating that sensitive schedule-dependent manner, five non-mitotic, non-sensitive one compartment circulating neutrophils. Conclusions: dependent. fractions predicted be lower when given regimen. successfully entire course neutropenia administration.