caa a22 4500 475818687 CHVBK 20180406123816.0 cr unu---uuuuu 170329e20001101xx s 000 0 eng 10.1007/s002280000181 doi (NATIONALLICENCE)springer-10.1007/s002280000181 Models of schedule dependent haematological toxicity of 2'-deoxy-2'-methylidenecytidine (DMDC) [Elektronische Daten] [L.E. Friberg, C.J. Brindley, M.O. Karlsson, A.J. Devlin] Abstract.: Objective: DMDC (2'-deoxy-2'-methylidenecytidine) is a potential antitumour deoxycytidine analogue of cytosine arabinoside. The major dose-limiting toxicity of DMDC is haematological depression, particularly neutropenia, and therefore quantitative exposure-toxicity relationships for DMDC are warranted. Methods: Data on the survival fraction at nadir of leukocytes, neutrophils and platelets from 66 patients receiving a once-daily regimen and 85 patients receiving a twice-daily regimen of DMDC were related to DMDC concentration-time profiles using area under the plasma concentration-time curve (AUC), threshold and general models. A semiphysiological model of neutrophils versus time after DMDC administration included transient compartments to imitate the differentiation stages in the bone marrow. Results: The relationship between plasma DMDC concentration-time profiles and the haematological toxicity at nadir was best described using an AUC-dependent model with separate functions for once- and twice-daily dosing, indicating schedule dependence of DMDC effects, even if differences in treatment duration had a similar explanatory value. Twice-daily dosing was associated with greater toxic effects than once-daily dosing. The AUC required for a 70% reduction in the neutrophils was 16mgh/l and 4.2mg·h/l for the once- and twice-daily regimens, respectively. The semiphysiological model included nine proliferating transient compartments that were sensitive to DMDC in a schedule-dependent manner, five non-mitotic, non-sensitive compartments and one compartment for circulating neutrophils. Conclusions: The haematological toxicity of DMDC is schedule dependent. The survival fractions of leukocytes, neutrophils and platelets are predicted to be lower when given on a twice-daily regimen than on a once-daily regimen. A semiphysiological model with transient compartments successfully described the entire time course of neutropenia after DMDC administration. Springer-Verlag, 2000 DMDC Schedule dependence Haematological toxicity nationallicence Friberg L.E. Division of Biopharmaceutics and Pharmacokinetics, Uppsala University, Box 580, SE-751 23, Uppsala, Sweden aut Brindley C.J. Department of Metabolism and Pharmacokinetics, Quintiles Scotland Limited, Edinburgh, UK aut Karlsson M.O. Division of Biopharmaceutics and Pharmacokinetics, Uppsala University, Box 580, SE-751 23, Uppsala, Sweden aut Devlin A.J. Protodigm Limited, Hemel Hempstead, UK aut European Journal of Clinical Pharmacology Springer-Verlag 56/8(2000-11-01), 567-574 0031-6970 56:8<567 2000 56 228 https://doi.org/10.1007/s002280000181 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s002280000181 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Friberg L.E. Division of Biopharmaceutics and Pharmacokinetics, Uppsala University, Box 580, SE-751 23, Uppsala, Sweden aut NATIONALLICENCE 700 1- Brindley C.J. Department of Metabolism and Pharmacokinetics, Quintiles Scotland Limited, Edinburgh, UK aut NATIONALLICENCE 700 1- Karlsson M.O. Division of Biopharmaceutics and Pharmacokinetics, Uppsala University, Box 580, SE-751 23, Uppsala, Sweden aut NATIONALLICENCE 700 1- Devlin A.J. Protodigm Limited, Hemel Hempstead, UK aut NATIONALLICENCE 773 0- European Journal of Clinical Pharmacology Springer-Verlag 56/8(2000-11-01), 567-574 0031-6970 56:8<567 2000 56 228 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer