L E Friberg1, C J Brindley, M O Karlsson, A J Devlin. 1. Division of Biopharmaceutics and Pharmacokinetics, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden. Lena.Friberg@biof.uu.se
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 16 mg.h/l and 4.2 mg.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.
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 16 mg.h/l and 4.2 mg.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.
Authors: Charlotte van Kesteren; Anthe S Zandvliet; Mats O Karlsson; Ron A A Mathôt; Cornelis J A Punt; Jean-Pierre Armand; Eric Raymond; Alwin D R Huitema; Christian Dittrich; Herlinde Dumez; Henri H Roché; Jean-Pierre Droz; Miroslav Ravic; S Murray Yule; Jantien Wanders; Jos H Beijnen; Pierre Fumoleau; Jan H M Schellens Journal: Invest New Drugs Date: 2005-06 Impact factor: 3.850
Authors: A A Moghadamnia; A Rostami-Hodjegan; R Abdul-Manap; C E Wright; A H Morice; G T Tucker Journal: Br J Clin Pharmacol Date: 2003-07 Impact factor: 4.335
Authors: Anthe S Zandvliet; Mats O Karlsson; Jan H M Schellens; William Copalu; Jos H Beijnen; Alwin D R Huitema Journal: Invest New Drugs Date: 2009-02-06 Impact factor: 3.850