Models of schedule dependent haematological toxicity of 2'-deoxy-2'-methylidenecytidine (DMDC).
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.
Friberg
L E
LE
Division of Biopharmaceutics and Pharmacokinetics, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden. Lena.Friberg@biof.uu.se
Brindley
C J
CJ
Karlsson
M O
MO
Devlin
A J
AJ
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D001825:Body Fluid Compartments; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D006402:Hematologic Diseases / Q000097:blood / Q000139:chemically induced*; D006801:Humans; D007958:Leukocyte Count; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy; D008954:Models, Biological; D009503:Neutropenia / Q000139:chemically induced; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D010976:Platelet Count
D000970:Antineoplastic Agents; D003841:Deoxycytidine; C056034:2'-deoxy-2'-methylenecytidine