Modeling the pharmacodynamics of highly schedule-dependent agents: exemplified by cytarabine-based regimens in acute myeloid leukemia.
BACKGROUND
Many agents in antineoplastic chemotherapy are highly schedule dependent. Therefore, variables such as total dose and also the area under the curve (AUC) that are schedule insensitive are generally insufficient to adequately represent treatment strength.


OBJECTIVE
To establish a descriptor of treatment strength that takes into account the differential contribution of plasma concentrations (C) and exposure times (T) towards the cytotoxic effect and to investigate whether such a pharmacodynamically weighed descriptor is better correlated to the clinical effect than conventional variables.


METHODS
The paradigm "C(N) x T = constant" (for an isoeffect) incorporates a weighing factor N (concentration coefficient) into the conventional description of the AUC that quantitates the differential contribution of C and T towards the cytotoxic effect. N was to be numerically derived from a multitude of in vitro isoeffect analyses of the major agents in acute myeloid leukemia (AML) therapy from patient samples (n = 57).


RESULTS
For cytarabine, N was 0.45, numerically expressing the substantially higher relevance of T versus C for its cytotoxic effect. In a meta-analysis of 49 study arms involving >10,000 patients, neither total dose, dose intensity, nor AUC was correlated to the clinical effect. However, when AUC was pharmacodynamically weighed (N-weighed AUC, N-AUC = C(0.45) x T), this new descriptor was highly significantly correlated to the clinical effect (P < 0.001).


CONCLUSIONS
The N-AUC concept is able to characterize schedule-dependent agents and is the only descriptor of cytarabine treatment strength actually correlated to the clinical effect in AML.
Braess
Jan
J
Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany. jan.braess@med.uni-muenchen.de
Fiegl
Michael
M
Lorenz
Isolde
I
Waxenberger
Karin
K
Hiddemann
Wolfgang
W
D000208:Acute Disease; D000328:Adult; D000465:Algorithms; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015201:Meta-Analysis as Topic; D008954:Models, Biological; D016032:Randomized Controlled Trials as Topic
D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine