Modeling the Pharmacodynamics of Highly Schedule-Dependent Agents: Exemplified by Cytarabine-Based Regimens in Acute Myeloid Leukemia

Abstract

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. Purpose: 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. Patients and Methods: The paradigm ''C N Â 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 Â T), this new descriptor was highly significantly correlated to the clinical effect (P < 0.001). Conclusion: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.

Erufosine, a novel alkylphosphocholine, in acute myeloid leukemia: single activity and combination with other antileukemic drugs

“…From these data, the concentration coefficient N for ErPC3 can be determined as 1.9 for HL 60 cells and 1.2 for patient samples, therefore being close to 1 in both settings. Concluding from our experience of ex vivo drug measurement in AML [ 4 , 6 ] exposure concentration as well as exposure time is (almost) equally important for this drug in AML, especially in patient samples. Taking these data into account, the determined LC 50 for HL 60 cells in our study is higher than in previous studies that found the IC 50 for HL 60 cells to be 1.54 μM [ 7 ].…”

“…The concept of the concentration coefficient N is described in detail elsewhere [ 4 ]. In brief, it is based on the finding that the equation C × T = constant ( C = concentration of drug, T = exposure time of the drug) is not sufficient to describe the pharmacodynamic relationship between both parameters for several cytotoxic agents (e.g., cytarabine) to achieve a certain cell kill.…”

“…N < 1 is found for drugs that are dependent on long exposure times rather than on high concentrations. The detailed method to determine N has been described by our group recently [ 4 , 6 ]. In brief, double logarithmic transformation of a time/concentration isoeffective analysis results in a linear relationship from which the parameter N can be extracted as the negative gradient.…”

Selenium and Glutathione Peroxidase Status in Adult Egyptian Patients with Acute Myeloid Leukemia

“…All the patients were treated by the "3+7" regimen, three consecutive days of anthracyclines, generally doxorubicin, at 25 mg/m 2 /day on days 1 to 3 given as an intravenous (IV) bolus and continuous IV infusion of cytosine arabinoside 100-200 mg/m 2 over 7 days from days 4 to 10 [17] except AML M3 patients treated by all-trans retinoic acid in addition to chemotherapy [18].…”

Aktuelle Therapiestrategien in der Behandlung der akuten myeloischen Leukämie

“…Taken together, cure can be achieved in about 40% of patients, however, with large interindividual variability. publizierten Studien, die randomisiert hochdosiertes Cytarabin mit standarddosiertem Cytarabin in der Induktionstherapie verglichen, hat ein definitiv besseres Ergebnis der Hochdosis hinsichtlich der CR-Raten ergeben [9][10][11][12]; dies konnte durch eine Metaanalyse bestätigt werden [13]. Günstige Effekte finden sich hinsichtlich des Langzeitüberlebens (Tabelle 1).…”