Modeling of In Vitro Drug Activity and Prediction of Clinical Outcome in Acute Myeloid Leukemia

Abstract

The objectives of this study were to develop a population pharmacodynamic model describing the in vitro drug sensitivity of tumor cells and to relate in vitro parameters to clinical outcome. Cell samples from 179 patients with acute myelocytic leukemia were exposed to cytosine arabinoside and daunorubicin, and cytotoxicity was analyzed using the fluorometric microculture cytotoxicity assay. A sigmoid E(max)-model for daunorubicin and an E(max)-model for cytosine arabinoside described the data. The model predicted drug potency (EC(50)) adequately from 1 concentration measurement. A logistic regression on individual in vitro parameters of 46 patients treated with the daunorubicin plus cytosine arabinoside regimen showed that the probability of complete response was significantly (P < .05) related to the product of the E(max)/EC(50) ratio of the two drugs. The findings demonstrate the value of population pharmacodynamic modeling of in vitro drug sensitivity data and a significant relationship between the in vitro parameters and clinical outcome.

Differences in Ex-Vivo Chemosensitivity to Anthracyclines in First Line Acute Myeloid Leukemia

“…the increase of the accuracy obtained modeling ex vivo activity with PD population models in one single step;49…”

Prediction of individual response to anticancer therapy: historical and future perspectives

“…The MTT assay is therefore not applicable when the tumor biopsy is small. For the SRB assay [ 117 ] and the FMC assay [ 27 ] around 2,000 cells/well are sufficient. The ATP assay is reported to be able to detect down to ten cells/well.…”

Design of optimal patient-specific chemotherapy protocols for the treatment of acute myeloid leukemia (AML)

“…PK parameters for Ara-C (Dedrick et al, 1972) and DNR (Loveless, Arena, & Felsted, 1978) are taken from what have been described previously. PD parameters for both drugs have also been previously described (Quartino et al, 2007) and are used for this work. Parameters for normal human cell populations are estimated based on published work (Colin & Mackey, 2005).…”

“…The most widely used models are those of drug effect (Holford & Sheiner, 1982), which relate drug concentration to effect; in the case of chemotherapy, this desired effect is the number of dead cells. These models contain estimated parameters from real-life data and express drug effect dependent only on drug concentration (Quartino, 2007).…”