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ACUTE MYELOID LEUKEMIA

Background

In the last few decades, modern pharmacology, in general, and hematological cancers, in particular, largely benefited from the development of molecular targeted drugs on the basis of monoclonal antibodies (MA). Cancer cells can develop resistance to the conjugated antibodies by several mechanisms such as low expression of the target membrane antigen, rapid metabolism, and rapid excretion from the cell, or resistance to the conjugate toxin. All the aforementioned resistance mechanisms contribute to the high variability in patiemts’ response, already observed in MA-based drugs (MA-BD).

Methods and Results

We developed a physiologically-based mathematical model for MA-BD PK/PD (pharmacokinetic/pharmacodynamic), which includes blood PK and detailed MA-BD interactions with its target receptor. We applied our model to experimental data of Gemtuzumab Ozogamycin in vitro and in vivo interactions with leukemic blasts, in order to evaluate individual model parameter values in the patient population. Mathematical analysis of model behavior under physiological parameter value ranges allowed the formulation of general principles of treatment by targeted drug delivery, including identification of parameters with highest influence on drug efficacy and optimization of treatment schedule. Furthermore, the predictions of the model were validated in prospective randomized clinical trial.

Conclusions

Modelling the interactions between MA-BD and its target receptor in conjunction with in vitro evaluated model parameters can aid in prediction individual patients’ response to specific MA-BD.

For further reading

Jager, E., van der Velden, V.H.J., te Marvelde, J.G., Walter, R.B., Agur, Z., Vainstein, V. Targeted drug delivery by gemtuzumab ozogamicin: mechanism-based pharmacokinetic model for treatment strategy improvement and prediction of individual responses. (submitted)