(448c) Platelet Count Control in Immune Thrombocytopenic Purpura Patient: Optimum Romiplostim Dose Profile

Tsai, C. H., University of Delaware
Sandler, S. I., University of Delaware
Ogunnaike, B. A., University of Delaware

Patients with immune thrombocytopenic purpura (ITP), a disease characterized by abnormally low platelet count, are susceptible to excessive bleeding as a direct consequence. While the problem of low platelet count can be addressed fundamentally either by slowing down the rate of platelet destruction or by increasing platelet production, or both, one of the more effective means of treating ITP patients is to increase platelet production with romiplostim, a relatively new drug that has recently been approved for treating patients who have not responded to other treatments. However, current romiplostim treatment strategies tend to result in undesirable responses where platelet counts oscillate between dangerously low values followed extremely high peaks, as a direct consequence of the complex nonlinear dynamics associated with platelet count regulation. The objective of this study is to employ a model-based approach to determine the optimum dose profile of romiplostim required to maintain a steady platelet count of 70×109/L for a specific ITP patient.

Using clinical platelet count data obtained from the patient in response to a series of subcutaneously applied doses of romiplostim, a standard pharmacokinetics and pharmacodynamics (PKPD) model was modified, validated, and analyzed first to obtain insight into the patient’s physiological characteristics. The customized model was then subsequently used to investigate, via simulation, the performance of three control strategies (“fixed dose” open-loop control, “variable dose” discrete PI feedback control, and “variable dose” open-loop optimal control) implemented for both weekly and biweekly treatment regimens. Our results indicate that with both treatment frequencies, the “fixed dose” open-loop control strategy resulted in unacceptable sustained oscillating platelet counts while the PI feedback control and optimal open-loop control led to stable platelet count profiles after about 50 days but only for weekly injections. Additional details concerning the controller designs and performance under various conditions will be discussed along with other notable observations, for example: that the time span required to achieve a stable platelet count is very sensitive to the values of initial doses administered at the very beginning of the treatment; and that, for the specific patient in question, regardless of control strategy, it is nearly impossible to maintain stable, non-oscillatory platelet count with biweekly injections.