Platelet count control in immune thrombocytopenic purpura patient: optimum romiplostim dose profile

Abstract

Abstract 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. However, current romiplostim treatment strategies tend to produce undesirable responses where platelet counts oscillate between dangerously low values and extremely high peaks, as a direct consequence of the complex nonlinear dynamics associated with platelet count regulation. The objective of this study is to determine the optimum dose profile of romiplostim for a specific ITP patient required to maintain a platelet count of 70×109/L. Using clinical data of the specific patient's platelet count obtained in response to a series of subcutaneously applied doses of romiplostim, a standard pharmacokinetics/pharmacodynamics (PKPD) model was developed, validated, and analyzed to obtain insight into the patient's physiological characteristics. The model was subsequently used to investigate the performance of three control strategies: “fixed dose” open-loop control, “variable dose” discrete PI feedback control, and “variable dose” model-based open-loop optimal control. The control strategies were implemented for weekly and bi-weekly treatment regimens. With both treatment frequencies, the fixed dose open-loop control strategy resulted in unacceptable sustained oscillating platelet count. PI feedback control and model-based optimal open-loop control led to stable platelet count profiles after approximately 50 days but only for weekly injections. In summary, a stable platelet count is more likely to be achieved consistently in the specific patient with weekly treatments. Bi-weekly treatments are less effective because, as we show, fundamental pharmaceutical characteristics of romiplostim make oscillations in platelet count unavoidable at this treatment frequency. The results show that model-based decisions determined using patient-specific mathematical models are potentially useful for designing better treatment regimens for ITP patients.