Ryosuke Shimizu, Takayuki Katsube, and Toshihiro Wajima
Shionogi & Co., Ltd. Osaka Japan
Objectives: Quantitative systems pharmacology (QSP) modeling provides mechanistic insight and contributes the comprehensive understanding of drug efficacy and effects of underlying disease. Platelets are produced by the hematopoietic stem cells via megakaryocytes in the bone marrow [1] and play a critical role in hemostasis. Thrombopoietin (TPO) which is produced in liver, is the most important humoral factor in the process of the proliferation and differentiation of megakaryocytes and regulates platelet production by binding with the TPO receptor. Thrombocytopenia (TCP) is developed by various diseases such as chronic liver disease (CLD) and chemotherapeutic treatment and increases the risk of bleeding. Platelet transfusion is the current standard of care for replenishment of platelets and TPO receptor agonists are also use for the treatment of TCP patients with CLD or Idiopathic thrombocytopenic purpura. Since thrombopoiesis and platelet life-cycle includes the complicated processes, understanding the process based on QSP modeling gives important information about prediction of platelet count profiles and the investigation of the most influential factors on the profiles for each disease. The objective of the study is to develop the platelet model for thrombopoiesis and platelet life-cycle based on physiological mechanism and clinical observations by QSP approach. The model was applied for thrombopoiesis of lusutrombopag, a TPO receptor agonist, in healthy subjects and the TCP patients with CLD.
Methods: A platelet model was constructed based on the scheme of thrombopoiesis and platelet life-cycle reported by Szilvassy [1] and Craig [2], and included the components of proliferation from progenitor cells, maturation from megakaryoblast to megakaryocyte and its reservoir, platelet production from megakaryocyte, platelet distribution to spleen and elimination, and effect of endogenous TPO.
The platelet model was used for simulation of platelet count profiles after administration of lusutrombopag in healthy subjects. In this simulation, the effects of TPO and lusutrombopag were considered to be additive on thrombopoiesis via TPO receptor. For simulation in thrombocytopenic patients with CLD, the mechanism of TCP was modeled and integrated to the platelet model since it has been reported that the major mechanisms for TCP in cirrhosis are decreases in production of TPO in the liver and splenic platelet sequestration [3]. All kinetic parameters related to thrombopoiesis, platelet life-cycle, and PK parameters of TPO and lusutrombopag were fixed to the clinical observations, published data, and calculated values from the clinical observations These simulations were performed using MATLAB®. The predictability was assessed visually against clinical trials of lusutrombopag (1,408 platelet counts from 78 healthy subjects and 3,526 platelet counts from 347 thrombocytopenic patients with CLD).
Results: The platelet model consists of 44 components. Visual inspection suggested that the platelet model could well describe the observed platelet profiles for healthy subjects after administration of lusutrombopag. In the prediction, maximum increase of platelet count and time to peak platelet count for the 14-day fixed dose of 2 mg were typically 23.3×10,000/μL and 16.6 days after first dose, respectively, which were consistent with those based on the observed data. The results suggest that the kinetic parameters of the model were reasonably set. In thrombocytopenic patients with CLD, the platelet count profiles well predicted by incorporating the mechanism of decreased production of TPO in the liver and platelet sequestration in spleen in the model (predicted maximum increase of platelet count and time to peak platelet count for the 7-day fixed dose of 3 mg of 3.39×10,000/μL and 12.9 days after first dose, respectively).
Conclusions: The platelet model could adequately describe the platelet count profiles after administration of lusutrombopag for both healthy subjects and the thrombocytopenic patients with CLD. The platelet model constructed in this study is useful for understanding the process of thrombopoiesis and platelet life-cycle, the effect of TPO for platelet production, and pharmacodynamics of TPO agonist. In addition, the model would be applicable for predicting platelet count profiles in TCP driven by various diseases.
References:
[1] Szilvassy, S.J. Expert. Opin. Biol. Ther. 6, 983-992 (2006).
[2] Craig M, CPT:PSP (2017) 6, 293–304.
[3] Peck-Radosavljevic M. Liver Int. (2017) 37(6):778-793.
Reference: PAGE 28 (2019) Abstr 8914 [www.page-meeting.org/?abstract=8914]
Poster: Drug/Disease Modelling - Other Topics