Scientific Publications by FDA Staff

Br J Clin Pharmacol 2013 Jun;75(6):1445-54

Romiplostim dose-response in patients with myelodysplastic syndromes.

Ruixo JJP, Doshi S, Wang YMC, Mould DR

Aim: To characterize the romiplostim dose response in subjects with low- or intermediate-1 risk myelodysplastic syndromes (MDS) receiving subcutaneous romiplostim. Methods: Data from 44 MDS subjects receiving subcutaneous romiplostim (dose range: 300-1500 µg/week) were used to develop a pharmacodynamic model consisting of a romiplostim-sensitive progenitor cell compartment linked to the peripheral blood compartment through four transit compartments representing the maturation in the bone marrow from megakaryocytes to platelets. A kinetics of drug effect model was used to quantify the stimulatory effect of romiplostim on the proliferation of sensitive progenitor cells and pharmacodynamics-mediated disposition was modeled by assuming the kinetics of drug effect constant (kDE) to be proportional to the change in platelet count relative to baseline. Results: The estimated values (between-subject variability) for baseline platelet count, mean transit time, and kDE were 24x109/L (47%), 9.6 days (44%), and 0.28 days-1, respectively. MDS subjects had a shorter platelet lifespan (42h) than healthy subjects (257h). Romiplostim response was described for responders (78%) and non-responders (22%). The average weekly stimulatory effect of romiplostim on the sensitive progenitor cells at baseline was 269% per 100 µg/week for responders. Body weight, age, sex, and race were not statistically related to romiplostim pharmacodynamic parameters. Visual predictive checks confirmed the model adequacy. Conclusion: The time course of platelet counts in MDS subjects receiving subcutaneous administration of a titrated dose of romiplostim was characterized and evidenced a linear dose response for romiplostim to increase the platelet counts.