Romiplostim Dose-response in Patients with Myelodysplastic Syndromes

Overview

Journal Br J Clin Pharmacol

Specialty Pharmacology

Date 2012 Nov 23

PMID 23171070

Citations 5

Authors

Juan Jose Perez Ruixo

Sameer Doshi

Yow-Ming C Wang

Diane R Mould

Affiliations

Soon will be listed here.

Abstract

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(-1) ) 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 modelled 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 24 × 10(9) l(-1) (47%), 9.6 days (44%) and 0.28 days(-1) , respectively. MDS subjects had a shorter platelet lifespan (42 h) than healthy subjects (257 h). Romiplostim effect was described for responders (78%) and non-responders (22%). The average weekly stimulatory effect of romiplostim on the production rate of sensitive progenitor cells at baseline was 269% per 100 μg week(-1) for responders. Body weight, age, gender 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 escalating doses of romiplostim was characterized and showed a linear dose-response for romiplostim responders to increase the platelet counts.

Citing Articles

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Alternative agents to prophylactic platelet transfusion for preventing bleeding in people with thrombocytopenia due to chronic bone marrow failure: a meta-analysis and systematic review.

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