Investigation of the pharmacokinetics of romiplostim in rodents with a focus on the clearance mechanism

Abstract

Purpose: Romiplostim, a treatment for adults with immune thrombocytopenia (ITP), is a novel thrombopoietin mimetic agent with a similar mechanism of action as thrombopoietin with no sequence homology. Structurally, it is a peptibody containing thrombopoietin mimetic peptides and the Fc portion of human IgG(1). We investigated romiplostim pharmacokinetics in rodents with a focus on the clearance mechanism.

Methods: Studies with appropriate controls were conducted in four models: FcRn knockout mice, thrombocytopenic mice, splenectomized rats, and bilateral nephrectomized rats. Catabolic breakdown of romiplostim was investigated in normal rats. The primary analytical method determines the intact/active romiplostim concentration, and the secondary method determines the sum of romiplostim and its catabolic degradants.

Results: FcRn interaction results in prolonged exposure. Platelets are involved in the target-mediated elimination, a saturable process and more prominent at low dose. Splenectomy does not affect the romiplostim pharmacokinetics in rats, an observation not unexpected. Nephrectomy in rats results in a greater increase of romiplostim exposure at a higher romiplostim dose, a nonlinearity likely due to saturation of competing pathway. Catabolism plays a major role in romiplostim elimination.

Conclusion: Romiplostim clearance involves multiple mechanisms, including a nonlinear pathway. Consequently, the relative contribution of different mechanisms appears to be dose dependent.