Investigation of the Pharmacokinetics of Romiplostim in Rodents with a Focus on the Clearance Mechanism

Abstract

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

Closed form solutions and dominant elimination pathways of simultaneous first-order and Michaelis–Menten kinetics

“…Our theoretical findings give a rational to previous experimental results reported in [2,18], where the renal elimination has been found to play a major role when the drug concentration is high, and conversely, the MichaelisMenten elimination was dominant for lower concentrations.…”

“…However, the saturating process involved in the Michaelis-Menten elimination can make its t 1=2 rise to infinity, which contrasts with the linear or simultaneous cases. In fact, it is the linear elimination which keeps the half-time of the simultaneous [18,19]. For example, authors in [19] observed that an increase of 10 fold in dose of filgrastim (from 100 to 1000 ug/kg) results in 1.5-fold increase in t 1=2 (from 1.7 to 3.1 h) for the wild-type mice.…”

“…In this section, using mathematical analysis, we will reveal the dominant role of each elimination pathway in terms of model parameters. This will set up a solid foundation for a better understanding of the mechanisms of drugs exhibiting such kinetics, hormone drugs for example [2,18]. From the model (Eq.…”

A novel recombinant human thrombopoietin therapy for the management of immune thrombocytopenia in pregnancy

“…Romiplostim contains the CH2 and CH3 domains of the IgG-Fc, which enable it to bind Fc receptors. 48 This structure not only contributes to the long circulating half-life of romiplostim 49 but also promotes its transportation across the placenta. [50][51][52] In rodents, 12 days after romiplostim administration, the drug was detected in both fetal serum and amniotic fluid.…”

Romiplostim for the treatment of primary immune thrombocytopenia

“…In rats, s plenectomy did not affect the r omiplostim pharmacokinetics whereas n ephrectomy increased the r omiplostim exposure only at the higher doses. Pharmacokinetics suggests that catabolic d egradants of r omiplostim account for approximately t wo-thirds of the total circulating species with fragmented T PO-receptor binding peptides bound to F c [12].…”