Despite being named in 1958 (90), TPO was not isolated until 1994 when this was achieved simultaneously by five groups (91-95). TPO is the seminal regulator of platelet production, which, like M-CSF and G-CSF, is consumed by its target cells (megakaryocytes and platelets) that express the c-mpl receptor (57,58). Two forms of recombinant human TPO were initially examined in clinical studies: a full-length and glycosylated molecule that is equivalent to the native growth factor (rHuTPO) and a truncated and pegylated version known as megakaryocyte growth and development factor (MGDF). None of these "firstgeneration" agents attained regulatory approval mainly because of the production of antibodies by the human immune system that were directed against the administered therapeutic (96,97). These antibodies were also capable of neutralizing endogenous TPO causing extended-term refractory thrombocytopenia. This spurred the creation of novel mpl ligands, seven of which have been recently discussed (98) and all of which have the feature of no overlap in amino acid sequence with endogenous TPO.

The PK of MGDF is reflected in a predictable absorption and elimination profile (99), with Cmax being observed three to four days after a single SC administration. Elimination is, as mentioned above, affected by the PD response to the drug (57,58). In monkeys, the Cmax is attained in about 3 hours and MGDF is eliminated with a half-life of around 8 to 13 hours (100). The PK and PD characteristics of full-length recombinant human TPO and MGDF are similar (101). Elimination half-lives are 24 to 40 hours for rHuTPO and 31 hours for MGDF in humans.

The platelet response to administered MGDF is not immediate (102), taking three to four days before even reticulated platelets (a controversial though acceptable measure of early platelet increases) are detected in the circulation, with platelet counts peaking only after around 13 to 15 days. This probably reflects the indirect nature of mpl agonism on thrombocytopoiesis, the main action being confined to an increase in megakaryocyte ploidy and maturation rather than platelet formation (99). Similar kinetics are also exhibited by AMG 531 (Nplate®, romiplostim), one of the third-generation synthetic peptide mpl agonists (103). The medical exploitation of mpl ligands is not yet complete, with several third-generation molecules being developed for the treatment of immune thrombocytopenic purpura (ITP). As with many biopharmaceuticals, it is still unclear for which diseases they will finally be used and how the disease setting will affect their PK/PD.

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