Recombinant human thrombopoietin (rhTPO) after autologous bone marrow transplantation: a phase I pharmacokinetic and pharmacodynamic study

Thrombocytopenia following myelotoxic therapy is a common problem and when severe (<20 000/<mu>1) can lead to severe morbidity and mortality. Thrombop oietin (TPO) is a naturally occurring glycosylated peptide which stimulates the differentiation of bone marrow stem cells into megakaryocyte progenito r cells, induces the expression of megakaryocyte differentiation markers, p romotes megakaryocyte proliferation, polyploidization and, ultimately, the formation of increased numbers of platelets in the circulation. TPO has now been produced by recombinant technology and has entered clinical trials. T his open label phase I study was designed to determine the safety, toleranc e and pharmacokinetics of recombinant thrombopoietin (rhTPO) when administe red to patients after undergoing high-dose chemotherapy followed by autolog ous bone marrow transplantation. rhTPO was administered intravenously by bo lus injection at doses ranging from 0.3 to 4.8 mug/kg/day every 3 days to 3 0 patients and 0.6 mug/kg daily to three patients. rhTPO was begun the day after marrow infusion and continued until platelet recovery to >20 000/mu1. G-CSF was concomitantly administered to promote myeloid recovery. Serious adverse events or neutralizing antibodies to rhTPO were not observed during the study. Median platelet recovery after ABMT was 19 days (range, 11-41), Neither the dose nor the schedule of rhTPO appeared to have any impact upo n the time course of platelet recovery. In this phase I study, rhTPO was fo und to be well tolerated without the development of neutralizing antibodies and without compromising neutrophil recovery. Platelet recovery was simila r for all doses studied warranting further evaluation in phase II and III t rials designed to test for platelet recovery efficacy.