New TPO treatment schedules of increased safety and efficacy: pre-clinical validation of a thrombopoiesis simulation model

Abstract

Thrombopoietin (TPO) immunogenicity hampers its development as a therapeutic agent for attenuating thrombocytopenia and improving platelet harvest in donors. This work was aimed at validating, in mouse and in monkey experiments, a thrombopoiesis computer-model prediction that platelet counts, similar to those obtained with accepted TPO dose scheduling, can also be achieved by new and safer schedules of significantly reduced doses. To this end we compared, in a two-arm mouse experiment, platelet increases obtained with a single intraperitoneal dosing of recombinant mouse TPO (17.5 microg/kg), with those obtained by the model-suggested protocol of a significantly reduced dose (2 microg/kg on 4 consecutive days). The two TPO regimens generated similar platelet profiles, peaking at ca. 2700 x 10(9)/l platelets. In rhesus monkeys, treated by rhesus monkey recombinant TPO (5 microg/kg on 4 consecutive days), the suggested protocol yielded effective platelet stimulation with significantly reduced immunogenicity. The model's ability to predict individual monkey responses to several new TPO administration protocols was further validated, proving sufficient robustness in providing good predictions with limited input data. The simulation tool could be used for testing the effects of different therapeutic agents on thrombopoiesis. Human trials are warranted for testing the suggested improved TPO protocol, possibly in conjunction with chemotherapy.