A Phase I Study To Investigate the Pharmacokinetics (PK) and Pharmacodynamics (PD) of an Oral Platelet Growth Factor (SB-559448) in Healthy Subjects.

Introduction: SB-559448, is an orally bioavailable, non peptide, small molecule thrombopoietin receptor agonist that induces proliferation and differentiation of megakaryocytes and progenitor cells, ultimately increasing the production of platelets.

Method: In a randomized, single blind, placebo-controlled, parallel group, phase I study in healthy subjects, SB-559448 was administered as oral capsules once daily for 1 day and, after a 7-day washout, for 10 days at doses of 160 to 640 mg. In this dose escalation study, subjects were randomized into 4 groups of 9 subjects to receive either active or placebo medication in a ratio of 6:3. Serial blood samples were collected to determine SB-559448 concentrations and estimate PK parameters following single- and repeat-dosing. PD assessments were performed every 4 to 5 days up to 31 days following initiation of repeat dosing.

Results: The preliminary results showed that SB-559448 was well tolerated in the study, there were no serious adverse events, no significant changes in laboratory or cardiovascular safety parameters and there was no observed relationship between the incidence or severity of adverse events and dose. Most adverse events were mild in intensity and self-limiting. SB-559448 was also shown to be orally bioavailable in humans with a pharmacokinetic profile suitable for a once daily oral dosing. When administered at oral doses of 160 mg and above for 10 days, a dose dependent increase in the platelet count was observed with maximum platelet count observed on days 14 to 15 following initiation of repeat dosing.

Conclusion: The results suggest that SB-559448 is an orally administered agent that increased platelet counts in healthy subjects. Additional studies will be needed to evaluate its effects in individuals with thrombocytopenia.