Safety, Pharmacokinetics and Pharmacodynamics of Hetrombopag Olamine, a Novel TPO ‐R Agonist, in Healthy Individuals

Hetrombopag olamine (hetrombopag) is a novel small‐molecule, orally bioavailable, non‐peptide thrombopoietin (TPO) receptor agonist that is being developed as the treatment for thrombocytopenia. Two randomized, placebo‐controlled phase I studies were conducted in 72 healthy individuals to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of hetrombopag. Hetrombopag was orally administered with a single dose in five dose cohorts (5 mg, 10 mg, 20 mg, 30 mg or 40 mg) in the first study, and given once daily for 10 days in three dose cohorts (2.5 mg, 5.0 mg or 7.5 mg) in the second study, respectively. Hetrombopag was well tolerated, and the majority of adverse events associated with medicine were platelet elevations significantly above the normal range in healthy individuals. The single dose‐escalation study revealed a Tmax of approximate 8 hr, and a t1/2 of 11.9 hr to 40.1 hr in a dose‐prolonged manner. A dose‐proportional increase in maximum concentration (Cmax) of hetrombopag was observed, with area under the curve (AUC) increasing in a greater than dose‐proportional manner. The plasma concentration of hetrombopag reached the steady‐state after 7 days. The steady‐state AUC0–24 hr and Cmax were dose‐proportionally elevated from the 5.0 mg to 7.5 mg dose level. The potent pharmacological effect of the hetrombopag‐induced platelet elevation was observed in a time‐ and dose‐dependent manner. Furthermore, the thrombopoietic response was significantly (p < 0.0001) correlated to the plasma exposure level of hetrombopag in single and multiple administration studies. Taken together, results of this study support further clinical development of hetrombopag in patients with thrombocytopenia.