A phase I trial of PRN1008, a novel reversible covalent inhibitor of Bruton's tyrosine kinase, in healthy volunteers

Aim: To evaluate the safety, tolerability, and pharmacokinetics/pharmacodynamics of PRN1008, a novel Bruton's tyrosine kinase (BTK) inhibitor, in healthy volunteers, and thus determine the dose range for future clinical studies. Methods: This was a two-part randomized, placebo controlled study in healthy volunteers using a liquid formulation. Part I was a single ascending dose design with dose levels of 50–1200 mg (n = 6 active, two placebos per cohort); Part II was a multiple ascending dose design, with dose regimens ranging from 300 to 900 mg daily, either four times or twice daily for 10 days. Plasma pharmacokinetics, adverse events, vital signs, electrocardiograms and laboratory parameters were assessed. BTK occupancy in peripheral blood mononuclear cells was evaluated as a marker of target engagement. Results: PRN1008 was rapidly absorbed following oral administration, and was safe and well tolerated in all dose regimens evaluated in both single and multiple doses. PRN1008 demonstrated a large volume of distribution, and a half-life of approximately 3–4 h. BTK occupancy of >90% was observed within 4 h after dosing in both single and multiple dose regimens, and was closely linked to maximum plasma concentration. BTK occupancy decay was slow (–1.6% h^–1), and occupancy was sustained despite drug concentrations being undetectable. No severe or serious adverse events occurred, and the most common adverse events were gastrointestinal in nature. Conclusions: PRN1008 was safe and well-tolerated following oral administration, and achieved high, sustained levels of BTK occupancy in peripheral blood mononuclear cells.