Safety, tolerability, and pharmacokinetics of single and multiple ascending Oral doses of DA‐8010 in healthy subjects: First‐in‐human phase I study

Abstract

Abstract This study assessed the safety, tolerability, and pharmacokinetics of single and multiple oral doses of DA‐8010, a muscarinic M3 receptor antagonist, in healthy subjects. This was a randomized, double‐blind, placebo‐controlled, ascending single (Part A: 1, 2.5, 5, 20, and 40 mg QD fasted and 10 mg QD fasted and fed) and multiple doses (Part B: 5, 10, and 20 mg QD from Days 1 to 7 fasted), sequential‐group study. Safety data were analyzed descriptively, time to maximum plasma concentration (tmax) nonparametrically, and pharmacokinetic parameters using power and mixed models and ANOVA. Of 109 subjects randomized (Part A = 69 and Part B = 40; each part consisted a female group), 31 (44.9%) in Part A and 29 (72.5%) in Part B experienced treatment‐emergent adverse events (TEAEs) in a dose‐related manner. Common drug‐related TEAEs in Part A and B were dizziness (8.7% and 15.0%), headache (5.8% and 12.5%) and blurred vision (8.7% and 20%). One male (20 mg) and one female (10 mg) from Part B discontinued the study due to a confusional state, and nausea and vomiting. Irrespective of sex, DA‐8010 was steadily absorbed following single and multiple doses in the fasted state with increased systemic exposure in a dose‐proportional manner with maximum plasma concentration occurring at a median tmax between 4.0 and 6.0 h. A high‐fat meal increased systemic exposure. DA‐8010 was safe, well tolerated, and well absorbed at lower doses and moderately tolerated at higher doses without any notable effects of food and sex.

Keywords

• drug safety
• pharmacokinetics
• phase I
• randomized controlled trial