Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel CRTH2 Antagonist BI 1021958 at Single Oral Doses in Healthy Men and Multiple Oral Doses in Men and Women With Well-Controlled Asthma
| Autor: | Abhya Gupta, Rüdiger Koenen, Dominik Kappeler, Andy Fowler, Ewald Benediktus, Chester C. Wood, James Hilbert, Jon Blatchford |
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| Rok vydání: | 2017 |
| Předmět: |
Adult
Male 0301 basic medicine Receptors Prostaglandin Cmax Administration Oral Pharmacology Food-Drug Interactions 03 medical and health sciences 0302 clinical medicine Double-Blind Method Pharmacokinetics Humans Medicine Single-Blind Method Pharmacology (medical) Anti-Asthmatic Agents Receptors Immunologic Adverse effect Asthma Cross-Over Studies Dose-Response Relationship Drug business.industry Antagonist medicine.disease Eosinophils 030104 developmental biology 030228 respiratory system Tolerability Area Under Curve Pharmacodynamics Female Prostaglandin binding business Half-Life |
| Zdroj: | The Journal of Clinical Pharmacology. 57:1444-1453 |
| ISSN: | 0091-2700 |
| DOI: | 10.1002/jcph.947 |
| Popis: | BI 1021958, a novel antagonist of the chemoattractant-receptor-homologous molecule (CRTH2), targets airway inflammation in asthma by inhibiting prostaglandin binding to CRTH2 receptors. Two phase 1 studies assessed BI 1021958 safety/tolerability and pharmacokinetics (PK)/pharmacodynamics (PD) following single doses in healthy men and multiple doses in men/women with well-controlled asthma. Studies 1 had 2 parts: a placebo-controlled, fixed-sequence, single-blind, single-rising-dose part (n = 56) and a randomized, 2-way crossover, open-label, repeated-dose part studying the food effect on PK/PD (n = 12). Study 2 was a placebo-controlled, single-center, double-blind multiple-rising-dose study (n = 84). Primary end points were safety/tolerability and PK/PD (both studies); secondary end points were eosinophil shape change (ESC; study 1) and dose proportionality/linearity following first dose and at steady state (study 2). BI 1021958 was adequately tolerated in both studies; adverse events were infrequent, generally mild to moderate, and occurred similarly in treatment groups. Maximum measured concentration (Cmax) was achieved in ≤2.5 hours in study 1 and ≤2.0 hours in study 2. BI 1021958 exposure increased proportionally with dose. In study 1, following a single 60-mg dose, AUC parameters and Cmax were 20% and 15% lower, respectively, after a high-fat meal compared with the fasted state. After ≥60-mg single doses (study 1) and >40-mg multiple doses (study 2), >95% ESC inhibition was observed for ≥24 hours. PK/PD was similar in healthy subjects and subjects with well-controlled asthma. Data support further investigation of CRTH2 antagonists for the treatment of asthma. |
| Databáze: | OpenAIRE |
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