Safety, tolerability and pharmacokinetics of GSK3008348, a novel integrin αvβ6 inhibitor, in healthy participants
| Autor: | Richard P. Marshall, David Fairman, Simon Parry, Pauline T. Lukey, Stuart Kendrick, Juliet Kay Simpson, Nadia Garman, Maria J. Costa, William A. Fahy, Robert J. Slack, Charlotte H. Maden, Michelle Chalker, Tim Mant |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Adult Male medicine.medical_specialty Integrins Pyrrolidines Cmax Idiopathic pulmonary fibrosis Integrin αvβ6 inhibitor Gastroenterology 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Double-Blind Method Antigens Neoplasm Internal medicine Administration Inhalation medicine Humans Pharmacology (medical) Naphthyridines Adverse effect Pharmacology Cross-Over Studies business.industry General Medicine Middle Aged medicine.disease Crossover study Clinical Trial Healthy Volunteers Clinical trial Butyrates 030104 developmental biology 030228 respiratory system Tolerability Toxicity Pyrazoles Female GSK3008348 Safety business |
| Zdroj: | European Journal of Clinical Pharmacology |
| ISSN: | 1432-1041 |
| Popis: | Purpose Inhaled drug delivery is an attractive route by which to deliver drugs to lungs of patients with idiopathic pulmonary fibrosis (IPF). GSK3008348 is a potent and selective small molecule being developed as the first inhaled inhibitor of the αvβ6 integrin for the treatment of IPF. The phase 1 first-time-in-human clinical trial (NCT02612051) presented here was designed to investigate the safety, tolerability and pharmacokinetic (PK) profile of single doses of GSK3008348 in healthy participants. Methods Single ascending doses of GSK3008348 were administered to three cohorts of eight healthy participants in a randomised, double-blind, placebo-controlled, 4-period crossover design. Safety, tolerability and PK were assessed after single doses of 1–3000 mcg given by nebulisation. Results A total of 29 participants were enrolled and received at least one dose of study treatment. There were no serious adverse events (AE) reported in any participant. No trends or clinically important differences were noted in the incidence or intensity of AEs or other safety assessments. Maximum plasma concentrations of GSK3008348 were generally attained within approximately 30 min after start of nebulisation, with geometric mean terminal elimination half-lives ranging from 7.95 to 10.2 h. Exposures, as measured by area under the plasma concentration-time curve (AUC), were dose proportional across all doses where estimates were possible (100–3000 mcg). Dose normalised geometric mean Cmax increased with dose up to 3000 mcg. This supra proportionality was relatively modest, with a less than 3-fold increase over the range from 30 to 3000 mcg. The reason(s) for this observation are currently not known but may be due to slower absorption at the lowest doses. All exposures were within the exposure margins set by the non-clinical toxicity studies and so this is not expected to have any impact on safety. Conclusions In summary, GSK3008348 was well tolerated at single doses up to 3000 mcg in healthy participants, and its PK profile was dose proportional at potentially clinically relevant doses (300–3000 mcg). These findings support further development of GSK3008348 as a novel inhaled treatment option for IPF. Electronic supplementary material The online version of this article (10.1007/s00228-018-2435-3) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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