AIMS: The main objectives of these two phase I studies were to investigate safety and tolerability as well as the pharmacokinetic/pharmacodynamic profile of the novel potent and selective formyl peptide receptor type 2 (FPR2)/Lipoxin A4 receptor (ALX) agonist ACT-389949. A challenge model was used to assess the drug's anti-inflammatory potential, with the aim of selecting a dosing regimen for future patient studies. METHODS: Two double-blind, randomized phase I studies investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of ACT-389949 at different doses and dosing regimens. Drug exposure was correlated with target engagement markers such as receptor internalization and cytokine measurements. The effect of FPR2/ALX agonism on neutrophil migration was studied in a lipopolysaccharide (LPS) inhalation model. RESULTS:ACT-389949 was well tolerated. Maximum concentrations were reached around 2 h after dosing, with a mean terminal half-life of 29.3 h [95% confidence interval (CI) 25.5, 33.7]. After multiple-dose administration, exposure increased by 111% (95% CI 89, 136), indicating drug accumulation. Administration of ACT-389949 resulted in a dose-dependent, long-lasting internalization of FPR2/ALX into leukocytes. Pro- and anti-inflammatory cytokines were dose-dependently but transiently upregulated only after the first dose. No pharmacological effect on neutrophil count was observed in the LPS challenge test performed at steady state. CONCLUSIONS:FPR2/ALX agonism with ACT-389949 was shown to be safe and well tolerated in healthy subjects. Receptor internalization and downstream mediators pointed towards a desensitization of the system, which may explain the lack of effect on neutrophil recruitment in the LPS challenge model.
RCT Entities:
AIMS: The main objectives of these two phase I studies were to investigate safety and tolerability as well as the pharmacokinetic/pharmacodynamic profile of the novel potent and selective formyl peptide receptor type 2 (FPR2)/Lipoxin A4 receptor (ALX) agonist ACT-389949. A challenge model was used to assess the drug's anti-inflammatory potential, with the aim of selecting a dosing regimen for future patient studies. METHODS: Two double-blind, randomized phase I studies investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of ACT-389949 at different doses and dosing regimens. Drug exposure was correlated with target engagement markers such as receptor internalization and cytokine measurements. The effect of FPR2/ALX agonism on neutrophil migration was studied in a lipopolysaccharide (LPS) inhalation model. RESULTS: ACT-389949 was well tolerated. Maximum concentrations were reached around 2 h after dosing, with a mean terminal half-life of 29.3 h [95% confidence interval (CI) 25.5, 33.7]. After multiple-dose administration, exposure increased by 111% (95% CI 89, 136), indicating drug accumulation. Administration of ACT-389949 resulted in a dose-dependent, long-lasting internalization of FPR2/ALX into leukocytes. Pro- and anti-inflammatory cytokines were dose-dependently but transiently upregulated only after the first dose. No pharmacological effect on neutrophil count was observed in the LPS challenge test performed at steady state. CONCLUSIONS:FPR2/ALX agonism with ACT-389949 was shown to be safe and well tolerated in healthy subjects. Receptor internalization and downstream mediators pointed towards a desensitization of the system, which may explain the lack of effect on neutrophil recruitment in the LPS challenge model.
Authors: Anna K Stalder; Dominik Lott; Daniel S Strasser; Hans G Cruz; Andreas Krause; Peter M A Groenen; Jasper Dingemanse Journal: Br J Clin Pharmacol Date: 2016-11-15 Impact factor: 4.335
Authors: Anna K Stalder; Dominik Lott; Daniel S Strasser; Hans G Cruz; Andreas Krause; Peter M A Groenen; Jasper Dingemanse Journal: Br J Clin Pharmacol Date: 2016-11-15 Impact factor: 4.335
Authors: John Lupisella; Stéphane St-Onge; Marilyn Carrier; Erica M Cook; Tao Wang; Chi Sum; Gayani Fernando; Kendra Apgar; Rongan Zhang; Nancy Carson; Bradley J Snyder; Carol S Ryan; Xiuying Ma; Elizabeth A Dierks; Sean Little; Ellen K Kick; Nicholas R Wurtz; Michel Bouvier; Madeleine Héroux; Ricardo A Garcia Journal: ACS Pharmacol Transl Sci Date: 2022-09-14
Authors: Claudia Vergelli; Andrei I Khlebnikov; Letizia Crocetti; Gabriella Guerrini; Niccolò Cantini; Liliya N Kirpotina; Igor A Schepetkin; Agostino Cilibrizzi; Mark T Quinn; Patrizia Rossi; Paola Paoli; Maria Paola Giovannoni Journal: Chem Biol Drug Des Date: 2021-07-01 Impact factor: 2.817