Proof of pharmacology of Org 48775-0, a p38 MAP kinase inhibitor, in healthy volunteers.

Autor: Moerland M; Centre for Human Drug Research, Leiden, the Netherlands.; Leiden University Medical Center, Leiden, The Netherlands., Kales AJ; Former affiliation Centre for Human Drug Research, Leiden, the Netherlands., Broekhuizen K; Centre for Human Drug Research, Leiden, the Netherlands., Nässander U; Former affiliation Organon/Schering Plough, Oss, the Netherlands., Nelissen R; Former affiliation Organon/Schering Plough, Oss, the Netherlands., de Kam ML; Centre for Human Drug Research, Leiden, the Netherlands., Peeters PAM; Former affiliation Organon/Schering Plough, Oss, the Netherlands.; Present affiliation Curare Consulting, Etten-Leur, the Netherlands., Burggraaf J; Centre for Human Drug Research, Leiden, the Netherlands.; Leiden University Medical Center, Leiden, The Netherlands.; Leiden Academic Centre for Drug Research, Leiden, the Netherlands.
Jazyk: angličtina
Zdroj: British journal of clinical pharmacology [Br J Clin Pharmacol] 2021 May; Vol. 87 (5), pp. 2321-2332. Date of Electronic Publication: 2020 Dec 23.
DOI: 10.1111/bcp.14655
Abstrakt: Aim: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of the highly selective oral p38alpha/beta mitogen-activated protein (MAP) kinase inhibitor Org 48,775-0 in a first-in-human study.
Methods: In the single ascending dosing (SAD) study, an oral dose of Org 48,775-0 (0.3-600 mg) was evaluated in healthy males. In the multiple ascending dosing (MAD) study, levels of 30, 70 and 150 mg were dosed for six consecutive days, twice daily. Both studies were performed in a double-blind, randomized, placebo-controlled, cross-over fashion and evaluated pharmacokinetics, pharmacodynamics (ex vivo inhibition of lipopolysaccharide [LPS]-induced tumor necrosis factor (TNFα) release) and routine clinical and laboratory data. Pharmacokinetic and pharmacodynamic parameters of Org 48,775-0 were compared between healthy males and postmenopausal females, and the effect of a standardized fat meal was evaluated.
Results: All adverse events observed in the SAD (16; dizziness and headache, diarrhoea and catheter-related phlebitis) and MAD (43; mainly somnolence, dizziness, headache and nasopharyngitis) cohorts were mild, transient and completely reversible. Pharmacokinetics were linear up to single doses of 400 mg. Median T max ranged from 0.5 to 1.8 hours, geometric mean for T 1/2 from 7.0 to 14.4 hours. Org 48,775-0 doses equal to and greater than 30 mg significantly inhibited LPS-induced TNFα release (42.3%; 95% CI = -65.2, -4.3) compared to placebo. In the MAD study, Org 48,775-0 treatment inhibited LPS-induced TNFα release during the entire steady-state period. Levels of inhibition amounted 30-75% for 30 mg, 53-80% for 70 mg and 77-92% for 150 mg Org 48,775-0.
Conclusion: Org 48,775-0 has the capacity to significantly inhibit MAP kinase activity in humans without safety concerns.
(© 2020 British Pharmacological Society.)
Databáze: MEDLINE
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