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Proof of Pharmacology of Org 48775-0, a p38 MAP-kinase inhibitor, in Healthy Volunteers
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  • Matthijs Moerland,
  • Andrea Kales,
  • Ulla Nässander,
  • Pierre Peeters,
  • Rob Nelissen,
  • Jacobus Burggraaf
Matthijs Moerland
Centre for Human Drug Research
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Andrea Kales
Centre for Human Drug Research
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Ulla Nässander
Organon Schering Plough
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Pierre Peeters
Curare Consulting
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Rob Nelissen
Organon Schering Plough
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Jacobus Burggraaf
Centre for Human Drug Research
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Abstract

Aim: To investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the highly selective oral p38α/β MAP-kinase inhibitor Org 48775-0, a first-in-human study was conducted. Methods: In the SAD study part, an oral dose of Org 48775-0 ranging from 0.3 mg to 600 mg was evaluated in healthy males. In the MAD study part, dose levels of 30, 70 and 150 mg were evaluated with dosing for six consecutive days, twice daily. Both studies were performed in a double-blind, randomized, placebo-controlled, cross-over fashion and evaluated pharmacokinetics (PK), pharmacodynamics (PD; inhibition of LPS-induced TNFα release) and routine clinical and laboratory data. Moreover, the effect of a standardized fat meal on PK and PD parameters of Org 48775-0 was evaluated, and PK and PD parameters of Org 48775-0 were compared between healthy males and postmenopausal females. Results: All adverse events observed in the SAD and MAD cohorts were mild, transient and completely reversible without medical intervention. Pharmacokinetics were linear up to single dose s of 400 mg. Org 48775-0 doses equal to and greater than 30 mg significantly inhibited LPS-induced TNFα release (42.3% increase in inhibition, 95% CI=-65.2; -4.3) compared to placebo. In the MAD study, Org 48775-0 treatment inhibited the 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 48775-0. Conclusion: This study demonstrates that Org 48775-0 has the capacity to significantly inhibit MAP-kinase activity in humans, without raising safety concerns.

Peer review status:IN REVISION

17 Jul 2020Submitted to British Journal of Clinical Pharmacology
20 Jul 2020Assigned to Editor
20 Jul 2020Submission Checks Completed
27 Jul 2020Reviewer(s) Assigned
26 Aug 2020Review(s) Completed, Editorial Evaluation Pending
29 Aug 2020Editorial Decision: Revise Minor