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A first‐in‐human study to evaluate the safety, tolerability and pharmacokinetics of RP3128, an oral calcium release‐activated calcium (CRAC) channel modulator in healthy volunteers
Author(s) -
Barde Prajak J.,
Viswanadha Srikant,
Veeraraghavan Sridhar,
Vakkalanka Swaroop V.,
Nair Ajit
Publication year - 2021
Publication title -
journal of clinical pharmacy and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.622
H-Index - 73
eISSN - 1365-2710
pISSN - 0269-4727
DOI - 10.1111/jcpt.13322
Subject(s) - tolerability , pharmacokinetics , pharmacology , medicine , placebo , pharmacodynamics , adverse effect , dosing , toxicity , anesthesia , pathology , alternative medicine
What is known and objective RP3128, a novel, orally available modulator of calcium released activated calcium (CRAC) channel, is being developed for the potential treatment of autoimmune and inflammatory diseases. RP3128 showed nano‐molar potency and activity in a range of in vitro and in vivo models of inflammation. We report a first‐in‐human study investigating the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of RP3128 in healthy subjects. Methods A randomized, double‐blind, placebo‐controlled trial of single (25, 50, 100, 200 and 400 mg) and multiple (7 days: 25, 100 and 400 mg once daily) doses of RP3128 were performed. Thirty‐two and 24 subjects were randomized in the single ascending dose (SAD) and multiple ascending dose (MAD) parts, respectively. Results and discussion RP3128 was well tolerated, with no dose‐limiting toxicity at single and multiple doses. Incidence of treatment emergent adverse events (TEAEs) did not increase with ascending RP3128 doses. No changes were seen in cognitive function and ECG parameters. RP3128 was rapidly absorbed. Elimination was slow with a half‐life of more than 80 h. Exposures increased with increasing doses. Accumulation was seen on repeated dosing. PD response, as evidenced by lower plasma levels of tumour necrosis factor‐alfa (TNFα) and interleukin‐4 (IL‐4), was seen when compared to pre‐dose values or placebo. What is new and conclusion The safety, tolerability and PK/PD profile of RP3128 demonstrates its potential to be developed in inflammatory disorders and support further clinical development (ClinicalTrials.gov number: NCT02958982).