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
| Autor: | Srikant Viswanadha, Ajit Nair, Sridhar Veeraraghavan, Swaroop Vakkalanka, Prajak J Barde |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
Male Adolescent chemistry.chemical_element Pharmacology Calcium Placebo 030226 pharmacology & pharmacy Autoimmune Diseases Food-Drug Interactions Young Adult 03 medical and health sciences 0302 clinical medicine Double-Blind Method Pharmacokinetics Humans Potency Medicine Pharmacology (medical) 030212 general & internal medicine Organic Chemicals Adverse effect Dose-Response Relationship Drug Tumor Necrosis Factor-alpha business.industry Middle Aged Calcium Release Activated Calcium Channels Healthy Volunteers Tolerability chemistry Pharmacodynamics Toxicity Female Interleukin-4 business Half-Life |
| Zdroj: | Journal of Clinical Pharmacy and Therapeutics. 46:677-687 |
| ISSN: | 1365-2710 0269-4727 |
| DOI: | 10.1111/jcpt.13322 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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