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We present the first results of the proof‐of‐concept phase 2a study of oral NLRP3 inflammasome inhibitor in subjects with cryopyrin‐associated periodic syndromes (CAPS). Three adult subjects with a confirmed diagnosis of CAPS were enrolled and administered 50 mg of ZYIL1 twice daily for 7 days. A total of 5 treatment‐emergent adverse events (TEAEs) were reported in 2 subjects. All 5 TEAEs were mild in severity and considered unrelated to the study drug. At steady state, the average plasma concentration and trough concentration ranged from 2.5 to 4.2 and 1.4 to 2.5 µg/mL, respectively. Inflammatory markers and disease activity (physician and patient global assessment score) decreased notably 12 hours post‐last dose. [ABSTRACT FROM AUTHOR]

ZYIL1 is a nucleotide‐binding oligomerization domain, leucine rich repeat and pyrin domain‐containing 3 (NLRP3) inflammasome inhibitor, which prevents NLRP3‐induced apoptosis‐associated speck‐like protein containing a caspase activation and recruitment domain oligomerization, thus inhibiting NLRP3 inflammasome pathway. We investigated the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ZYIL1 after single and multiple doses in healthy subjects. The subjects aged 18–55 years were enrolled in 2 different studies: single and multiple ascending dose. Blood/urine samples were collected at designated time points for pharmacokinetic and pharmacodynamic analysis. In the single‐ascending‐dose study, 30 subjects were enrolled (6 subjects each in 5 dose groups). One adverse event was reported during the study. ZYIL1 was well absorbed with median time to maximum plasma concentration at 1–1.5 hours. The exposures were dose proportional across the dose ranges. ZYIL1 is excreted as an unchanged form via the renal route. The mean elimination half‐life was 6–7 hours. In the multiple‐ascending‐dose study, 18 subjects were enrolled (6 subjects each in 3 dose groups). Eleven adverse events were reported by 6 subjects during the study. The accumulation index at steady state for area under the plasma concentration–time curve indicated that ZYIL1 has a marginal accumulation upon repeated dosing. Dose‐proportional exposure was observed across the dose ranges. All subjects showed >90% interleukin (IL)‐1β inhibition in all dose groups for both studies. Inhibition in IL‐1β and IL‐18 was observed throughout the 14 days of treatment in the multiple‐dose study. The safety profile, rapid absorption, marginal accumulation, and significant inhibition of IL‐1β and IL‐18 level support its development for the management of inflammatory disorders. [ABSTRACT FROM AUTHOR]

Methotrexate is an old drug that has found use in several therapeutic areas, such as cancer to treat various malignancies, rheumatoid arthtritis and inflammatory bowel disease. Owing to its structural properties of possessing two carboxylic acid groups and having low native fluorescence, it has provided technical challenges for development of bioanalytical methods. Also, in vivo metabolism leading to circulatory metabolites such as 7-hydroxymethotrexate and 2,4-diamino N10-methylpteroic acid, as well as the formation of polyglutamate metabolites intracellularly have added further complexity for the assays in terms of the analytes that need to be quantified in addition to methotrexate. The present review is aimed at providing a concise tabular summary of chromatographic assays with respect to method nuances including assay/chromatographic conditions, key validation parameters and applicable remarks. Several case studies are reviewed under various subheadings to provide the challenges involved in the method development for methotrexate and metabolites. Finally, a discussion section is devoted to overall perspectives obtained from this review. [ABSTRACT FROM AUTHOR]