First-in-human safety, tolerability, and pharmacokinetic results of DFV890, an oral low-molecular-weight NLRP3 inhibitor.
Clin Transl Sci
; 17(5): e13789, 2024 May.
Article
em En
| MEDLINE
| ID: mdl-38761014
ABSTRACT
This first-in-human study evaluated the safety, tolerability, single- and multiple-dose pharmacokinetic profiles with dietary influence, and pharmacodynamics (PD) of DFV890, an oral NLRP3 inhibitor, in healthy participants. In total, 122 participants were enrolled into a three-part trial including single and 2-week multiple ascending oral doses (SAD and MAD, respectively) of DFV890, and were randomized (31) to DFV890 or placebo (SAD [3-600 mg] and MAD [fasted 10-200 mg, once-daily or fed 25 and 50 mg, twice-daily]). DFV890 was generally well-tolerated. Neither deaths nor serious adverse events were reported. A less than dose-proportional increase in exposure was observed with the initially used crystalline suspension (3-300 mg); however, an adjusted suspension formulation using spray-dried dispersion (SDD; 100-600 mg) confirmed dose-proportional increase in exposure. Relative bioavailability between crystalline suspension and tablets, and food effect were evaluated at 100 mg. Under fasting conditions, Cmax of the tablet yielded 78% compared with the crystalline suspension, and both formulations showed comparable AUC. The fed condition led to a 2.05- and 1.49-fold increase in Cmax and AUC0-last compared with the fasting condition. The median IC50 and IC90 for ex-vivo lipopolysaccharide-stimulated interleukin IL-1ß release inhibition (PD) were 61 (90% CI 50, 70) and 1340 ng/mL (90% CI 1190, 1490). Crystalline tablets of 100 mg once-daily or 25 mg twice-daily were sufficient to maintain ~90% of the IL-1ß release inhibition over 24 h at steady state. Data support dose and formulation selection for further development in diseases, in which an overactivated NLRP3 represents the underlying pathophysiology.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Relação Dose-Resposta a Droga
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Interleucina-1beta
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Proteína 3 que Contém Domínio de Pirina da Família NLR
Limite:
Adolescent
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Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Clin Transl Sci
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Suíça