Safety, tolerability, pharmacokinetics, and pharmacodynamics of oral JNJ-64794964, a TLR-7 agonist, in healthy adults
| Autor: | Bart Fevery, Liviawati S Wu, Rui Li, Leen Slaets, An De Creus, Abbie Oey, Ilham Smyej, Ullrich Schwertschlag, Samia Siddiqui, Pieter Van Remoortere, Christian Schwabe, E.J. Gane, Mina Pastagia, Joris Vandenbossche, Clark Musto |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Pharmacology Agonist business.industry medicine.drug_class Interferon-alpha Safety tolerability Multiple dosing Infectious Diseases Adjuvants Immunologic Double-Blind Method Toll-Like Receptor 7 Tolerability Pharmacokinetics Area Under Curve Pharmacodynamics Cytokines Humans Medicine Pharmacology (medical) business |
| Zdroj: | Antiviral Therapy. 26:58-68 |
| ISSN: | 2040-2058 1359-6535 |
| Popis: | Background This Phase I, two-part, first-in-human study assessed safety/tolerability and pharmacokinetics/pharmacodynamics of single-ascending doses (SAD) and multiple doses (MD) of the oral toll-like receptor-7 agonist, JNJ-64794964 (JNJ-4964) in healthy adults. Methods In the SAD phase, participants received JNJ-4964 0.2 ( N = 6), 0.6 ( N = 6), 1.25 ( N = 8) or 1.8 mg ( N = 6) or placebo ( N = 2/dose cohort) in a fasted state. Food effect was evaluated for the 1.25 mg cohort following ≥6 weeks washout. In the MD phase, participants received JNJ-4964 1.25 mg ( N = 6) or placebo ( N = 2) weekly (fasted) for 4 weeks. Participants were followed-up for 4 weeks. Results No serious adverse events (AEs) occurred. 10/34 (SAD) and 5/8 (MD) participants reported mild-to-moderate (≤Grade 2), transient, reversible AEs possibly related to JNJ-4964. Five (SAD) participants had fever/flu-like AEs, coinciding with interferon-α serum levels ≥100 pg/mL and lymphopenia (9/L), between 24–48 h after dosing and resolving approximately 96 h after dosing. One participant (MD) had an asymptomatic Grade 1 AE of retinal exudates (cotton wool spots) during follow-up, resolving 6 weeks after observation. JNJ-4964 exhibited dose-proportional pharmacokinetics, with rapid absorption (tmax 0.5–0.75 h) and distribution, and a long terminal half-life (150–591 h). Overall, no significant differences in JNJ-4964 pharmacokinetic parameters were observed in the fed versus fasted state. JNJ-4964 dose-dependently and transiently induced cytokines with potential anti-HBV activity, including interferon-α, IP-10, IL-1 RA, and/or MCP-1, and interferon-stimulated genes (ISG15, MX1, and OAS1) in serum. Conclusions In healthy adults, JNJ-4964 was generally well-tolerated, exhibited dose-proportional pharmacokinetics and induced cytokines/ISGs, with possible anti-HBV activity. |
| Databáze: | OpenAIRE |
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