First-in-human study to assess the safety, tolerability, and pharmacokinetics of intravenous SHPL-49 following single- and multiple-ascending-dose administration in healthy adults.
J Pharm Biomed Anal
; 249: 116314, 2024 Oct 15.
Article
en En
| MEDLINE
| ID: mdl-39033613
ABSTRACT
SHPL-49 is an innovative glycoside derivative that is synthesized by structural modifications of salidrosideï¼demonstrating therapeutic effects on animal models of ischemia in pre-clinical experiments. A phase I, single-center, randomized, double-blind, placebo-controlled, single and multiple dose administration study of SHPL-49 was conducted in healthy Chinese volunteers. In single-ascending-dose (SAD) study, 32 subjects randomized 62 to receive SHPL-49 (30â¯mg, 75â¯mg, 150â¯mg, 300â¯mg) or placebo with 30â¯minutes infusion. In multiple-ascending-dose (MAD) study, subjects were randomized 62 to receive SHPL-49 (75â¯mg, 150â¯mg, 300â¯mg) or placebo with 30â¯minutes infusion every 8â¯h for 7 days. Safety evaluations were conducted throughout the studies. Plasma and urine concentrations of SHPL-49 were detected and its metabolites were identified. Pharmacokinetic parameters were calculated using noncompartmental methods. SHPL-49 was generally safe and well-tolerated at single ascending doses (30-300â¯mg) and multiple ascending doses (75-300â¯mg). All adverse events were mild and resolved without any intervention. No serious adverse events were reported. In the SAD study, SHPL-49 exhibited dose-proportional plasma pharmacokinetics, with peak plasma concentration (Cmax) ranging from 673.83 to 6275.00â¯ng/mL, area under the plasma concentration-time curve (AUC0-t) ranging from 338.57 to 3732.67â¯h·ng/mL, and elimination half-life (t1/2) ranging from 0.49 to 0.67â¯h. In the MAD, the exposure was also dose-proportional and there was no significant accumulation following multiple dosing. Four metabolites were identified in urine and plasma. SHPL-49 shows a favorable pharmacokinetic, safety, and tolerability profile in healthy Chinese volunteers following a single- and multiple-ascending- dose administration in this study. For future therapeutic investigations, it is recommended to administer SHPL-49 intravenously at 8-hour intervals with a dosage range of 150-300â¯mg.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Relación Dosis-Respuesta a Droga
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Voluntarios Sanos
Límite:
Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
J Pharm Biomed Anal
Año:
2024
Tipo del documento:
Article
Pais de publicación:
Reino Unido