Studies of the safety, pharmacokinetics and immunogenicity of repeated doses of intravenous staphylococcal protein A in cynomolgus monkeys.
Basic Clin Pharmacol Toxicol
; 115(5): 448-55, 2014 Nov.
Article
en En
| MEDLINE
| ID: mdl-24674306
Three Good Laboratory Practice safety studies were performed with intravenous injections of highly purified staphylococcal protein A (SPA) in cynomolgus monkeys, in support of a clinical development programme utilizing this protein as an immunomodulator. These studies established a no-observable-adverse-effect level (NOAEL) for up to 12 weekly doses of SPA, as well as toxicokinetic profiles for SPA, evaluation of antiproduct antibodies and biomarkers to better characterize the pharmacodynamic response to SPA. Biomarkers included neopterin, C-reactive protein (CRP), troponin I and the change in the blood absolute lymphocyte count (ALC) 24 hr after SPA dosing. The transient decrease in ALC noted at 24 hr after dosing was similar to that seen in human Phase 1 trials. The majority of active-treated monkeys developed antibodies against SPA. Cmax was not affected by development of antidrug antibodies (ADAs), and after the first dose was 87 (SD 19) ng/mL, 330 (SD 84) ng/mL and 1191 (SD 208) ng/mL for 5, 25 and 100 µg/kg doses, respectively. The development of ADAs increased plasma clearance of SPA. By the sixth weekly dose, the AUC was decreased by 76%, 54% and 66% for the 5, 25 and 100 µg/kg dose groups, respectively. These results indicate that SPA can be administered intravenously to non-human primates without observable toxicity at weekly doses of up to 100 µg/kg.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteína Estafilocócica A
/
Factores Inmunológicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Basic Clin Pharmacol Toxicol
Asunto de la revista:
FARMACOLOGIA
/
TOXICOLOGIA
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Reino Unido