Pharmacokinetics and efficacy of a vaginally administered maraviroc gel in rhesus macaques.
J Antimicrob Chemother
; 68(3): 678-83, 2013 Mar.
Article
en En
| MEDLINE
| ID: mdl-23111849
ABSTRACT
OBJECTIVES:
To investigate the pharmacokinetics (PK) of maraviroc, a CCR5-targeted HIV-1 entry inhibitor, in rhesus macaques following vaginal administration of various maraviroc-loaded aqueous hydroxyethylcellulose (HEC) gels, and to correlate the PK data with efficacy in a single high-dose vaginal SHIV-162P3 challenge model.METHODS:
Maraviroc concentrations in vaginal fluid (Weck-Cel(®) sponge), vaginal tissue (punch biopsy) and plasma were assessed over 72 h following single-dose vaginal application of various maraviroc-loaded HEC gels. The range of maraviroc gel concentrations was sufficiently broad (0.003%-3.3% w/w) that test gels included both fully solubilized and predominantly dispersed formulations. The efficacy of the HEC gels against a single high-dose vaginal SHIV-162P3 challenge was also measured, and correlated with the PK concentrations.RESULTS:
Maraviroc concentrations in vaginal fluid (range 10(4)-10(7) ng/mL), vaginal tissue (100-1200 ng/g) and plasma (<10(2) ng/mL) were highly dependent on maraviroc gel loading, irrespective of the form of the maraviroc component within the gel (solubilized versus dispersed). Fluid and plasma concentrations were generally highest 0.5 or 2 h after gel application, before declining steadily through to 72 h. Maraviroc concentrations in the various biological compartments correlated strongly with the extent of protection against vaginal SHIV-162P3 challenge. Complete protection was achieved with a 3.3% w/w maraviroc gel.CONCLUSIONS:
A high degree of correlation between PK and efficacy was observed. Based on the data obtained with the 3.3% w/w maraviroc gel, maintenance of vaginal fluid and tissue levels in the order of 10(7) ng/mL and 10(3) ng/g, respectively, are required for complete protection with this compound.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Triazoles
/
Cremas, Espumas y Geles Vaginales
/
Síndrome de Inmunodeficiencia Adquirida del Simio
/
Ciclohexanos
/
Inhibidores de Fusión de VIH
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Antimicrob Chemother
Año:
2013
Tipo del documento:
Article
País de afiliación:
Reino Unido