Plasma pharmacokinetics and distribution of ruxolitinib into skin following oral and topical administration in minipigs.
Int J Pharm
; 590: 119889, 2020 Nov 30.
Article
em En
| MEDLINE
| ID: mdl-32949620
ABSTRACT
This preclinical study compared plasma concentrations and distribution of ruxolitinib in the skin of Göttingen minipigs following twice a day oral (40 mg/kg) versus topical administration (1.5% w/w cream applied to 10% of body surface area). Following oral administration, the plasma area-under-the-curve was approximately 31-fold and maximum drug concentration was 38-fold higher than those observed following topical application. Following ruxolitinib cream application, the average plasma concentration at steady-state was 2.7 ± 1.8 nM, a concentration that is not pharmacologically relevant. The average total dermis concentration of ruxolitinib at steady-state after topical administration was 507-fold higher versus that following oral dosing, while the ratio for the total epidermal concentration following topical vs oral dosing was 1989-fold. The concentration of unbound ruxolitinib in the dermis after topical application was predicted to result in sustained and near-complete inhibition of Janus kinase/signal transducer and activator of transcription proteins (JAK/STAT) signaling in this tissue. In contrast, only partial inhibition of downstream signaling was predicted to occur after oral dosing. In conclusion, ruxolitinib cream affords an attractive disposition profile in minipigs, wherein dermis concentrations of ruxolitinib are fully effective whereas corresponding plasma concentrations are negligible. Consequently, this distribution profile should maximize the efficacy of ruxolitinib cream in the skin while minimizing the potential for deleterious systemic effects.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
/
Preparações Farmacêuticas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Int J Pharm
Ano de publicação:
2020
Tipo de documento:
Article