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Employing zero-inflated beta distribution in an exposure-response analysis of TYK2/JAK1 inhibitor brepocitinib in patients with plaque psoriasis.
Tsamandouras, Nikolaos; Qiu, Ruolun; Hughes, Jim H; Sweeney, Kevin; Prybylski, John P; Banfield, Christopher; Nicholas, Timothy.
Afiliação
  • Tsamandouras N; Clinical Pharmacology, Early Clinical Development, Worldwide Research, Development and Medical, Pfizer, Cambridge, MA, USA. nikolaos.tsamandouras@pfizer.com.
  • Qiu R; Clinical Pharmacology, Early Clinical Development, Worldwide Research, Development and Medical, Pfizer, Cambridge, MA, USA.
  • Hughes JH; Clinical Pharmacology, Global Product Development, Pfizer, Groton, CT, USA.
  • Sweeney K; Clinical Pharmacology, Global Product Development, Pfizer, Groton, CT, USA.
  • Prybylski JP; Clinical Pharmacology, Global Product Development, Pfizer, Groton, CT, USA.
  • Banfield C; Clinical Pharmacology, Early Clinical Development, Worldwide Research, Development and Medical, Pfizer, Cambridge, MA, USA.
  • Nicholas T; Clinical Pharmacology, Global Product Development, Pfizer, Groton, CT, USA.
J Pharmacokinet Pharmacodyn ; 51(3): 265-277, 2024 Jun.
Article em En | MEDLINE | ID: mdl-38431923
ABSTRACT
Brepocitinib is an oral selective dual TYK2/JAK1 inhibitor and based on its cytokine inhibition profile is expected to provide therapeutic benefit in the treatment of plaque psoriasis. Efficacy data from a completed Phase 2a study in patients with moderate-to-severe plaque psoriasis were utilized to develop a population exposure-response model that can be employed to inform dose selection decisions for further clinical development. A modeling approach that employs the zero-inflated beta distribution was used to account for the bounded nature and distributional characteristics of the Psoriasis Area and Severity Index (PASI) score data. The developed exposure-response model provided an adequate description of the observed PASI scores across all the treatment arms tested and across both the induction and maintenance dosing periods of the study. In addition, the developed model exhibited a good predictive capacity with regard to the derived responder metrics (e.g., 75%/90%/100% improvement in PASI score [PASI75/90/100]). Clinical trial simulations indicated that the induction/maintenance dosing paradigm explored in this study does not offer any advantages from an efficacy perspective and that doses of 10, 30, and 60 mg once-daily may be suitable candidates for clinical evaluation in subsequent Phase 2b studies.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Psoríase / Inibidores de Proteínas Quinases / Janus Quinase 1 / TYK2 Quinase Limite: Adult / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Psoríase / Inibidores de Proteínas Quinases / Janus Quinase 1 / TYK2 Quinase Limite: Adult / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2024 Tipo de documento: Article