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Moving Beyond Boundaries: Utilization of Longitudinal Exposure-Response Model for Bounded Outcome Score to Inform Decision Making in the Accelerated Drug Development Paradigm.
Huh, Yeamin; Wojciechowski, Jessica; Purohit, Vivek S.
Afiliación
  • Huh Y; Worldwide Development, Research and Medical, Pfizer Inc, 280 Shennecossett Rd, Groton, CT, 06340, USA. yeamin.huh@pfizer.com.
  • Wojciechowski J; Worldwide Development, Research and Medical, Pfizer Inc, 280 Shennecossett Rd, Groton, CT, 06340, USA.
  • Purohit VS; Worldwide Development, Research and Medical, Pfizer Inc, 280 Shennecossett Rd, Groton, CT, 06340, USA.
Clin Pharmacokinet ; 63(3): 381-394, 2024 03.
Article en En | MEDLINE | ID: mdl-38358645
ABSTRACT
BACKGROUND AND

OBJECTIVES:

As drug development scientists strive to accelerate availability of therapies for patients, model-informed drug development (MIDD) plays an important role in contextualizing existing information and facilitating decision making. This paper describes an example of MIDD, where modeling and simulation informed decision making in the circumstance of a combined phase 2b and single pivotal study for ritlecitinib (JAK3/TEC family kinases inhibitor).

METHODS:

Longitudinal exposure-response (ER) modeling was conducted to describe ritlecitinib efficacy in alopecia areata patients. The Severity of Alopecia Tool (SALT) score (a continuous bounded outcome [CBO] score [0-100]) was used as the efficacy response. The average concentration during the time interval between two adjacent SALT scores was used as the exposure metric driving efficacy.

RESULTS:

The developed model well described the longitudinal SALT profile of ritlecitinib as well as the frequency of boundary data. The CBO model indicated tested doses in the phase 2b/3 clinical trial are in the ascending region of ER and contextualized a loading dose effect that impacted onset of efficacy without long-term benefit. It also identified disease severity as the only covariate impacting efficacy. The model-based simulation further informed impact of treatment interruption on the loss of efficacy in the absence of a dedicated treatment withdrawal study. Results indicated temporary treatment interruption ≤ 6 weeks is not expected to result in significant loss of efficacy.

CONCLUSION:

The CBO modeling approach and simulation supported the single pivotal trial strategy and guided dose selection in the accelerated drug development program of ritlecitinib, which can be applied to many indications where efficacy is measured on a bounded scale.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Proteínas Quinasas / Desarrollo de Medicamentos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Clin Pharmacokinet Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Proteínas Quinasas / Desarrollo de Medicamentos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Clin Pharmacokinet Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza