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Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Modeling of Weight-Based Intravenous Reslizumab Dosing.
Passarell, Julie; Jaworowicz, David; Ludwig, Elizabeth; Rabinovich-Guilatt, Laura; Cox, Donna S; Levi, Micha; Garin, Margaret; Fiedler-Kelly, Jill; Bond, Mary.
Afiliação
  • Passarell J; Cognigen Corporation, a Simulations Plus company, Buffalo, New York, USA.
  • Jaworowicz D; Cognigen Corporation, a Simulations Plus company, Buffalo, New York, USA.
  • Ludwig E; Cognigen Corporation, a Simulations Plus company, Buffalo, New York, USA.
  • Rabinovich-Guilatt L; Teva Branded Pharmaceutical Products R&D Inc, West Chester, Pennsylvania, USA.
  • Cox DS; Teva Branded Pharmaceutical Products R&D Inc, West Chester, Pennsylvania, USA.
  • Levi M; Teva Branded Pharmaceutical Products R&D Inc, West Chester, Pennsylvania, USA.
  • Garin M; Teva Branded Pharmaceutical Products R&D Inc, West Chester, Pennsylvania, USA.
  • Fiedler-Kelly J; Cognigen Corporation, a Simulations Plus company, Buffalo, New York, USA.
  • Bond M; Teva Branded Pharmaceutical Products R&D Inc, West Chester, Pennsylvania, USA.
J Clin Pharmacol ; 60(8): 1039-1050, 2020 08.
Article em En | MEDLINE | ID: mdl-32333684
ABSTRACT
Reslizumab 3.0 mg/kg has demonstrated efficacy in clinical studies of patients with eosinophilic asthma and a history of exacerbations. A population pharmacokinetic (PK) model was developed to determine whether 3.0 mg/kg weight-based dosing is appropriate to obtain consistent reslizumab exposures in all patients. PK data in healthy volunteers and patients ≥12 years with moderate to severe asthma, eosinophilic asthma, or nasal polyposis were analyzed from 4 phase 1, 2 phase 2, and 2 phase 3 studies of intravenous (IV) reslizumab (N = 804). Covariates evaluated included age, race, sex, baseline weight, renal and liver function, concomitant medications, and antidrug antibody status. Exposure-response models were developed to characterize key efficacy (blood eosinophil levels, forced expiratory volume in 1 second [FEV1 ], Asthma Control Questionnaire [ACQ-7] scores), and safety end points (muscle disorder adverse events [AEs]). Vial-based dosing was evaluated as an alternative to weight-based dosing. IV reslizumab PK was accurately described by a 2-compartment PK model with 0-order input and first-order elimination. Body weight was the only covariate that significantly influenced PK parameters. However, with weight-based dosing, comparable steady-state exposures were observed across high and low body weights. Greater eosinophil lowering and longer response duration were observed with increasing dose; exposure-related effects on FEV1 and ACQ-7 were also seen, demonstrating the clinical importance of a dosing regimen to optimize reslizumab exposure. The probability of a muscle disorder AE appeared to increase with increasing exposure. Steady-state exposure measures were similar for both dosing regimens, showing vial-based dosing as an alternative method of achieving the benefits of weight-based dosing.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Antiasmáticos / Anticorpos Monoclonais Humanizados Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Antiasmáticos / Anticorpos Monoclonais Humanizados Idioma: En Ano de publicação: 2020 Tipo de documento: Article