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Leveraging in vitro and pharmacokinetic models to support bench to bedside investigation of XTMAB-16 as a novel pulmonary sarcoidosis treatment.
Offman, Elliot; Singh, Noopur; Julian, Mark W; Locke, Landon W; Bicer, Sabahattin; Mitchell, Jonah; Matthews, Thomas; Anderson, Kirsten; Crouser, Elliott D.
Afiliação
  • Offman E; Certara, Princeton, NJ, United States.
  • Singh N; Xentria, Inc., Chicago, IL, United States.
  • Julian MW; Division of Pulmonary, Critical Care and Sleep Medicine, The Dorothy M. Davis Heart and Lung Research Institute, Columbus, OH, United States.
  • Locke LW; Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
  • Bicer S; Department of Biomedical Engineering, The Ohio State University, Columbus, OH, United States.
  • Mitchell J; Department of Biomedical Engineering, The Ohio State University, Columbus, OH, United States.
  • Matthews T; Department of Biomedical Engineering, The Ohio State University, Columbus, OH, United States.
  • Anderson K; Xentria, Inc., Chicago, IL, United States.
  • Crouser ED; Xentria, Inc., Chicago, IL, United States.
Front Pharmacol ; 14: 1066454, 2023.
Article em En | MEDLINE | ID: mdl-37021060
ABSTRACT

Background:

Sarcoidosis is a chronic, multisystem inflammatory disorder characterized by non-caseating epithelioid granulomas; infiltration of mononuclear cells; and destruction of microarchitecture in the skin, eye, heart, and central nervous system, and the lung in >90% of cases. XTMAB-16 is a chimeric anti-tumor necrosis factor alpha (TNFα) antibody, distinct from other anti-TNF antibodies based on its molecular structure. The efficacy of XTMAB-16 has not been clinically demonstrated, and it is still undergoing clinical development as a potential treatment for sarcoidosis. The current study demonstrates the activity of XTMAB-16 in a well-established in vitro sarcoidosis granuloma model, although XTMAB-16 is not yet approved by the United States Food and Drug Administration (FDA) for treatment of sarcoidosis, or any other disease.

Objective:

To provide data to guide safe and efficacious dose selection for the ongoing clinical development of XTMAB-16 as a potential treatment for sarcoidosis.

Methods:

First, XTMAB-16 activity was evaluated in an established in vitro model of granuloma formation using peripheral blood mononuclear cells from patients with active pulmonary sarcoidosis to determine a potentially efficacious dose range. Second, data obtained from the first-in-human study of XTMAB-16 (NCT04971395) were used to develop a population pharmacokinetic (PPK) model to characterize the pharmacokinetics (PK) of XTMAB-16. Model simulations were performed to evaluate the sources of PK variability and to predict interstitial lung exposure based on concentrations in the in vitro granuloma model.

Results:

XTMAB-16 dose levels of 2 and 4 mg/kg, once every 2 weeks (Q2W) or once every 4 weeks (Q4W) for up to 12 weeks, were supported by data from the non-clinical, in vitro secondary pharmacology; the Phase 1 clinical study; and the PPK model developed to guide dose level and frequency assumptions. XTMAB-16 inhibited granuloma formation and suppressed interleukin-1ß (IL-1ß) secretion in the in vitro granuloma model with a half maximal inhibitory concentration (IC50) of 5.2 and 3.5 µg/mL, respectively. Interstitial lung concentrations on average, following 2 or 4 mg/kg administered Q2W or Q4W, are anticipated to exceed the in vitro IC50 concentrations.

Conclusion:

The data presented in this report provide a rationale for dose selection and support the continued clinical development of XTMAB-16 for patients with pulmonary sarcoidosis.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Front Pharmacol Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Front Pharmacol Ano de publicação: 2023 Tipo de documento: Article