Semi-Mechanistic PK/PD Modeling and Simulation of Irreversible BTK Inhibition to Support Dose Selection of Tirabrutinib in Subjects with RA.
Clin Pharmacol Ther
; 111(2): 416-424, 2022 02.
Article
in En
| MEDLINE
| ID: mdl-34623640
ABSTRACT
Tirabrutinib is an irreversible, small-molecule Bruton's tyrosine kinase (BTK) inhibitor, which was approved in Japan (VELEXBRU) to treat B-cell malignancies and is in clinical development for inflammatory diseases. As an application of model-informed drug development, a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for irreversible BTK inhibition of tirabrutinib was developed to support dose selection in clinical development, based on clinical PK and BTK occupancy data from two phase I studies with a wide range of PK exposures in healthy volunteers and in subjects with rheumatoid arthritis. The developed model adequately described and predicted the PK and PD data. Overall, the model-based simulation supported a total daily dose of at least 40 mg, either q.d. or b.i.d., with adequate BTK occupancy (> 90%) for further development in inflammatory diseases. Following the PK/PD modeling and simulation, the relationship between model-predicted BTK occupancy and preliminary clinical efficacy data was also explored and a positive trend was identified between the increasing time above adequate BTK occupancy and better efficacy in treatment for RA by linear regression.
Full text:
1
Database:
MEDLINE
Main subject:
Arthritis, Rheumatoid
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Pyrimidines
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Protein Kinase Inhibitors
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Agammaglobulinaemia Tyrosine Kinase
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Imidazoles
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Anti-Inflammatory Agents
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Models, Biological
Type of study:
Prognostic_studies
Limits:
Adolescent
/
Adult
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Female
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Humans
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Male
/
Middle aged
Language:
En
Journal:
Clin Pharmacol Ther
Year:
2022
Type:
Article
Affiliation country:
United States