Model-Based Selection and Recommendation for Subcutaneous Abatacept Dose in Patients With Polyarticular Juvenile Idiopathic Arthritis.

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  • Author(s): Gandhi Y;Gandhi Y; Passarell JA; Passarell JA; Roy A; Roy A; Murthy B; Murthy B
  • Source:
    Journal of clinical pharmacology [J Clin Pharmacol] 2021 May; Vol. 61 (5), pp. 688-699. Date of Electronic Publication: 2021 Jan 18.
  • Publication Type:
    Clinical Trial, Phase II; Clinical Trial, Phase III; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Wiley Country of Publication: England NLM ID: 0366372 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4604 (Electronic) Linking ISSN: 00912700 NLM ISO Abbreviation: J Clin Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: 2013- : Oxford : Wiley
      Original Publication: Stamford, Conn., Hall Associates.
    • Subject Terms:
      Abatacept/*pharmacokinetics ; Abatacept/*therapeutic use ; Antirheumatic Agents/*pharmacokinetics ; Antirheumatic Agents/*therapeutic use ; Arthritis, Juvenile/*drug therapy; Abatacept/administration & dosage ; Adolescent ; Age Factors ; Antirheumatic Agents/administration & dosage ; Body Weight ; Child ; Child, Preschool ; Dose-Response Relationship, Drug ; Female ; Glomerular Filtration Rate ; Humans ; Injections, Intravenous ; Injections, Subcutaneous ; Male ; Metabolic Clearance Rate ; Models, Biological ; Patient Acuity ; Sex Factors
    • Abstract:
      The selective T-cell costimulation modulator abatacept is approved for treatment of adult rheumatoid arthritis (RA) and polyarticular juvenile idiopathic arthritis (pJIA; 6-17 years [intravenous] and 2-17 years [subcutaneous]). An extrapolation approach was taken to determine subcutaneous weight-tiered doses of abatacept to evaluate in patients with pJIA. Population pharmacokinetic (PPK) and exposure-response (E-R) analyses were conducted to determine whether the weight-tiered subcutaneous regimen provides near-maximal efficacy and is therapeutically comparable to the intravenous regimen in patients with pJIA aged 2-17 years. Combined study data from intravenous or subcutaneous abatacept were used to assess clinically relevant exposure outcomes. The PPK model was developed with data from 13 phase 2/3 studies in RA and pJIA; the E-R model for the American College of Rheumatology pediatric scores (JIA-ACR 30/50/70/100 responses) in month 4 was developed with data from 2 phase 3 pJIA studies. Predefined covariates were investigated in both analyses. PPK model-predicted exposures were steady-state peak, trough (C minss ), and time-averaged concentrations. Abatacept PK was characterized by a linear 2-compartment model (zero-order intravenous infusion, first-order subcutaneous absorption, first-order elimination); body weight was the only clinically relevant covariate. C minss was the best exposure predictor for the JIA-ACR response: log odds for response increased in proportion to log-transformed C minss ; JIA-ACR30 approached a plateau when C minss ≥ 10 μg/mL. The PPK and E-R analyses demonstrated that the weight-tiered subcutaneous and intravenous abatacept dosing regimens provide near-maximal efficacy and are clinically comparable across children with pJIA who are > 2 years old.
      (© 2020 Bristol Myers Squibb. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
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    • Contributed Indexing:
      Keywords: JIA-ACR; abatacept; exposure-response; juvenile idiopathic arthritis; pediatric; population pharmacokinetics
    • Accession Number:
      0 (Antirheumatic Agents)
      7D0YB67S97 (Abatacept)
    • Publication Date:
      Date Created: 20201207 Date Completed: 20211220 Latest Revision: 20240809
    • Publication Date:
      20240809
    • Accession Number:
      PMC8048692
    • Accession Number:
      10.1002/jcph.1797
    • Accession Number:
      33284480