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Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer

Authors
  • Shemesh, Colby S.1
  • Chanu, Pascal2
  • Jamsen, Kris3
  • Wada, Russ3
  • Rossato, Gianluca4
  • Donaldson, Francis5
  • Garg, Amit1, 6
  • Winter, Helen1, 6
  • Ruppel, Jane7
  • Wang, Xin1
  • Bruno, Rene2
  • Jin, Jin1
  • Girish, Sandhya1
  • 1 Department of Clinical Pharmacology Oncology, Genentech Inc., South San Francisco, CA, 94080, USA , South San Francisco (United States)
  • 2 Clinical Pharmacology, Modeling and Simulation, Genentech/Roche, Marseille, France , Marseille (France)
  • 3 Certara Strategic Consulting, Princeton, NJ, USA , Princeton (United States)
  • 4 Clinical Science, F. Hoffmann-La Roche Ltd, Basel, Switzerland , Basel (Switzerland)
  • 5 Safety Science, Roche Products Ltd, Welwyn Garden City, UK , Welwyn Garden City (United Kingdom)
  • 6 Present address: Quantitative Pharmacology and Disposition, Seattle Genetics, South San Francisco, CA, USA , South San Francisco (United States)
  • 7 Bioanalytical Sciences, Genentech Inc., South San Francisco, CA, USA , South San Francisco (United States)
Type
Published Article
Journal
Journal for ImmunoTherapy of Cancer
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Nov 21, 2019
Volume
7
Issue
1
Identifiers
DOI: 10.1186/s40425-019-0791-x
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundThe iMATRIX-atezolizumab study was a phase I/II, multicenter, open-label study designed to assess the safety and pharmacokinetics of atezolizumab in pediatric and young adult patients. We describe the pharmacokinetics (PK), exposure-safety, and immunogenicity of atezolizumab in pediatric and young adults with metastatic solid tumors or hematologic malignancies enrolled in this study.MethodsPatients aged < 18 years (n = 69) received a weight-adjusted dose of atezolizumab (15 mg/kg every 3 weeks [q3w]; maximum 1200 mg); those aged ≥ 18 years (n = 18) received a flat dose (1200 mg q3w). A prior two-compartment intravenous infusion input adult population-PK (popPK) model of atezolizumab was used as a basis to model pediatric data.ResultsA total of 431 atezolizumab serum concentrations from 87 relapse-refractory pediatric and young adult patients enrolled in the iMATRIX-atezolizumab study were used for the popPK analysis. The dataset comprised predominantly patients aged < 18 years, including two infants aged < 2 years, with a wide body weight and age range. The clearance and volume of distribution estimates of atezolizumab were 0.217 L/day and 3.01 L, respectively. Atezolizumab geometric mean trough exposures were ~ 20% lower in pediatric patients versus young adults; this was not clinically meaningful as both groups achieved the target concentration (6 μg/mL). Safety was similar between pediatric and young adult patients with no exposure-safety relationship observed. Limited responses (4/87) precluded an exposure-response assessment on outcomes. A comparable rate (13% vs 11%) of atezolizumab anti-drug antibodies was seen in pediatric and young adult patients.ConclusionsThese findings demonstrate a similar exposure-safety profile of atezolizumab in pediatric and young adult patients, supportive of weight-based dosing in pediatric patients.Trial registrationNCT02541604.

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