Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer.
Atezolizumab
Cancer immunotherapy
Clinical pharmacology
Exposure-safety
Immune checkpoint inhibitor
Pediatric oncology
Population pharmacokinetics
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
21 11 2019
21 11 2019
Historique:
received:
16
08
2019
accepted:
25
10
2019
entrez:
23
11
2019
pubmed:
23
11
2019
medline:
3
7
2020
Statut:
epublish
Résumé
The 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. Patients 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. A 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. These findings demonstrate a similar exposure-safety profile of atezolizumab in pediatric and young adult patients, supportive of weight-based dosing in pediatric patients. NCT02541604.
Sections du résumé
BACKGROUND
The 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.
METHODS
Patients 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.
RESULTS
A 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.
CONCLUSIONS
These findings demonstrate a similar exposure-safety profile of atezolizumab in pediatric and young adult patients, supportive of weight-based dosing in pediatric patients.
TRIAL REGISTRATION
NCT02541604.
Identifiants
pubmed: 31753029
doi: 10.1186/s40425-019-0791-x
pii: 10.1186/s40425-019-0791-x
pmc: PMC6868826
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Antineoplastic Agents
0
atezolizumab
52CMI0WC3Y
Banques de données
ClinicalTrials.gov
['NCT02541604']
Types de publication
Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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