Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer
Abstract 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 p...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2019-11-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-019-0791-x |
| _version_ | 1819082863794978816 |
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| author | Colby S. Shemesh Pascal Chanu Kris Jamsen Russ Wada Gianluca Rossato Francis Donaldson Amit Garg Helen Winter Jane Ruppel Xin Wang Rene Bruno Jin Jin Sandhya Girish |
| author_facet | Colby S. Shemesh Pascal Chanu Kris Jamsen Russ Wada Gianluca Rossato Francis Donaldson Amit Garg Helen Winter Jane Ruppel Xin Wang Rene Bruno Jin Jin Sandhya Girish |
| author_sort | Colby S. Shemesh |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-21T20:23:26Z |
| format | Article |
| id | doaj.art-b996c2b9893a413b9905987d3a8dc5c2 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-21T20:23:26Z |
| publishDate | 2019-11-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-b996c2b9893a413b9905987d3a8dc5c22022-12-21T18:51:26ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-11-017111310.1186/s40425-019-0791-xPopulation pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancerColby S. Shemesh0Pascal Chanu1Kris Jamsen2Russ Wada3Gianluca Rossato4Francis Donaldson5Amit Garg6Helen Winter7Jane Ruppel8Xin Wang9Rene Bruno10Jin Jin11Sandhya Girish12Department of Clinical Pharmacology Oncology, Genentech Inc.Clinical Pharmacology, Modeling and Simulation, Genentech/RocheCertara Strategic ConsultingCertara Strategic ConsultingClinical Science, F. Hoffmann-La Roche LtdSafety Science, Roche Products LtdDepartment of Clinical Pharmacology Oncology, Genentech Inc.Department of Clinical Pharmacology Oncology, Genentech Inc.Bioanalytical Sciences, Genentech Inc.Department of Clinical Pharmacology Oncology, Genentech Inc.Clinical Pharmacology, Modeling and Simulation, Genentech/RocheDepartment of Clinical Pharmacology Oncology, Genentech Inc.Department of Clinical Pharmacology Oncology, Genentech Inc.Abstract 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.http://link.springer.com/article/10.1186/s40425-019-0791-xAtezolizumabCancer immunotherapyClinical pharmacologyExposure-safetyImmune checkpoint inhibitorPediatric oncology |
| spellingShingle | Colby S. Shemesh Pascal Chanu Kris Jamsen Russ Wada Gianluca Rossato Francis Donaldson Amit Garg Helen Winter Jane Ruppel Xin Wang Rene Bruno Jin Jin Sandhya Girish Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer Journal for ImmunoTherapy of Cancer Atezolizumab Cancer immunotherapy Clinical pharmacology Exposure-safety Immune checkpoint inhibitor Pediatric oncology |
| title | Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer |
| title_full | Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer |
| title_fullStr | Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer |
| title_full_unstemmed | Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer |
| title_short | Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer |
| title_sort | population pharmacokinetics exposure safety and immunogenicity of atezolizumab in pediatric and young adult patients with cancer |
| topic | Atezolizumab Cancer immunotherapy Clinical pharmacology Exposure-safety Immune checkpoint inhibitor Pediatric oncology |
| url | http://link.springer.com/article/10.1186/s40425-019-0791-x |
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