Development of a pediatric physiologically-based pharmacokinetic model to support recommended dosing of atezolizumab in children with solid tumors.
| Title: | Development of a pediatric physiologically-based pharmacokinetic model to support recommended dosing of atezolizumab in children with solid tumors. |
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| Authors: | Huang W; Genentech Inc, South San Francisco, CA, United States.; Stader F; Certara UK Limited, Sheffield, United Kingdom.; Chan P; Genentech Inc, South San Francisco, CA, United States.; Shemesh CS; Genentech Inc, South San Francisco, CA, United States.; Chen Y; Genentech Inc, South San Francisco, CA, United States.; Gill KL; Certara UK Limited, Sheffield, United Kingdom.; Jones HM; Certara UK Limited, Sheffield, United Kingdom.; Li L; Certara UK Limited, Sheffield, United Kingdom.; Rossato G; F. Hoffmann-La Roche Ltd, Basel, Switzerland.; Wu B; Genentech Inc, South San Francisco, CA, United States.; Jin JY; Genentech Inc, South San Francisco, CA, United States.; Chanu P; Genentech Inc, South San Francisco, CA, United States. |
| Source: | Frontiers in pharmacology [Front Pharmacol] 2022 Sep 26; Vol. 13, pp. 974423. Date of Electronic Publication: 2022 Sep 26 (Print Publication: 2022). |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Frontiers Media] Country of Publication: Switzerland NLM ID: 101548923 Publication Model: eCollection Cited Medium: Print ISSN: 1663-9812 (Print) Linking ISSN: 16639812 NLM ISO Abbreviation: Front Pharmacol Subsets: PubMed not MEDLINE |
| Imprint Name(s): | Original Publication: [Lausanne : Frontiers Media] |
| Abstract: | Background: Atezolizumab has been studied in multiple indications for both pediatric and adult patient populations. Generally, clinical studies enrolling pediatric patients may not collect sufficient pharmacokinetic data to characterize the drug exposure and disposition because of operational, ethical, and logistical challenges including burden to children and blood sample volume limitations. Therefore, mechanistic modeling and simulation may serve as a tool to predict and understand the drug exposure in pediatric patients. Objective: To use mechanistic physiologically-based pharmacokinetic (PBPK) modeling to predict atezolizumab exposure at a dose of 15 mg/kg (max 1,200 mg) in pediatric patients to support dose rationalization and label recommendations. Methods: A minimal mechanistic PBPK model was used which incorporated age-dependent changes in physiology and biochemistry that are related to atezolizumab disposition such as endogenous IgG concentration and lymph flow. The PBPK model was developed using both in vitro data and clinically observed data in adults and was verified across dose levels obtained from a phase I and multiple phase III studies in both pediatric patients and adults. The verified model was then used to generate PK predictions for pediatric and adult subjects ranging from 2- to 29-year-old. Results: Individualized verification in children and in adults showed that the simulated concentrations of atezolizumab were comparable (76% within two-fold and 90% within three-fold, respectively) to the observed data with no bias for either over- or under-prediction. Applying the verified model, the predicted exposure metrics including Cmin, Cmax, and AUCtau were consistent between pediatric and adult patients with a geometric mean of pediatric exposure metrics between 0.8- to 1.25-fold of the values in adults. Conclusion: The results show that a 15 mg/kg (max 1,200 mg) atezolizumab dose administered intravenously in pediatric patients provides comparable atezolizumab exposure to a dose of 1,200 mg in adults. This suggests that a dose of 15 mg/kg will provide adequate and effective atezolizumab exposure in pediatric patients from 2- to 18-year-old.; (Copyright © 2022 Huang, Stader, Chan, Shemesh, Chen, Gill, Jones, Li, Rossato, Wu, Jin and Chanu.) |
| Competing Interests: | Authors WH, PChan, CS, YC, BW, JJ, Pchanu are salaried employees and stockholders of Genentech, Inc. FS, KG, HJ are salaried employees and stockholders of Certara LL was a salaried employee and stockholder of Certara during the execution of the study presented in this manuscript and now is a salaried employee of Daiichi Sankyo. Author GR was employed by F Hoffmann-La Roche Ltd. |
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| Contributed Indexing: | Keywords: alveolar soft part sarcoma; atezolizumab; clinical pharmacology; pediatric extrapolation; pediatric oncology; physiologically-based pharmacokinetic (PBPK) modeling; quantitative pharmacology; solid tumor |
| Entry Date(s): | Date Created: 20221013 Latest Revision: 20221014 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC9548535 |
| DOI: | 10.3389/fphar.2022.974423 |
| PMID: | 36225583 |
| Database: | MEDLINE |
Journal Article