Rituximab pediatric drug development: Pharmacokinetic and pharmacodynamic modeling to inform regulatory approval for rituximab treatment in patients with granulomatosis with polyangiitis or microscopic polyangiitis
Abstract Anti‐neutrophil cytoplasmic antibody‐associated vasculitides granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are rare, potentially organ‐ and life‐threatening autoimmune conditions affecting adult and pediatric patients. An open‐label phase II study was conducted t...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-09-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13351 |
| _version_ | 1818063708405891072 |
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| author | Candice Jamois Leonid Gibiansky Clarisse Chavanne Melissa Cheu Patricia B. Lehane Pooneh Pordeli Simone Melega Jacques Gaudreault |
| author_facet | Candice Jamois Leonid Gibiansky Clarisse Chavanne Melissa Cheu Patricia B. Lehane Pooneh Pordeli Simone Melega Jacques Gaudreault |
| author_sort | Candice Jamois |
| collection | DOAJ |
| description | Abstract Anti‐neutrophil cytoplasmic antibody‐associated vasculitides granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are rare, potentially organ‐ and life‐threatening autoimmune conditions affecting adult and pediatric patients. An open‐label phase II study was conducted to determine safe and effective dosing regimens of rituximab in pediatric patients with GPA/MPA. To determine the selection of an appropriate dose regimen in children for induction and maintenance, a population pharmacokinetic approach was used (nonlinear mixed‐effect modeling), combining pediatric data with data from adults with GPA/MPA. The time course of B‐cell depletion was assessed in both populations. The exposure‐effect relationship was assessed by logistic regression. Twenty‐five pediatric patients (80% female patients; age range, 6–17 years) were enrolled in the trial and received the induction regimen of intravenous rituximab 375 mg/m2 weekly for 4 weeks, which resulted in a similar exposure to that of adults. Based on pharmacokinetic modeling, a maintenance dosing regimen of 250 mg/m2 administered twice over 14 days followed by 250 mg/m2 every 6 months is expected to result in similar rituximab exposure as that of adults receiving the approved maintenance dose of 500 mg administered twice over 14 days followed by 500 mg every 6 months. The time course of B‐cell depletion was similar between the pediatric and adult populations, supporting the similarities in response in both populations and allowing extrapolation to patients less than 6 years old. Using a partial extrapolation approach helped identify safe and effective dosing regimens of rituximab in pediatric patients with GPA/MPA and lead to regulatory approval. |
| first_indexed | 2024-12-10T14:24:24Z |
| format | Article |
| id | doaj.art-2c34e1cfb5614cc3ba73e1f72bdbe412 |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-12-10T14:24:24Z |
| publishDate | 2022-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-2c34e1cfb5614cc3ba73e1f72bdbe4122022-12-22T01:45:06ZengWileyClinical and Translational Science1752-80541752-80622022-09-011592172218310.1111/cts.13351Rituximab pediatric drug development: Pharmacokinetic and pharmacodynamic modeling to inform regulatory approval for rituximab treatment in patients with granulomatosis with polyangiitis or microscopic polyangiitisCandice Jamois0Leonid Gibiansky1Clarisse Chavanne2Melissa Cheu3Patricia B. Lehane4Pooneh Pordeli5Simone Melega6Jacques Gaudreault7Clinical Pharmacology, Pharmaceutical Sciences, Pharma Research and Early Development Roche Innovation Center Basel Basel SwitzerlandQuantPharm LLC North Potomac Maryland USAClinical Pharmacology, Pharmaceutical Sciences, Pharma Research and Early Development Roche Innovation Center Basel Basel SwitzerlandBioAnalytical Sciences Genentech Inc. South San Francisco California USAClinical Development Roche Welwyn Garden City UKRoche Canada Mississauga Ontario CanadaF. Hoffmann‐La Roche Ltd. Basel SwitzerlandJJG Pharma Consulting Basel SwitzerlandAbstract Anti‐neutrophil cytoplasmic antibody‐associated vasculitides granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are rare, potentially organ‐ and life‐threatening autoimmune conditions affecting adult and pediatric patients. An open‐label phase II study was conducted to determine safe and effective dosing regimens of rituximab in pediatric patients with GPA/MPA. To determine the selection of an appropriate dose regimen in children for induction and maintenance, a population pharmacokinetic approach was used (nonlinear mixed‐effect modeling), combining pediatric data with data from adults with GPA/MPA. The time course of B‐cell depletion was assessed in both populations. The exposure‐effect relationship was assessed by logistic regression. Twenty‐five pediatric patients (80% female patients; age range, 6–17 years) were enrolled in the trial and received the induction regimen of intravenous rituximab 375 mg/m2 weekly for 4 weeks, which resulted in a similar exposure to that of adults. Based on pharmacokinetic modeling, a maintenance dosing regimen of 250 mg/m2 administered twice over 14 days followed by 250 mg/m2 every 6 months is expected to result in similar rituximab exposure as that of adults receiving the approved maintenance dose of 500 mg administered twice over 14 days followed by 500 mg every 6 months. The time course of B‐cell depletion was similar between the pediatric and adult populations, supporting the similarities in response in both populations and allowing extrapolation to patients less than 6 years old. Using a partial extrapolation approach helped identify safe and effective dosing regimens of rituximab in pediatric patients with GPA/MPA and lead to regulatory approval.https://doi.org/10.1111/cts.13351 |
| spellingShingle | Candice Jamois Leonid Gibiansky Clarisse Chavanne Melissa Cheu Patricia B. Lehane Pooneh Pordeli Simone Melega Jacques Gaudreault Rituximab pediatric drug development: Pharmacokinetic and pharmacodynamic modeling to inform regulatory approval for rituximab treatment in patients with granulomatosis with polyangiitis or microscopic polyangiitis Clinical and Translational Science |
| title | Rituximab pediatric drug development: Pharmacokinetic and pharmacodynamic modeling to inform regulatory approval for rituximab treatment in patients with granulomatosis with polyangiitis or microscopic polyangiitis |
| title_full | Rituximab pediatric drug development: Pharmacokinetic and pharmacodynamic modeling to inform regulatory approval for rituximab treatment in patients with granulomatosis with polyangiitis or microscopic polyangiitis |
| title_fullStr | Rituximab pediatric drug development: Pharmacokinetic and pharmacodynamic modeling to inform regulatory approval for rituximab treatment in patients with granulomatosis with polyangiitis or microscopic polyangiitis |
| title_full_unstemmed | Rituximab pediatric drug development: Pharmacokinetic and pharmacodynamic modeling to inform regulatory approval for rituximab treatment in patients with granulomatosis with polyangiitis or microscopic polyangiitis |
| title_short | Rituximab pediatric drug development: Pharmacokinetic and pharmacodynamic modeling to inform regulatory approval for rituximab treatment in patients with granulomatosis with polyangiitis or microscopic polyangiitis |
| title_sort | rituximab pediatric drug development pharmacokinetic and pharmacodynamic modeling to inform regulatory approval for rituximab treatment in patients with granulomatosis with polyangiitis or microscopic polyangiitis |
| url | https://doi.org/10.1111/cts.13351 |
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