Rituximab pharmacokinetic and pharmacokinetic–pharmacodynamic evaluation based on a study in diffuse large B‐cell lymphoma: Influence of tumor size on pharmacokinetic and assessment of pharmacokinetic similarity
Abstract Dr. Reddy's Laboratories rituximab (DRL_RI; Dr. Reddy's Laboratories SA, Basel, Switzerland) is under development as a rituximab biosimilar. Study RI‐01‐002 (Clinical Trials Registry ‐ India/2012/11/003129), comparing DRL_RI to the reference medicinal product (RMP) MabThera® (Roch...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-02-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.12885 |
| _version_ | 1797905490394480640 |
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| author | Robin J. Svensson Qing Xi Ooi Lena E. Friberg Narendra Maharaj Pramod Kumar Reddy Luis López‐Lázaro Emma Hansson |
| author_facet | Robin J. Svensson Qing Xi Ooi Lena E. Friberg Narendra Maharaj Pramod Kumar Reddy Luis López‐Lázaro Emma Hansson |
| author_sort | Robin J. Svensson |
| collection | DOAJ |
| description | Abstract Dr. Reddy's Laboratories rituximab (DRL_RI; Dr. Reddy's Laboratories SA, Basel, Switzerland) is under development as a rituximab biosimilar. Study RI‐01‐002 (Clinical Trials Registry ‐ India/2012/11/003129), comparing DRL_RI to the reference medicinal product (RMP) MabThera® (Roche, Grenzach‐Wyhlen, Germany), demonstrated pharmacokinetic (PK) equivalence and showed comparable pharmacodynamic, efficacy, safety, and immunogenicity profiles. We used data from the same study to perform population PK and PK–pharmacodynamic analyses: first exploring possible factors influencing the PK similarity assessment between products and then performing simulations to investigate the impact of tumor size on rituximab PK. Nonlinear mixed‐effects models for PK, tumor size, tumor size–PK, and tumor response were developed independently. The final PK model included drug product as a dose‐scaling parameter and predicted a 6.75% higher dose reaching the system in RMP‐treated patients. However, when tumor size was included in the tumor size–PK model, the drug product effect was no longer observed. The model rather indicated that patients with larger tumor size have higher clearance. Further simulations confirmed that higher baseline tumor size is associated to slightly lower rituximab exposure. Tumor response, described by a continuous‐time Markov model, did not differ between drug products. Both had higher effects during the first 20 weeks of treatment. Also, the model described a subpopulation of nonresponders to treatment (42%) with faster transitions to a worse state. The different rituximab exposure initially detected between drug products (6.75%) was shown using PK/PK–pharmacodynamic analysis to be attributed to a tumor size imbalance between treatment groups. PK/PK–pharmacodynamic analyses may contribute to PK similarity assessments. |
| first_indexed | 2024-04-10T10:06:10Z |
| format | Article |
| id | doaj.art-d9761b2646aa411991644ebe95845175 |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-04-10T10:06:10Z |
| publishDate | 2023-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-d9761b2646aa411991644ebe958451752023-02-15T21:42:18ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062023-02-0112215416710.1002/psp4.12885Rituximab pharmacokinetic and pharmacokinetic–pharmacodynamic evaluation based on a study in diffuse large B‐cell lymphoma: Influence of tumor size on pharmacokinetic and assessment of pharmacokinetic similarityRobin J. Svensson0Qing Xi Ooi1Lena E. Friberg2Narendra Maharaj3Pramod Kumar Reddy4Luis López‐Lázaro5Emma Hansson6Pharmetheus AB Uppsala SwedenPharmetheus AB Uppsala SwedenPharmetheus AB Uppsala SwedenDr. Reddy's Laboratories Ltd Hyderabad Telangana IndiaDr. Reddy's Laboratories Ltd Hyderabad Telangana IndiaDr. Reddy's Laboratories SA Basel SwitzerlandPharmetheus AB Uppsala SwedenAbstract Dr. Reddy's Laboratories rituximab (DRL_RI; Dr. Reddy's Laboratories SA, Basel, Switzerland) is under development as a rituximab biosimilar. Study RI‐01‐002 (Clinical Trials Registry ‐ India/2012/11/003129), comparing DRL_RI to the reference medicinal product (RMP) MabThera® (Roche, Grenzach‐Wyhlen, Germany), demonstrated pharmacokinetic (PK) equivalence and showed comparable pharmacodynamic, efficacy, safety, and immunogenicity profiles. We used data from the same study to perform population PK and PK–pharmacodynamic analyses: first exploring possible factors influencing the PK similarity assessment between products and then performing simulations to investigate the impact of tumor size on rituximab PK. Nonlinear mixed‐effects models for PK, tumor size, tumor size–PK, and tumor response were developed independently. The final PK model included drug product as a dose‐scaling parameter and predicted a 6.75% higher dose reaching the system in RMP‐treated patients. However, when tumor size was included in the tumor size–PK model, the drug product effect was no longer observed. The model rather indicated that patients with larger tumor size have higher clearance. Further simulations confirmed that higher baseline tumor size is associated to slightly lower rituximab exposure. Tumor response, described by a continuous‐time Markov model, did not differ between drug products. Both had higher effects during the first 20 weeks of treatment. Also, the model described a subpopulation of nonresponders to treatment (42%) with faster transitions to a worse state. The different rituximab exposure initially detected between drug products (6.75%) was shown using PK/PK–pharmacodynamic analysis to be attributed to a tumor size imbalance between treatment groups. PK/PK–pharmacodynamic analyses may contribute to PK similarity assessments.https://doi.org/10.1002/psp4.12885 |
| spellingShingle | Robin J. Svensson Qing Xi Ooi Lena E. Friberg Narendra Maharaj Pramod Kumar Reddy Luis López‐Lázaro Emma Hansson Rituximab pharmacokinetic and pharmacokinetic–pharmacodynamic evaluation based on a study in diffuse large B‐cell lymphoma: Influence of tumor size on pharmacokinetic and assessment of pharmacokinetic similarity CPT: Pharmacometrics & Systems Pharmacology |
| title | Rituximab pharmacokinetic and pharmacokinetic–pharmacodynamic evaluation based on a study in diffuse large B‐cell lymphoma: Influence of tumor size on pharmacokinetic and assessment of pharmacokinetic similarity |
| title_full | Rituximab pharmacokinetic and pharmacokinetic–pharmacodynamic evaluation based on a study in diffuse large B‐cell lymphoma: Influence of tumor size on pharmacokinetic and assessment of pharmacokinetic similarity |
| title_fullStr | Rituximab pharmacokinetic and pharmacokinetic–pharmacodynamic evaluation based on a study in diffuse large B‐cell lymphoma: Influence of tumor size on pharmacokinetic and assessment of pharmacokinetic similarity |
| title_full_unstemmed | Rituximab pharmacokinetic and pharmacokinetic–pharmacodynamic evaluation based on a study in diffuse large B‐cell lymphoma: Influence of tumor size on pharmacokinetic and assessment of pharmacokinetic similarity |
| title_short | Rituximab pharmacokinetic and pharmacokinetic–pharmacodynamic evaluation based on a study in diffuse large B‐cell lymphoma: Influence of tumor size on pharmacokinetic and assessment of pharmacokinetic similarity |
| title_sort | rituximab pharmacokinetic and pharmacokinetic pharmacodynamic evaluation based on a study in diffuse large b cell lymphoma influence of tumor size on pharmacokinetic and assessment of pharmacokinetic similarity |
| url | https://doi.org/10.1002/psp4.12885 |
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