Sistema de Salut de Catalunya
Institut Català de la Salut
[Kuchimanchi M] GSK, Waltham, MA, USA. [Jørgensen TL] Odense University Hospital, Odense, Denmark. [Hanze E] qPharmetra, Uppsala, Sweden. [André T] Saint-Antoine Hospital, INSERM, Unité Mixte de Recherche Scientifique 938, and SIRIC CURAMUS, Sorbonne University, Paris, France. [Jain A] Fox Chase Cancer Center, Philadelphia, PA, USA. [Berton D] GINECO & Institut de Cancerologie de l’Ouest, Centre René Gauducheau, Saint-Herblain, France. [Oaknin A] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
Vall d'Hebron Barcelona Hospital Campus
2025-03-10T12:41:45Z
2025-03-10T12:41:45Z
2024
2025-03
Clinical pharmacology; Oncology; Pharmacokinetics
Farmacología clínica; Oncología; Farmacocinética
Farmacologia clínica; Oncologia; Farmacocinètica
Aims Dostarlimab-gxly is a humanized monoclonal antibody of the IgG4 isotype that binds to the programmed cell death protein-1 (PD-1) receptor and blocks its ligands. RUBY (NCT03981796) is a two-part multicentre study in patients with recurrent or primary advanced endometrial cancer. The overall aims were to characterise the population pharmacokinetics (PopPK) from Part 1 of this study, identify relevant covariates of interest, and assess exposure–efficacy/safety (ER) relationships. Methods A PopPK model developed using GARNET (NCT02715284) study data for dostarlimab monotherapy was externally validated with RUBY Part 1 study data. Subsequently, the model was updated with data across the two studies. Exposure–safety analyses for adverse events related to dostarlimab alone or in combination with standard of care (SOC) were modelled using logistic regression. Exposure–efficacy analysis included Cox proportional hazards analysis of the primary efficacy endpoint of progression-free survival (PFS). Results For the model update, 7957 pharmacokinetics observations from 868 patients pooled from both RUBY and GARNET studies were available. The model was consistent with the previous model. Dostarlimab clearance was estimated to be 7.79% lower when dostarlimab was given as SOC combination therapy. However, no significant covariates were clinically relevant. Hepatic or renal impairment did not affect pharmacokinetics. Among the safety endpoints, only rash showed a small yet statistically significant effect (P < .05) in all subjects; however, this was not not deemed clinically relevant. There were no other clinically significant exposure–safety or exposure–PFS relationships. Conclusions The addition of chemotherapy to dostarlimab had limited effect on dostarlimab PopPK, with no clinically significant covariates or clinically relevant exposure–safety or exposure–PFS relationships.
These studies (NCT02715284 and NCT03981796) were funded by GSK.
Article
Published version
English
Anticossos monoclonals - Farmacocinètica; Anticossos monoclonals - Ús terapèutic; Endometri - Càncer - Tractament; DISEASES::Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Female::Uterine Neoplasms::Endometrial Neoplasms; Other subheadings::Other subheadings::Other subheadings::/drug therapy; CHEMICALS AND DRUGS::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Antibodies, Monoclonal::Antibodies, Monoclonal, Humanized; Other subheadings::Other subheadings::Other subheadings::/pharmacokinetics; PHENOMENA AND PROCESSES::Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Dose-Response Relationship, Drug; ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales femeninos::neoplasias uterinas::neoplasias endometriales; Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia; COMPUESTOS QUÍMICOS Y DROGAS::aminoácidos, péptidos y proteínas::proteínas::proteínas sanguíneas::inmunoproteínas::inmunoglobulinas::anticuerpos::anticuerpos monoclonales::anticuerpos monoclonales humanizados; Otros calificadores::Otros calificadores::Otros calificadores::/farmacocinética; FENÓMENOS Y PROCESOS::fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::relación dosis-respuesta de medicamentos
Wiley
British Journal of Clinical Pharmacology;91(3)
https://doi.org/10.1111/bcp.16325
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
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