Lorin K. Roskos

Investigations of Enteric-Coated Tablet Propyl Gallate-Induced Nephrotoxicity in Beagles as well as Human and Dog Renal Proximal Tubule Epithelial Cells

Si Mou, B. Timothy Hummer, Jiaqi Yuan, Yue Huang et autres

During nonclinical development of an oral formulation for a glucagon-like peptide-1 (GLP-1) receptor agonist, MEDI7219, toxicology studies revealed that propyl gallate (PG), when administered in enteric-coated (EC) tablets, led to nephrotoxicity in beagles. While PG has been widely used in food and …

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Investigations of Enteric-Coated Propyl Gallate-induced Nephrotoxicity in Beagles and Human and Dog Renal Proximal Tubule Epithelial Cells

Si Mou, B. Timothy Hummer, Jiaqi Yuan, Yue Huang et autres

Permeability plays a major role in oral biotherapeutic delivery and permeation enhancers can improve the intestinal permeability of poorly absorbed active pharmaceutical ingredients such as peptides. As part of nonclinical development of an oral formulation for a glucagon-like peptide-1 (GLP-1) receptor agonist, …

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Multiplex Bioanalytical Methods for Comprehensive Characterization and Quantification of the Unique Complementarity-Determining-Region Deamidation of MEDI7247, an Anti-ASCT2 Pyrrolobenzodiazepine Antibody–Drug Conjugate

Yue Huang, Jiaqi Yuan, Ruipeng Mu, Kathryn Ball et autres

Deamidation, a common post-translational modification, may impact multiple physiochemical properties of a therapeutic protein. MEDI7247, a pyrrolobenzodiazepine (PBD) antibody-drug conjugate (ADC), contains a unique deamidation site, N102, located within the complementarity-determining region (CDR), impacting the affinity of MEDI7247 to its target. Therefore, …

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Combining pharmacometric models with predictive and prognostic biomarkers for precision therapy in Crohn's disease: A case study of brazikumab

Nan Zhang, Ming Liang Chan, Jing Li, Philip Z. Brohawn et autres

Pharmacometric models were used to investigate the utility of biomarkers in predicting the efficacy (Crohn's Disease Activity Index [CDAI]) of brazikumab and provide a data-driven framework for precision therapy for Crohn's disease (CD). In a phase IIa trial in patients with moderate …

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Comparison of sequential and joint nonlinear mixed effects modeling of tumor kinetics and survival following Durvalumab treatment in patients with metastatic urothelial carcinoma

Ting Chen, Yanan Zheng, Lorin K. Roskos, Donald E. Mager

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Population Pharmacokinetics and Exposure–Response Analysis for the Phase 3 COSMIC-311 Trial of Cabozantinib for Radioiodine-Refractory Differentiated Thyroid Cancer

Neang S. Ly, Jing Li, Raffaella Faggioni, Lorin K. Roskos et autres

In the USA, cabozantinib was approved for the treatment of patients aged ≥ 12 years with radioiodine-refractory differentiated thyroid cancer (DTC) who progressed on prior vascular endothelial growth factor (VEGFR)-targeted therapy based on the Phase 3 COSMIC-311 trial, which evaluated cabozantinib 60 …

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Cabozantinib exposure–response analysis for the phase 3 CheckMate 9ER trial of nivolumab plus cabozantinib versus sunitinib in first-line advanced renal cell carcinoma

Benjamin Duy Tran, Jing Li, Neang S. Ly, Raffaella Faggioni et autres

PURPOSE: In the phase 3 CheckMate 9ER trial, intravenous nivolumab (240 mg every 2 weeks) plus oral cabozantinib (40 mg/day) improved progression-free survival (PFS) versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC). To support cabozantinib dosing with the combination, …

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Nonlinear Population Pharmacokinetics of Anifrolumab in Healthy Volunteers and Patients With Systemic Lupus Erythematosus

J.O. Almquist, Denison Kuruvilla, Tu Mai, Raj Tummala et autres

We characterized the population pharmacokinetics of anifrolumab, a type I interferon receptor-blocking antibody. Pharmacokinetic data were analyzed from the anifrolumab (intravenous [IV], every 4 weeks) arms from 5 clinical trials in patients with systemic lupus erythematosus (SLE) (n = 664) and healthy …

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Mechanistic modeling of a human IgG4 monoclonal antibody (tralokinumab) Fab‐arm exchange with endogenous IgG4 in healthy volunteers

Bing Wang, Jo Goodman, Lorin K. Roskos

Abstract Therapeutic IgG4 antibodies engage in Fab‐arm exchange with endogenous human immunoglobulin G4 (IgG4) to form monovalent hybrid molecules. A mechanistic population model was developed to quantitatively characterize the dynamic Fab‐arm exchange of tralokinumab, a human IgG4 monoclonal antibody currently being developed …

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Chronic pharmacological antagonism of the GM-CSF receptor in mice does not replicate the pulmonary alveolar proteinosis phenotype but does alter lung surfactant turnover

Dominic J. Corkill, Alan N. Hunt, Mary Jane Hinrichs, Nicholas E. White et autres

Granulocyte macrophage colony stimulating factor (GM-CSF) is a key participant in, and a clinical target for, the treatment of inflammatory diseases including rheumatoid arthritis (RA). Therapeutic inhibition of GM-CSF signalling using monoclonal antibodies to the α-subunit of the GM-CSF receptor (GMCSFRα) has …

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P48.21 Population Pharmacokinetics and Exposure-Response with Durvalumab Plus Platinum-Etoposide in ES-SCLC: Results from CASPIAN

Yingying Zheng, Dayong Jin, Y. Guan, Mustafa Özgüroğlu et autres

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Exposure–response analysis for selection of optimal dosage regimen of anifrolumab in patients with systemic lupus erythematosus

Yen Lin Chia, Linda Santiago, Bing Wang, Denison Kuruvilla et autres

OBJECTIVES: The randomized, double-blind, phase 2 b MUSE study evaluated the efficacy and safety of the type I IFN receptor antibody anifrolumab (300 mg or 1000 mg every 4 weeks) compared with placebo for 52 weeks in patients with chronic, moderate to …

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