PMID- 37021060 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230407 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 14 DP - 2023 TI - Leveraging in vitro and pharmacokinetic models to support bench to bedside investigation of XTMAB-16 as a novel pulmonary sarcoidosis treatment. PG - 1066454 LID - 10.3389/fphar.2023.1066454 [doi] LID - 1066454 AB - Background: Sarcoidosis is a chronic, multisystem inflammatory disorder characterized by non-caseating epithelioid granulomas; infiltration of mononuclear cells; and destruction of microarchitecture in the skin, eye, heart, and central nervous system, and the lung in >90% of cases. XTMAB-16 is a chimeric anti-tumor necrosis factor alpha (TNFalpha) antibody, distinct from other anti-TNF antibodies based on its molecular structure. The efficacy of XTMAB-16 has not been clinically demonstrated, and it is still undergoing clinical development as a potential treatment for sarcoidosis. The current study demonstrates the activity of XTMAB-16 in a well-established in vitro sarcoidosis granuloma model, although XTMAB-16 is not yet approved by the United States Food and Drug Administration (FDA) for treatment of sarcoidosis, or any other disease. Objective: To provide data to guide safe and efficacious dose selection for the ongoing clinical development of XTMAB-16 as a potential treatment for sarcoidosis. Methods: First, XTMAB-16 activity was evaluated in an established in vitro model of granuloma formation using peripheral blood mononuclear cells from patients with active pulmonary sarcoidosis to determine a potentially efficacious dose range. Second, data obtained from the first-in-human study of XTMAB-16 (NCT04971395) were used to develop a population pharmacokinetic (PPK) model to characterize the pharmacokinetics (PK) of XTMAB-16. Model simulations were performed to evaluate the sources of PK variability and to predict interstitial lung exposure based on concentrations in the in vitro granuloma model. Results: XTMAB-16 dose levels of 2 and 4 mg/kg, once every 2 weeks (Q2W) or once every 4 weeks (Q4W) for up to 12 weeks, were supported by data from the non-clinical, in vitro secondary pharmacology; the Phase 1 clinical study; and the PPK model developed to guide dose level and frequency assumptions. XTMAB-16 inhibited granuloma formation and suppressed interleukin-1beta (IL-1beta) secretion in the in vitro granuloma model with a half maximal inhibitory concentration (IC(50)) of 5.2 and 3.5 mug/mL, respectively. Interstitial lung concentrations on average, following 2 or 4 mg/kg administered Q2W or Q4W, are anticipated to exceed the in vitro IC(50) concentrations. Conclusion: The data presented in this report provide a rationale for dose selection and support the continued clinical development of XTMAB-16 for patients with pulmonary sarcoidosis. CI - Copyright (c) 2023 Offman, Singh, Julian, Locke, Bicer, Mitchell, Matthews, Anderson and Crouser. FAU - Offman, Elliot AU - Offman E AD - Certara, Princeton, NJ, United States. FAU - Singh, Noopur AU - Singh N AD - Xentria, Inc., Chicago, IL, United States. FAU - Julian, Mark W AU - Julian MW AD - Division of Pulmonary, Critical Care and Sleep Medicine, The Dorothy M. Davis Heart and Lung Research Institute, Columbus, OH, United States. FAU - Locke, Landon W AU - Locke LW AD - Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, OH, United States. AD - Department of Biomedical Engineering, The Ohio State University, Columbus, OH, United States. FAU - Bicer, Sabahattin AU - Bicer S AD - Department of Biomedical Engineering, The Ohio State University, Columbus, OH, United States. FAU - Mitchell, Jonah AU - Mitchell J AD - Department of Biomedical Engineering, The Ohio State University, Columbus, OH, United States. FAU - Matthews, Thomas AU - Matthews T AD - Xentria, Inc., Chicago, IL, United States. FAU - Anderson, Kirsten AU - Anderson K AD - Xentria, Inc., Chicago, IL, United States. FAU - Crouser, Elliott D AU - Crouser ED AD - Division of Pulmonary, Critical Care and Sleep Medicine, The Dorothy M. Davis Heart and Lung Research Institute, Columbus, OH, United States. LA - eng PT - Journal Article DEP - 20230320 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC10067675 OTO - NOTNLM OT - TNFalpha OT - XTMAB-16 OT - granuloma OT - population pharmacokinetic modeling OT - sarcoidosis COIS- The study was funded by Xentria, Inc. Publication of the study results was not contingent on censorship of the manuscript. All in vitro work was conducted independently at The Ohio State University under the supervision of EC. All data was objectively analyzed and presented in this publication in its entirety and free of any bias from Xentria. EO is employed by Certara and contracted by Xentria, Inc. to perform pharmacokinetic analysis and translational modeling and simulation. NS, TM, and KA are employed by Xentria, Inc. MJ, LL, JM, SB, and EC are employed by The Ohio State University. EDAT- 2023/04/07 06:00 MHDA- 2023/04/07 06:01 PMCR- 2023/03/20 CRDT- 2023/04/06 02:14 PHST- 2022/10/20 00:00 [received] PHST- 2023/02/24 00:00 [accepted] PHST- 2023/04/07 06:01 [medline] PHST- 2023/04/06 02:14 [entrez] PHST- 2023/04/07 06:00 [pubmed] PHST- 2023/03/20 00:00 [pmc-release] AID - 1066454 [pii] AID - 10.3389/fphar.2023.1066454 [doi] PST - epublish SO - Front Pharmacol. 2023 Mar 20;14:1066454. doi: 10.3389/fphar.2023.1066454. eCollection 2023.