Pharmacokinetics and Pharmacodynamics of Burixafor Hydrobromide (GPC‐100), a Novel C‐X‐C Chemokine Receptor 4 Antagonist and Mobilizer of Hematopoietic Stem/Progenitor Cells, in Mice and Healthy Subjects

• Published in: Clinical pharmacology in drug development Vol. 12; no. 11; pp. 1114 - 1120
• Main Authors: Sukhtankar, Devki D., Chang, Li‐wen, Tsai, Cheng‐yuan, Cardarelli, Pina M., Caculitan, Niña G.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.11.2023
• Subjects: Chemokines; Leukocytes; Pharmacodynamics; Pharmacokinetics; Stem cell transplantation; pharmacokinetics; burixafor; stem cell mobilization; CXCR4 inhibitor; pharmacodynamics; safety
• ISSN: 2160-763X; 2160-7648; 2160-7648
• DOI: 10.1002/cpdd.1302

Adequate mobilization of hematopoietic stem cells (HSCs), especially CD34 + cells, is necessary for stem cell transplantation in patients with hematological malignancies or autoimmune diseases. Burixafor is an inhibitor of the C‐X‐C Chemokine Receptor 4 that disrupts the C‐X‐C motif chemokine 12 (CXCL12)/CXCR4 axis in the bone marrow, releasing HSCs into circulation. In mice, a single intravenous dose of burixafor was rapidly absorbed (time to maximum concentration, 5 minutes) and increased peripheral white blood cell counts within 30 minutes. Additionally, burixafor was administered to 64 healthy subjects in a randomized, double‐blind, placebo‐controlled, single‐ascending‐dose study to evaluate safety, pharmacokinetics, and pharmacodynamics. Subjects received burixafor intravenous doses ranging from 0.10 to 4.40 mg/kg in 8 cohorts. Single doses were generally safe and well tolerated. Gastrointestinal events were reported at doses of 2.24 mg/kg or greater. Exposure (maximum concentration and area under the concentration–time curve) increased in an approximately dose‐proportional manner. Time to maximum concentration occurred with a median of 0.26–0.30 hours that was not dose proportional. As expected, white blood cell, CD133 + cell, and CD34 + cell concentrations generally increased with the increases in burixafor dose from 0.10 to 3.14 mg/kg. At maximal levels, the CD34 + cell counts increased 3‐ to 14‐fold from baseline levels. These results provide support for continued clinical development of burixafor.