Centrally Acting Agents: ADMET Fundamentals, Blood-Brain Barrier Penetration, and Their Role in Clinical Pharmacokinetics and Toxicology

Centrally acting agents, drugs whose intended pharmacological target resides within the central nervous system, must cross the blood-brain barrier in sufficient quantity to achieve a therapeutically relevant brain concentration, a requirement that imposes distinctive physicochemical and transporter-related constraints not present for a peripherally acting drug (Pardridge, 2005). This article examines the ADMET fundamentals specific to this drug category, the assays used to characterize blood-brain barrier penetration and central nervous system distribution, the toxicology considerations specific to centrally acting mechanisms, and the clinical pharmacokinetic study design implications of distinguishing central from peripheral drug exposure. The article closes with recommendations for regulatory affairs and clinical pharmacology professionals developing a centrally acting drug program.Keywords: blood-brain barrier; central nervous system penetration; P-glycoprotein efflux; cerebrospinal fluid; microdialysis; unbound brain-to-plasma ratio; regulatory artificial intelligence