To characterize the ADME and PK properties of SPV-400

The brain-derived neurotrophic factor (BDNF)/TrkB pathway is a promising therapeutic target with neuroprotection and synaptic plasticity properties in nervous system disorders. However, the delivery of BDNF remains a challenge due to its short half-life, limited blood-brain barrier penetration, and instability in blood. SPV-400 is a novel small molecule of TrkB receptor activator that is expected to directly activate TrkB receptor and downstream signaling and overcome BDNF’s limitations.

ADME assessments included plasma protein binding, solubility, permeability, hepatocytes intrinsic clearance, cytochrome (CYP) 450 inhibition, and transporters.

PK study was conducted for intravenous (IV), intraperitoneal (IP), and oral (PO) routes of administration after a single dose. The brain and retina concentrations were evaluated after IP administration.

SPV-400 shows consistent 46-56% plasma protein bindings across 3 species and high aqueous solubility with a range of 183-192 μM. The transporter and permeability data (>5 x10^-6 cm/s) supports having brain exposures as not a potent substrate. Evaluation with CYP 450 enzymes shows SPV-400’s limited interaction with CYP 450 enzymes. The half-life (T_1/2) of intrinsic clearance in human, dog, and rat hepatocytes was 53-76 minutes.

In the PK analysis, plasma C₀ and AUC_last were 13,137 ng/mL and 1,603 h*ng/mL with a T_1/2 of 0.5 hours following IV administration. Following PO administration, plasma C_max and AUC_last were 332 ng/mL and 234 h*ng/mL with a T_1/2 of 4.9 hours. Oral bioavailability was 15%. Following IP administration, plasma C_max and AUC_last were 4,618 ng/mL and 1,782 h*ng/mL with a T_1/2 of 1.9 hours. SPV-400 crossed the blood brain barrier.

SPV-400 demonstrates the ADME and PK profiles suitable for further drug development for nervous system disorders.