Clinical Micro-Dose Studies to Explore the Human Pharmacokinetics of Four Selective Inhibitors of Human Nav1.7 Voltage-Dependent Sodium Channels

Background: The emergence of genetic data linking Nav1.7 Sodium Channel over- and under- expression to human pain signalling has led to an interest in the treatment of chronic pain through inhibition of Nav1.7 channels.

Objective: We describe the pharmacokinetic (PK) results of a clinical microdose study performed with four potent and selective Nav1.7 inhibitors and the subsequent modelling resulting in the selection of a single compound to explore Nav1.7 pharmacology at higher doses.

Methods: A clinical microdose study to investigate the intravenous and oral PK of four compounds (PF-05089771, PF-05150122, PF-05186462 and PF-05241328) was performed in healthy volunteers. PK parameters were derived via noncompartmental analysis. A physiologically-based PK (PBPK) model was used to predict exposure and multiples of Nav1.7 50 % inhibitory concentration (IC50) for each compound at higher doses.

Results: Plasma clearance, volume of distribution and bioavailability ranged from 45 to 392 mL/min/kg, 13 to 36 L/kg and 38 to 110 %, respectively. The PBPK model for PF-05089771 predicted a 1 g oral dose would be required to achieve exposures of approximately 12× Nav1.7 IC50 at maximum concentration (C max), and approximately 3× IC50 after 12 h (minimum concentration [C min] for a twice-daily regimen). Lower multiples of Nav1.7 IC50 were predicted with the same oral doses of PF-05150122, PF-05186462, and PF-05241328. In a subsequent single ascending oral dose clinical study, the predictions for PF-05089771 compared well with observed data.

Conclusion: Based on the human PK data obtained from the microdose study and subsequent modelling, PF-05089771 provided the best opportunity to explore Nav1.7 blockade for the treatment of acute or chronic pain conditions.