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

Abstract

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.

• Authors: Hannah M Jones, Richard P Butt, Rob W Webster, Ian Gurrell, Pawel Dzygiel, Neil Flanagan, Daniela Fraier, Tanya Hay, Laura Else Iavarone, Jacquelynn Luckwell, Hannah Pearce, Alex Phipps, Jill Segelbacher, Bill Speed, Kevin Beaumont
• Journal: Clinical pharmacokinetics (Clin Pharmacokinet) Vol. 55 Issue 7 Pg. 875-887 (07 2016) ISSN: 1179-1926 [Electronic] Switzerland
• PMID: 26895021 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• PF-05089771
• Phenyl Ethers
• Sulfonamides
• Voltage-Gated Sodium Channel Blockers

Topics

• Adolescent
• Adult
• Area Under Curve
• Biological Availability
• Dose-Response Relationship, Drug
• Double-Blind Method
• Humans
• Hydrogen-Ion Concentration
• Male
• Metabolic Clearance Rate
• Middle Aged
• Models, Biological
• Phenyl Ethers (administration & dosage, pharmacokinetics)
• Sulfonamides (administration & dosage, pharmacokinetics)
• Voltage-Gated Sodium Channel Blockers (administration & dosage, pharmacokinetics)
• Young Adult