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

• Published in: Clinical pharmacokinetics Vol. 55; no. 7; pp. 875 - 887
• Main Authors: Jones, Hannah M., Butt, Richard P., Webster, Rob W., Gurrell, Ian, Dzygiel, Pawel, Flanagan, Neil, Fraier, Daniela, Hay, Tanya, Iavarone, Laura Else, Luckwell, Jacquelynn, Pearce, Hannah, Phipps, Alex, Segelbacher, Jill, Speed, Bill, Beaumont, Kevin
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.07.2016; Springer Nature B.V
• Subjects: Adolescent; Adult; Area Under Curve; Biological Availability; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Hydrogen-Ion Concentration; Internal Medicine; Male; Medicine; Medicine & Public Health; Metabolic Clearance Rate; Middle Aged; Models, Biological; Original Research Article; Pharmacology/Toxicology; Pharmacotherapy; Phenyl Ethers - administration & dosage; Phenyl Ethers - pharmacokinetics; Sulfonamides - administration & dosage; Sulfonamides - pharmacokinetics; Voltage-Gated Sodium Channel Blockers - administration & dosage; Voltage-Gated Sodium Channel Blockers - pharmacokinetics; Young Adult; Single Ascend Dose Study; Microdose Study; Erythromelalgia; PBPK Model; Single Ascend Dose
• ISSN: 0312-5963; 1179-1926; 1179-1926
• DOI: 10.1007/s40262-015-0365-0

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 (IC 50 ) 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 IC 50 at maximum concentration ( C max ), and approximately 3× IC 50 after 12 h (minimum concentration [ C min ] for a twice-daily regimen). Lower multiples of Nav1.7 IC 50 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.