title: Clinical Micro-Dose Studies to Explore the Human Pharmacokinetics of Four Selective Inhibitors of Human Nav1.7 Voltage-Dependent Sodium Channels.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide R&D, Sandwich, Kent, UK.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Jones
authors.affiliation: Neuroscience and Pain Research Unit, Pfizer Worldwide R&D, Granta Park, Cambridge, CB21 6GS, UK. richard.butt@pfizer.com.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Butt
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide R&D, Sandwich, Kent, UK.
authors.forename: Rob W
authors.initials: RW
authors.lastname: Webster
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide R&D, Sandwich, Kent, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Gurrell
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide R&D, Sandwich, Kent, UK.
authors.forename: Pawel
authors.initials: P
authors.lastname: Dzygiel
authors.affiliation: Department of Pharmaceutical Sciences, Pfizer Worldwide R&D, Sandwich, Kent, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Flanagan
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide R&D, Sandwich, Kent, UK.
authors.forename: Daniela
authors.initials: D
authors.lastname: Fraier
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide R&D, Sandwich, Kent, UK.
authors.forename: Tanya
authors.initials: T
authors.lastname: Hay
authors.affiliation: Clinical Pharmacology, Pfizer Worldwide R&D, Sandwich, Kent, UK.
authors.forename: Laura Else
authors.initials: LE
authors.lastname: Iavarone
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide R&D, Sandwich, Kent, UK.
authors.forename: Jacquelynn
authors.initials: J
authors.lastname: Luckwell
authors.affiliation: Department of Pharmaceutical Sciences, Pfizer Worldwide R&D, Sandwich, Kent, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Pearce
authors.affiliation: Clinical Pharmacology, Pfizer Worldwide R&D, Sandwich, Kent, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Phipps
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide R&D, Sandwich, Kent, UK.
authors.forename: Jill
authors.initials: J
authors.lastname: Segelbacher
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide R&D, Sandwich, Kent, UK.
authors.forename: Bill
authors.initials: B
authors.lastname: Speed
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide R&D, Sandwich, Kent, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Beaumont
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D010647:Phenyl Ethers / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D061567:Voltage-Gated Sodium Channel Blockers / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D055815:Young Adult; D000096926:Benzenesulfonamides
chemical_list: D010647:Phenyl Ethers; D013449:Sulfonamides; D061567:Voltage-Gated Sodium Channel Blockers; C000618268:PF-05089771; D000096926:Benzenesulfonamides