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- Title
Clinical Micro-Dose Studies to Explore the Human Pharmacokinetics of Four Selective Inhibitors of Human Nav1.7 Voltage-Dependent Sodium Channels.
- Authors
Jones, Hannah; Butt, Richard; Webster, Rob; Gurrell, Ian; Dzygiel, Pawel; Flanagan, Neil; Fraier, Daniela; Hay, Tanya; Iavarone, Laura; Luckwell, Jacquelynn; Pearce, Hannah; Phipps, Alex; Segelbacher, Jill; Speed, Bill; Beaumont, Kevin; Jones, Hannah M; Butt, Richard P; Webster, Rob W; Iavarone, Laura Else
- Abstract
<bold>Background: </bold>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.<bold>Objective: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>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.
- Subjects
CHRONIC pain treatment; DRUG dosage; ORAL medication; SODIUM channel inhibition; CELLULAR signal transduction; PHARMACOKINETICS; BIOAVAILABILITY; BIOLOGICAL models; BIOTRANSFORMATION (Metabolism); COMPARATIVE studies; DOSE-effect relationship in pharmacology; HYDROGEN-ion concentration; RESEARCH methodology; MEDICAL cooperation; RESEARCH; STATISTICAL sampling; SULFONAMIDES; EVALUATION research; RANDOMIZED controlled trials; BLIND experiment; PHENYL ethers; SODIUM channel blockers
- Publication
Clinical Pharmacokinetics, 2016, Vol 55, Issue 7, p875
- ISSN
0312-5963
- Publication type
journal article
- DOI
10.1007/s40262-015-0365-0