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Clinical Pharmacokinetics
Erschienen in: Clinical Pharmacokinetics 7/2016

19.02.2016 | Original Research Article

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

verfasst von: 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

Erschienen in: Clinical Pharmacokinetics | Ausgabe 7/2016

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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.
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Metadaten
Titel
Clinical Micro-Dose Studies to Explore the Human Pharmacokinetics of Four Selective Inhibitors of Human Nav1.7 Voltage-Dependent Sodium Channels
verfasst von
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
Publikationsdatum
19.02.2016
Verlag
Springer International Publishing
Erschienen in
Clinical Pharmacokinetics / Ausgabe 7/2016
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-015-0365-0

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