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

Abstract

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.

Insensitivity to pain induced by a potent selective closed-state Nav1.7 inhibitor

“…However, although several selective Nav1.7 inhibitors have been described in the literature101112, none have fully recapitulated the dramatic analgesia observed in Nav1.7-null subjects1112 and clinical progress has been slow1314. While the absence of efficacy has discouraged many in the field, and led some to question the drugabililty of Nav1.7, one possible explanation is that the pharmacological tools utilized provided sub-optimal block of Nav1.7.…”

Phase 0/microdosing approaches: time for mainstream application in drug development?

“…Multiple preclinical candidates 11,12,97,[100][101][102][103][104]133 Selection using cassette microdosing 11 Microdosing study results and PBPK modelling combined to inform candidate selection 104 Conflicting or inadequate preclinical data Uncertainty in extrapolating pharmacokinetic and/or pharmacodynamic data from preclinical models to humans…”

“…Conflicting data from in vivo and/or in vitro experiments and inability to validate extrapolation methods Modelling and simulation produce results inconsistent with in vivo and/or in vitro data or with existing human data from related compounds given in therapeutic doses Inconsistent pharmacokinetic profiles 13,35,101,102,[104][105][106][107][108]119 Challenging allometric scaling due to high plasma protein binding 102 Demonstrated tumour penetration in contrast to preclinical data 109 Poor animal models of Alzheimer disease 9,10,100,117,126 Assessment of linearity across the microdose to therapeutic dose range in animals to enhance the validity of extrapolation 37,38 Toxicity/safety concerns Preclinical data suggest high toxicity potential (for example, binding to non-therapeutic targets)…”

The role of organic anion‐transporting polypeptides and formulation in the clearance and distribution of a novel Nav1.7 channel blocker

“…In turn the preclinical pharmacokinetic (PK) properties of many of these compounds proved difficult to predict, with measured plasma clearance (Cl p ) poorly predicted by in vitro metabolic stability, an observation subsequently rationalized by an understanding of the contribution of organic anion transporter polypeptides (OATP) mediated liver uptake to compound Cl p (Swain et al, ). Ultimately, selection of the development compound PF‐05089771 for the oral project was made following an intravenous and oral clinical micro‐dosing study of four compounds (Jones et al, ).…”