Population pharmacokinetic–pharmacodynamic modelling of the anti-hyperalgesic effect of 5′deoxy-N6-cylopentyladenosine in the mononeuropathic rat

The objective of this investigation was to characterise the pharmacokinetic–pharmacodynamic correlation of 5′-deoxy-N6-cyclopentyl-adenosine (5′dCPA) in the chronic constriction injury model of neuropathic pain. Following intravenous administration of 5′dCPA (0.30 or 0.75 mg kg−1), the time course of the drug concentration in plasma was determined in conjunction with the effect on (1) the mechanical paw pressure and (2) the Von Frey Hair monofilament withdrawal threshold. Population pharmacokinetic–pharmacodynamic analysis was applied to derive individual concentration–effect relationships. For mechanical paw pressure a composite model consisting of an Emax model for the anti-hyperalgesic effect in combination with a linear model for the anti-nociceptive effect accurately described the data. The EC50 for the anti-hyperalgesic effect was 178±51 ng ml−1 and the slope of the anti-nociceptive effect 0.055±0.008 g ml ng−1. For the Von Frey Hair monofilament withdrawal threshold responders and non-responders were observed. Typically, in responders, full pain relief was observed at concentrations exceeding 100 ng ml−1. The high plasma concentrations required for the anti-hyperalgesic effect relative to the receptor affinity are consistent with restricted transport of 5′dCPA to the site of action in the spinal cord and/or the brain. [Copyright &y& Elsevier]