Oxycodone Effect on Pupil Constriction in Recreational Opioid Users: A Pharmacokinetic/Pharmacodynamic Meta-Analysis Approach.

Abstract

Understanding the effect of oxycodone pharmacokinetics (PK) on µ-opioid receptor binding benefitsfrom an integrated approach to compiling the results of multiple studies. The current pharmacokinetic/pharmacodynamic (PK/PD)model analysis brings together various studies to support the interpretation of newly collected PK/PD data, putting the new results into the perspective of the full concentration-effect curve. A two-step modeling approach was applied to characterize the PK of oxycodone and its PK/PD relationshipfor the pupil diameter as a biomarker forµ-opioid receptor binding inrecreational opioid users. First, a model-based meta-analysis (MBMA) was used to quantify the state-of-the-art knowledge from seven published studies, each of which contained part of the data needed for full characterization. Subsequently, the estimated parameters with uncertainty from the MBMA were used as prior information for a model developed on newly collected clinical data after intranasal administration in a clinical abuse potential trial. The inclusion of intravenous data in the MBMAshowed thatthe PK of oxycodone can be described by a two-compartmental model, andallowed for the estimation of absolute bioavailability after intranasal and oral administration.A hysteresis loop was observed when plotting plasma concentrations and pupil constriction, which was approximated using an effect compartment. The totality of literature data enabled the identification of a Hill equation for the drug effect.The model with prior information fitted successfully to the newly collected data, where most parameter estimates had their confidence intervals overlapping with the prior distribution. The new data led to a slightly lower intranasal absorption rate constant, explaining the longer apparent half-life of oxycodone in the newly collected data. The PK/PD model parameters were confirmed by the new data, leading to the following estimates: half maximal inhibitory concentration (IC50) of26.5ng/mL, maximum pupil restriction of 66.0% from baseline, and a Hill factor of 1.05. The new data confirmed the PK profile and the PK/PD relationship identified using the MBMA, resulting in similar parameter estimates except for the intranasal absorption rate constant. The latter was lower than in the MBMA and explained the slightly longer apparent half-life of oxycodone in the newly collected data.