Staff Fellow US Food and Drug Administration, United States
Background: The use of opioid drugs is accompanied by the risk of adverse effects such as sedation and ventilation depression. Use of some sedative psychotropic drugs with opioids have additionally shown to have effects on other pharmacodynamic measures. Methods: A clinical study (NCT04310579) was conducted to investigate the effect of the sedative psychotropic drugs (midazolam, paroxetine, and quetiapine) with oxycodone on ventilation and sedation in healthy volunteers. A population PKPD model was developed to characterize the pharmacokinetics and pharmacodynamics of oxycodone alone as well as describe interactions from concomitant drugs. A two-compartment model with a fixed first order absorption rate constant adequately characterized and predicted the pharmacokinetics of both oxycodone and oxymorphone. Results: Midazolam affected oxymorphone clearance at a significance level of 0.05, while paroxetine affected the clearance of both oxymorphone and oxycodone at a significance level of 0.01. Ventilation data was adequately characterized by an indirect response (IDR) model with concentration-dependent inhibition of production. Pupillometry data was adequately characterized by an IDR model with concentration-dependent inhibition of production for oxycodone. Paroxetine and quetiapine exhibited opposing effects of mydriasis and miosis, respectively, on response. A correlation between pupillometry and ventilation existed which may be further explained by investigation of IDR parameters. Conclusion: The observed effects of concomitant drugs suggests that these drugs alter the pharmacokinetics of oxycodone and oxymorphone. More research is necessary to determine the relationship between ventilation and changes in pupil diameter for opioids administered alone or combined with sedative psychotropic drugs.
