Contributing OfficeCenter for Drug Evaluation and Research
In 2016, FDA issued a drug safety communication warning about concurrent use of opioids and benzodiazepines causing an increased risk of respiratory depression and death. Subsequently, a nonclinical in vivo rat study was performed using oxycodone and other sedative-psychotropic drugs (SPDs) to evaluate if other SPDs may have similar safety liabilities when used in combination. A subset of drug combinations demonstrated effects on respiratory depression (arterial partial pressure of carbon dioxide [pCO2]) beyond what may have been expected by oxycodone alone. While the recently published manuscript explored combination effects relative to oxycodone alone, there was interest in further exploring the effects of the drugs alone or in combination on pCO2.
Pharmacokinetic and blood gas levels from the nonclinical in vivo rat study, which evaluated oxycodone alone, SPDs alone, and the drugs in combination, were further analyzed in this project. Visual exploration of data was performed to evaluate the presence of hysteresis with respect to drug concentration. If the hysteresis was minimal, linear models were developed from data with oxycodone alone and the SPD alone, and the combined linear model was used to predict a surface of drug concentrations versus change from baseline pCO2 that would be expected from the drugs as a combination. The assessments focused on several drugs from the published manuscript which showed an increase when combined with oxycodone (diazepam, trazodone, ramelteon, quetiapine, and paroxetine) or showed no effect when combined with oxycodone (mirtazapine and topiramate).
Visual exploration showed oxycodone alone, as well as diazepam at medium and high doses, had a counterclockwise hysteresis, indicating a slight delay between drug exposure and changed in pCO2. Most of the other SPDs either did not show an effect on pCO2 alone or did not have evidence of delayed effects on pCO2. The magnitude of the hysteresis was considered minor, and linear models were adequate for describing individual drug effects. Further analysis was performed using a surface plot, generated by combining linear regressions from oxycodone alone or the SPD alone. This surface, which depicts predicted pCO2 assuming drug effects were additive, was then compared to the observed data from the combination studies. Data points above the surface indicate synergistic effects as the effect on pCO2 is greater than from the drug concentrations alone. Diazepam, ramelteon, and paroxetine had 68-85% of data points exceeding the predicted surface, suggesting the effects on pCO2 were above what would be expected from the drug concentrations alone. In contrast, quetiapine and trazodone had < 50% of data points above the surface, which were similar to findings from the negative controls, suggesting observed effects on pCO2 could be explained by the drug concentrations (predominantly oxycodone exposures).
Hysteresis plots suggested a slight delay between drug exposure and effect, but it was of small enough magnitude that linear regressions were considered appropriate for describing effects from the induvial drugs. For the surface plot analysis, diazepam, paroxetine, and ramelteon had a larger percentage of data points above the models’ predicted change in pCO2, suggesting an effect of the combination on pCO2 beyond that predicted from the individual drugs. This aligns with previous findings, which had concluded the observed effects on pCO2 could not be explained by oxycodone exposures alone.