Developing an animal model to detect drug-drug interactions impacting drug-induced respiratory depression

Lin Xu; Ashok Chockalingam; Sharron Stewart; Katherine Shea; Murali K Matta; Suresh Narayanasamy; Nageswara R Pilli; Donna A Volpe; James Weaver; Hao Zhu; Michael C Davis; Rodney Rouse

doi:10.1016/j.toxrep.2020.01.008

Developing an animal model to detect drug-drug interactions impacting drug-induced respiratory depression

Toxicol Rep. 2020 Jan 25:7:188-197. doi: 10.1016/j.toxrep.2020.01.008. eCollection 2020.

Affiliations

¹ Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Silver Spring, Maryland, USA.
² Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Silver Spring, Maryland, USA.
³ Division of Psychiatry Products, Office of Drug Evaluation I, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Silver Spring, Maryland, USA.

Abstract

Opioids and benzodiazepines were frequently co-prescribed to patients with pain and psychiatric or neurological disorders; however, co-prescription of these drugs increased the risk for severe respiratory depression and death. Consequently, the U.S. Food and Drug Administration added boxed label warnings describing this risk for all opioids and benzodiazepines. Sedating psychotropic drugs with differing mechanisms of action (e.g., antipsychotics, antidepressants, non-benzodiazepine sedative-hypnotics, etc.) may be increasingly prescribed in place of benzodiazepines. Despite being marketed for years, many sedating psychotropic drugs have neither human nor animal data that quantify or qualify the potential for causing respiratory depression, either alone or in combination with an opioid. In this study, diazepam was selected as the benzodiazepine to detect any additive or synergistic effects on respiratory depression caused by the opioid, oxycodone. Pharmacokinetic studies were conducted at three doses with oxycodone (6.75, 60, 150 mg/kg) and with diazepam (2, 20, 200 mg/kg). Dose dependent decrease in arterial partial pressure of oxygen and increase in arterial partial pressure of carbon dioxide were observed with oxycodone. Diazepam caused similar partial pressure changes only at the highest dose. Further decreases in arterial partial pressure of oxygen and increases in arterial partial pressure of carbon dioxide consistent with exacerbated respiratory depression were observed in rats co-administered oxycodone 150 mg/kg and diazepam 20 mg/kg. These findings confirm previous literature reports of exacerbated opioid-induced respiratory depression with benzodiazepine and opioid co-administration and support the utility of this animal model for assessing opioid-induced respiratory depression and its potential exacerbation by co-administered drugs.

Keywords: Animal model; Arterial partial pressure of carbon dioxide; Arterial partial pressure of oxygen; Opioids; Respiratory depression; Sedating psychotropic drugs.