• Xu Steven Xu, Mila Etropolski, David Upmalis, Akiko Okamoto, Rachel Lin, and Partha Nandy.
• Clinical Pharmacology, Advanced PK-PD Modeling and Simulation, Janssen Research and Development, Raritan, New Jersey, USA. sxu26@its.jnj.com
• Pharm. Res. 2012 Sep 1;29(9):2555-64.

PurposeTo understand the relationship between the risk of opioid-related gastrointestinal adverse effects (AEs) and exposure to tapentadol and oxycodone as well as its active metabolite, oxymorphone, using pharmacokinetic/pharmacodynamic models.MethodsThe analysis was based on a study in patients with moderate-to-severe pain following bunionectomy. Population PK modeling was conducted to estimate population PK parameters for tapentadol, oxycodone, and oxymorphone. Time to AEs was analyzed using Cox proportional-hazards models.ResultsRisk of nausea, vomiting, and constipation significantly increased with exposure to tapentadol or oxycodone/oxymorphone. However, elevated risk per drug exposure of AEs for tapentadol was ~3-4 times lower than that of oxycodone, while elevated AE risk per drug exposure of oxycodone was ~60 times lower than that for oxymorphone, consistent with reported in vitro receptor binding affinities for these compounds. Simulations show that AE incidence following administration of tapentadol IR is lower than that following oxycodone IR intake within the investigated range of analgesic noninferiority dose ratios.ConclusionsThis PK/PD analysis supports the clinical findings of reduced nausea, vomiting and constipation reported by patients treated with tapentadol, compared to patients treated with oxycodone.

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