Effect of physical manipulation on the oral pharmacokinetic profile of Xtampza® ER (oxycodone DETERx® formulation): A review of published studies

Abstract

Opioids can be an effective treatment option for appropriate patients with chronic pain for whom nonpharmacological or nonopioid treatment does not provide adequate pain relief. However, extended-release (ER) opioid formulations, because of their high drug content, are attractive options for nonmedical use and abuse. Xtampza® ER (oxycodone DETERx®) capsules, an ER abuse-deterrent formulation (ADF), contain microspheres that combine oxycodone with inactive ingredients to increase the difficulty of tampering with the ER mechanism. The aim of this article is to review five previously published studies highlighting the impact of physical manipulation (ie, crushing and chewing) on the pharmacokinetic (PK) properties of orally administered Xtampza ER compared with immediate-release (IR) oxycodone and/or reformulated OxyContin® (the first approved oxycodone ER ADF). Across five studies, manipulated (crushed or chewed) Xtampza ER retained an ER PK profile similar to that of intact Xtampza ER, with respect to maximum plasma concentration (Cmax) and time to Cmax. Additionally, bioequivalence was established between manipulated and intact Xtampza ER, based on Cmax and area under the concentration-time curve values in healthy volunteers and nondependent recreational opioid users. In contrast, crushed OxyContin failed to retain the ER PK profile of intact OxyContin and was bioequivalent to IR oxycodone, based on Cmax in healthy volunteers. The retention of ER PK properties when capsule contents are physically manipulated before oral administration suggests Xtampza ER has lower potential to be manipulated for oral abuse when compared with IR oxycodone or OxyContin.

Review of Opioid Abuse-Deterrent Formulations: Impact and Barriers to Access

“…ER opioid analgesics are indicated for the treatment of severe and persistent pain that requires an extended treatment period for which alternative pain management options are inadequate. [26][27][28][29] ER opioids have shown safety and efficacy in clinical trials for the control of various chronic pain conditions. [30][31][32][33] However, ER formulations typically have higher levels of active drugs that are appealing for nonmedical use and abuse and are therefore susceptible to abuse through tampering or swallowing multiple tablets.…”

“…[30][31][32][33] However, ER formulations typically have higher levels of active drugs that are appealing for nonmedical use and abuse and are therefore susceptible to abuse through tampering or swallowing multiple tablets. 25,26 The Research Abuse, Diversion and Addiction-Related Surveillance (RADARS) system found that prescription-adjusted rates of abuse and diversion (defined as an instance of unlawful channeling of a product of interest from legal sources that results in a written report or complaint) for ER opioids were 2.8-fold and 2.1-fold higher, respectively, than IR opioids. 34 This may be due to high-risk patients preferring to abuse ER medication.…”

“… 24 ER opioids are designed to provide an extended period of analgesia with less frequent dosing compared to IR formulations. 26 This is achieved by a controlled release of the active agent to provide consistent and prolonged plasma drug levels. 25 Furthermore, the time to peak blood concentration level (T max ) is generally longer with ER formulations, reducing abuse liabilities when taking whole tablets as intended.…”

The Importance of Drug Delivery in the Clinical Development and Lifecycle of Drug Products with Examples from Authorised Medicinal Products

“…Xtampza ER ® (Collegium Pharmaceutical Inc.) is an ER ADF of oxycodone, which was approved by the FDA in 2016. Xtampza ER ® is a microsphere-in-capsule formulation using the proprietary DETERx ® technology that makes it less susceptible to manipulation using a variety of tools and solvents relative to IR oxycodone tablets [69]. Brennan et al [70] reported that after oral administration of crushed IR oxycodone, a rapid increase in oxycodone concentration was observed.…”

Nonmedical Use of Xtampza® ER and Other Oxycodone Medications in Adults Evaluated for Substance Abuse Treatment: Real-World Data from the Addiction Severity Index-Multimedia Version (ASI-MV®)

“…Premarket in vitro and in vivo testing of Xtampza ER is well documented and demonstrates the difficulties in manipulating the product as well as the product's pharmacokinetic profile and human abuse potential. [7][8][9][10][11][12][13][14] Published postmarket data is limited to a recent publication comparing Xtampza ER to IR oxycodone, other ADF ER opioids, and non-ADF ER opioids which suggested that Xtampza ER has low relative abuse rates and low relative likelihood of non-oral use. 15 While these results were consistent across several data sources, additional real-world data are needed to further understand the relative risk of abuse of currently available opioid medications.…”