CERSI Collaborators: University of Maryland, School of Medicine: Paul W. Buehler, Pharm.D., Ph.D.

FDA Collaborators: Julia Pinto, Ph.D., Xiaoming Xu, Ph.D., Haiou Qu, Ph.D., Research Scientist, William Smith, Ph.D., Jin Hyen Baek, Ph.D.

Project Start: July 30, 2020
Project End: June 30, 2023

Regulatory Science Challenge

Several opioid products in tablet forms have incorporated abuse-deterrent (AD) technology to increase difficulty in crushing and dissolving with the goal of reducing nasal and injection abuse potential. For example, Endo Pharma began marketing reformulated Opana ER (oxymorphone hydrochloride extended release) oral tablets in 2012, which contained a “crush-resistant” excipient, high molecular weight (e.g., 7 million Da) polyethylene oxide (HMW-PEO). The post-marketing outcomes of the Opana ER reformulation were both unexpected and concerning, as epidemiologic data revealed a shift in misuse patterns following reformulation from nasal to intravenous injection. This shift was also accompanied by cases of a potentially fatal blood disorder called thrombotic microangiopathy and an outbreak of HIV in southern Indiana among individuals injecting reformulated Opana ER. These outcomes ultimately led to the withdrawal of Opana ER from the market. Among the many considered causes, the excipient (HMW-PEO) used in the product was thought to be a major factor leading to the rare blood disorder. Yet, similar PEO as well as other high molecular weight polymers have also been used in other opioid tablet products, raising concern over the general safety of this category of excipients if misused via non-intended intravenous administration. Our efforts to understanding the toxicological mechanism in translational pre-clinical studies are so far consistent with observations in human settings of acute intravenous HMW-PEO exposures. Therefore, it remains a critical and unmet regulatory need to understand the toxicity of PEO containing AD formulations to better determine how to regulate these products, limit public health risks and, if needed, optimize these formulations to prevent the additional adverse consequences of their misuse.

Project Description and Goals

Project goals: To better understand the relationship between tablet formulation components, manufacturing process variations, physical manipulation methods, and toxicological outcomes associated with misuse and abuse HMW-PEO AD tablets. The project involves preparation of AD surrogate tablet formulations (placebo and non-opioid containing), physical manipulation of AD tablets in a laboratory setting, and a comprehensive assessment of pathological outcomes in preclinical toxicology studies following intravenously administration of the tablet extracts.

Goal 1: Prepare placebo AD tablets using hot-melt extrusion manufacturing process.

Goal 2: Prepare intravenously injectable material by physical manipulation (e.g., cutting, milling and heating).

Goal 3: Examine in vivo toxicity profiles of the intravenously injected materials, including a single day multiple dose study and a sub-chronic study with multiple daily dosing (up to fourteen days).

Research Outcomes/Results

Through a collaboration between Dr. Paul W. Buehler, while working at Center for Biologics Evaluation and Research (CBER) Office of Blood and Research Review (OBRR), with Center for Drug Evaluation and Research (CDER) Office of Pharmaceutical Quality (OPQ), two studies were completed using PEO neat materials (not in a drug tablet product) of three molecular weights (PEO 1 MDa, 4 MDa and 7 MDa) with and without heat treatment. These studies provided a unique insight into the molecular size dependent acute toxicity of PEO, both alone and after heat treatment. Most interestingly the nonclinical toxicology mimics the adverse effects in humans who have misused opioid products containing the largest molecular weight PEO materials detailed in pre-CERSI funded work publications (1, 2). This project further defined acute dosing toxicity of physically manipulated placebo tablets and confirmed PEO as the polymer that modify toxicological response.

Research Impacts

The FDA regulatory science areas include the following:

Modernize Toxicology to Enhance Product Safety – This project improved FDA’s ability to evaluate and understand toxicologic response to PEO formulations used in opioid AD formulations and optimized toxicological evaluation to assess the safety risk of such formulations.

Improve scientific approaches to evaluate generic drugs – The Generic Drug User Fee Amendments (GDUFA) is designed to enhance public access to safe, high-quality generic drugs, and to reduce costs to industry. Several generic opioid formulations contain the same excipient material as brand name products. It is critical to ensure that efforts made to minimize regulatory burden and costs, and increase product availability, do not compromise product safety. The data obtained from the proposed studies may be used to support adoption of less labor-intensive in vitro testing methodologies.

The long-term anticipated impacts of the research based on CERSI Research Impact Metrics.

1. Develop translational animal models that are predictive of human toxicological response.
2. Promote a better understanding of toxicity mechanisms by evaluating safety assessment data at multiple levels of biological organization including genes, proteins, pathways, and cell/organ function.
3. Provide novel testing strategies to identify formulation components with improved safety profiles to reduce adverse effects.

Related Publications

1. Baek JH, Shin HKH, Koo SM, Gao Y, Qu H, Feng X, Xu X, Pinto J, Katneni U, Kimchi-Sarfaty C, Buehler PW. Polyethylene Oxide (PEO) molecular size determines the severity of atypical thrombotic microangiopathy in a guinea pig model of acute intravenous exposure. Toxicol Sci. 2020. Epub 2020/06/25. doi: 10.1093/toxsci/kfaa099. PubMed PMID: 32579216


2. Hunt R, Yalamanoglu A, Tumlin J, Schiller T, Baek JH, Wu A, Fogo AB, Yang H, Wong E, Miller P, Buehler PW, Kimchi-Sarfaty C. A mechanistic investigation of thrombotic microangiopathy associated with IV abuse of Opana ER. Blood. 2017;129(7):896-905. Epub 2016/11/20. doi: 10.1182/blood-2016-08-736579. PubMed PMID: 27864296; PMCID: PMC5314814.