Clinical relevance of the pharmacokinetic characteristics of an abuse-deterrent, extended-release, injection-molded morphine tablet

Jeffrey M. Dayno, MD; Gwendolyn Niebler, DO; John Lawler, BS; Torben Elhauge, MSc; Karsten Lindhardt, MSc, PhD, DBE

doi:10.5055/jom.2017.0375

Authors

Jeffrey M. Dayno, MD
Gwendolyn Niebler, DO
John Lawler, BS
Torben Elhauge, MSc
Karsten Lindhardt, MSc, PhD, DBE

DOI:

https://doi.org/10.5055/jom.2017.0375

Keywords:

morphine, extended-release, abuse-deterrent, pharmacokinetics, bioequivalence

Abstract

Objective: To characterize the pharmacokinetics (PK) and in vitro alcohol dissolution characteristics of extended-release (ER), injection-molded (IM) morphine tablets with abuse-deterrent (AD) features (morphine-ADER-IMT).

Design: In vivo, in vitro, and in silico studies were conducted. A randomized, two-cohort study evaluated the bioequivalence of morphine-ADER-IMT (60 mg) to morphine ER (60 mg; MS Contin®; Purdue Pharma LP, Stamford, CT) and characterized the effect of food on the PK profile of morphine-ADER-IMT. A three-treatment, three-period crossover study assessed the bioequivalence of morphine-ADERIMT (30 and 2 × 15 mg) to morphine ER (30 mg). Bioequivalence studies were performed in healthy male and female subjects (18-55 y of age) in the presence of naltrexone blockade. PK modeling was performed to assess steady-state bioequivalence for morphine-ADER-IMT 60 mg compared with morphine ER 60 mg. In vitro alcohol dissolution studies were performed with morphine-ADER-IMT (15 and 60 mg).

Results: Fifty-nine and 56 subjects completed the 60-mg bioequivalence/food effect study and 30-mg bioequivalence study, respectively. Bioequivalence of morphine-ADER-IMT 60, 30, and 2 × 15 mg and morphine ER was demonstrated to comparable doses of morphine ER. No clinically significant food effect was observed with morphine-ADER-IMT. Treatment-emergent adverse events were similar among all treatment groups. Steady-state modeling indicated bioequivalence between morphine-ADER-IMT 60 mg and morphine ER 60 mg when administered every 8 or 12 hours. No evidence of alcohol dose-dumping was observed with morphine-ADER-IMT.

Conclusions: Morphine-ADER-IMT, an ER morphine formulation with robust AD features, has a clinical PK profile that is well suited for patients with chronic pain.

Author Biographies

Jeffrey M. Dayno, MD

Chief Medical Officer, Egalet Corporation, Wayne, Pennsylvania

Gwendolyn Niebler, DO

Senior Vice-President, Clinical Development and Medical Affairs, Egalet Corporation, Wayne, Pennsylvania

John Lawler, BS

Executive Director, Clinical Operations, Egalet Corporation, Wayne, Pennsylvania

Torben Elhauge, MSc

Senior Scientist Specialist, Research and Development, Egalet Corporation, Wayne, Pennsylvania

Karsten Lindhardt, MSc, PhD, DBE

Senior Vice-President, Research and Development, Egalet Corporation, Wayne, Pennsylvania

References

Gaskin DJ, Richard P: The economic costs of pain in the United States. J Pain. 2012; 13(8): 715-724.

Nahin RL: Estimates of pain prevalence and severity in adults: United States, 2012. J Pain. 2015; 16(8): 769-780.

Dowell D, Haegerich TM, Chou R: CDC guideline for prescribing opioids for chronic pain: United States, 2016. MMWR Recomm Rep. 2016; 65(1): 1-49.

Katz N, Dart RC, Bailey E, et al: Tampering with prescription opioids: Nature and extent of the problem, health consequences, and solutions. Am J Drug Alcohol Abuse. 2011; 37(4): 205-217.

Webster LR, Bath B, Medve RA: Opioid formulations in development designed to curtail abuse: who is the target? Expert Opin Invest Drugs. 2009; 18(3): 255-263.

Gould HJ, 3rd, Paul D: Critical appraisal of extended-release hydrocodone for chronic pain: Patient considerations. Ther Clin Risk Manag. 2015; 11: 1635-1640.

National Institute on Drug Abuse: What is the federal government doing to combat the opioid abuse epidemic? Available at https://www.drugabuse.gov/about-nida/legislative-activities/testimony-to-congress/2016/what-federal-government-doing-tocombat-opioid-abuse-epidemic. Accessed February, 22, 2016.

Butler SF, Black RA, Cassidy TA, et al: Abuse risks and routes of administration of different prescription opioid compounds and formulations. Harm Reduct J. 2011; 8: 29.

Volkow ND, McLellan AT: Opioid abuse in chronic pain-misconceptions and mitigation strategies. N Engl J Med. 2016; 374(13): 1253-1263.

Substance Abuse and Mental Health Services Administration: Results from the 2013 National Survey on Drug Use and Health: Summary of national findings. Rockville, MD: US Department of Health and Human Services, 2014. HHS Publication (SMA) 14-4863.

Califf RM, Woodcock J, Ostroff S: A proactive response to prescription opioid abuse. N Engl J Med. 2016; 374(15): 1480-1485.

US Food and Drug Administration: Guidance for Industry: Abuse-Deterrent Opioids—Evaluation and Labeling. Silver Spring, MD: US Department of Health and Human Services, 2015.

White House Office of National Drug Control Policy: The administration's response to the prescription drug epidemic:Action items. Available at https://www.whitehouse.gov/sites/default/files/ondcp/issues-content/action_items_response_to_the_prescription_drug_epidemic.pdf. Accessed February 23, 2016.

Embeda (Morphine Sulfate and Naltrexone Hydrochloride Capsule Extended Release). Full Prescribing Information. New York, NY: Pfizer Inc, 2014.

MORPHABOND (Morphine Sulfate Extended-Release Tablets). Full Prescribing Information. Valley Cottage, NY: Inspirion Delivery Technologies LLC, 2015.

Butler SF, Budman SH, Licari A, et al: National addictions vigilance intervention and prevention program (NAVIPPRO): A real-time, product-specific, public health surveillance system for monitoring prescription drug abuse. Pharmacoepidemiol Drug Saf. 2008; 17(12): 1142-1154.

Cone EJ, Buchhalter AR, Lindhardt K, et al: Crushing and extraction resistance of EG-001, an abuse-deterrent ER morphine in clinical development. Abstract 32 presented at: PAINWeek; September 2-6, 2014; Las Vegas, NV.

Lindhardt K, Elhauge T, Skak N, et al: Injection and smoking resistance of EG-001, an abuse-deterrent ER morphine in clinical development. Paper presented at: PAINWeek; September 2-6, 2014; Las Vegas, NV.

Smith MD, Webster LR, Lawler J, et al: Human abuse potential of an abuse-deterrent (AD), extended-release (ER) morphine product candidate (Morphine-ADER Injection-Molded Tablets) versus extended-release morphine administered orally in nondependent recreational opioid users. Pain Med. 2016 (in press).

Webster LR, Smith MD, Lawler J, et al: Human abuse potential of an abuse-deterrent (AD), extended-release (ER) morphine product candidate (Morphine-ADER Injection-Molded Tablets) vs extended-release morphine administered intranasally in nondependent recreational opioid users. Pain Med. 2016 (in press).

Schmidt LE, Dalhoff K: Food-drug interactions. Drugs. 2002; 62(10): 1481-1502.

MS Contin (Moprhine Sulfate Tablet Film Coated Extended Release). Full Prescribing Information. Stamford, CT: Purdue Pharma L. P., 2014.

Meyer RJ, Hussain AS: FDA's ACPS meeting, October 2005. Awareness topic: Mitigating risks of ethanol induced dose dumping from oral sustained/controlled release dosage forms. Food and Drug Administration. Available at http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4187B1_01_08-Alcohol-Induced.pdf. Accessed October 28, 2015.

Walden M, Nicholls FA, Smith KJ, et al: The effect of ethanol on the release of opioids from oral prolonged-release preparations. Drug Dev Ind Pharm. 2007; 33(10): 1101-1111.

US Food and Drug Administration: FDA asks Purdue Pharma to withdraw palladone for safety reasons. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2005/ucm108460.htm. Accessed December 4, 2015.

US Food and Drug Administration: Guidance for Industry. Food-Effect Bioavailability and Fed Bioequivalence Studies. Silver Springs, MD: US Food and Drug Administration, 2002.

Gray V: Determining similarity of products-F2 criterion and variability of dissolution test. American Association of Pharmaceutical Scientists. Available at https://www.aaps.org/uploadedFiles/Content/Sections_and_Groups/Focus_Groups/GraySA.pdf. Accessed October 22, 2015.

Caldwell JR, Rapoport RJ, Davis JC, et al: Efficacy and safety of a once-daily morphine formulation in chronic, moderate-to-severe osteoarthritis pain: Results from a randomized, placebo-controlled, double-blind trial and an open-label extension trial. J Pain Symptom Manage. 2002; 23(4): 278-291.

Morasco BJ, Turk DC, Donovan DM, et al: Risk for prescription opioid misuse among patients with a history of substance use disorder. Drug Alcohol Depend. 2013; 127(1-3): 193-199.

Rosenblum A, Joseph H, Fong C, et al: Prevalence and characteristics of chronic pain among chemically dependent patients in methadone maintenance and residential treatment facilities. JAMA. 2003; 289(18): 2370-2378.

Sheu R, Lussier D, Rosenblum A, et al: Prevalence and characteristics of chronic pain in patients admitted to an outpatient drug and alcohol treatment program. Pain Med. 2008; 9(7): 911-917.

US Food and Drug Administration: Guidance for Industry. Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted under an ANDA. Silver Springs, MD: US Food and Drug Administration, 2013.

Anand O, Yu LX, Conner DP, et al: Dissolution testing for generic drugs: An FDA perspective. AAPS J. 2011; 13(3): 328-335.