Open Access Open Access  Restricted Access Subscription or Fee Access

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

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.


Keywords


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

Full Text:

PDF

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.




DOI: http://dx.doi.org/10.5055/jom.2017.0375

Refbacks

  • There are currently no refbacks.