Naldemedine (Symproic) for the Treatment of Opioid-Induced Constipation Kenneth Hu, Pharmd; and Mary Barna Bridgeman, Pharmd, BCPS, BCGP
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DRUG FORECAST Naldemedine (Symproic) for the Treatment Of Opioid-Induced Constipation Kenneth Hu, PharmD; and Mary Barna Bridgeman, PharmD, BCPS, BCGP INTRODUCTION as less severe, but potentially bother- (FDA) in March of 2017 for the treatment Pain, pain management, and the com- some, and can ultimately contribute to of OIC in adult patients with chronic non- plications associated with interventions non-compliance with the prescribed regi- cancer pain.9 intended to mitigate pain are associated men. In particular, gastrointestinal (GI) with signifi cant direct and indirect health side effects, including nausea, abdomi- PHARMACOLOGY care costs. Beyond the direct costs associ- nal pain, bloating, abdominal cramping, The mu (µ)-, delta (δ)-, and kappa ated with medications, hospitalizations, and constipation, can have an impact on (κ)-opioid receptors are common in provider visits, physical therapy, and the quality of life, dignity, and health of the central nervous system (CNS), but rehabilitation, chronic pain places an patients utilizing these agents for chronic they are also involved with GI function. enormous indirect burden on the affected pain management. Opioid-induced consti- While the δ- and κ-receptors are primarily individual’s productivity, quality of life, pation (OIC), new or worsening constipa- found in the proximal colon and stomach, and mental health. More than 100 mil- tion occurring when initiating, changing, the µ-receptors are widely distributed lion Americans are estimated to suffer or increasing opioid use, represents the throughout the GI tract. OIC is largely from chronic pain, with an estimated 3% most common of these GI effects (see due to enteric µ-opioid receptor activa- of adults in the United States receiving Table 1 for a depiction of the ROME IV tion, leading to non-peristaltic contrac- long-term opioid therapy for chronic defi nition of OIC).6 tions of the esophagus, reduced gastric non-cancer pain, at a national annual esti- Since tolerance does not develop to motility and emptying, decreased GI mated cost of approximately $560 billion the constipating effects of this class, secretions, inhibited intestinal propul- to $630 billion.1-4 OIC may occur at any point after initia- sion, and greater absorption of water from Opioid analgesics are commonly pre- tion of the opioids and can be directly bowel contents.10 scribed for the treatment of chronic pain attributed to the peripheral effects of the As a peripheral µ-opioid receptor antag- management. In 2012, prescriptions for opioid interacting with receptors found onist, naldemedine works by binding to opioid pain medications were written by within the GI tract. The frequency of OIC the µ-, δ-, and κ-opioid receptors and spe- health care providers 259 million times.5 increases with prolonged use of opioids, cifi cally reduces the constipating effects While opioids can be useful for alleviating and many patients may reduce the dose of opioids through its action as an antago- severe pain, the clinical utility of opioids or discontinue their opioid treatment due nist at the µ-opioid receptors in GI tract may be limited by an association with to the effects of constipation, resulting in tissue.9,11 Naldemedine shares a similar adverse effects. Severe adverse effects decreased treatment satisfaction.7 chemical structure to that of naltrexone, attributed to opioid use may include phys- Although there are several treatment with an additional side chain increasing ical dependence, respiratory and central options for OIC, an unmet clinical need the molecular weight and polar surface nervous system depression, tolerance, continues to exist for patients utilizing area.11 Naldemedine also acts as a sub- and hyperalgesia.2 Adverse effects related opioids chronically for pain management. strate of the P-glycoprotein (P-gp) effl ux to sedation, pruritus, nausea and vomit- Several novel treatment methods are in transporter. These properties reduce the ing, and constipation may be perceived development.8 This review focuses on the possibility of naldemedine interfering safety and effi cacy of naldemedine (Sym- with centrally mediated opioid analgesia At the time of writing, Dr. Hu was a PharmD proic, Shionogi), a peripherally acting mu by decreasing its penetration into the Candidate at the Ernest Mario School of (µ)-opioid receptor antagonist approved CNS at recommended dose levels.9 Pharmacy at Rutgers, The State University of by the Food and Drug Administration New Jersey; he is now a Global Regulatory Affairs Postdoctoral Fellow at Sanofi in Table 1 Characteristics of OIC According to the ROME IV Criteria6 Bridgewater, New Jersey. Dr. Bridgeman New or worsening symptoms when initiating, changing, or increasing opioid therapy that must is a Clinical Associate Professor at Rutgers include two or more of the following in ≥ 25% of defecations: University and an Internal Medicine Clinical • Straining to pass a bowel movement Pharmacist at Robert Wood Johnson Hospital • Passing lumpy or hard stools in New Brunswick, New Jersey. Drug Forecast • Experiencing the sensation of incomplete evacuation, obstruction, or blockage of stool is a regular column coordinated by Alan Caspi, • Requiring manual maneuvers to facilitate evacuation of stool PhD, PharmD, MBA, President of Caspi and • Fewer than three spontaneous bowel movements per week Associates in New York, New York. AND Disclosure: The authors report no commercial Rarely experiencing loose stools without laxative use or fi nancial interests in regard to this article. Vol. 43 No. 10 • October 2018 • P&T® 601 DRUG FORECAST Table 2 Comparison of FDA-Approved Medications for the Treatment of OIC9, 11-14 Features Naldemedine9,11 Methylnaltrexone12 Naloxegol13 Lubiprostone14* Mechanism µ-, δ-, and κ-opioid receptor µ-opioid receptor antagonist µ-opioid receptor antagonist Chloride channel activator antagonist Route of Administration Oral Subcutaneous; Oral Oral Oral Absorption 0.75 hours; 2.5 hours (with Subcutaneous: 30 minutes; <2 hours; in majority of M3: ~1.1 hours (Time to Peak) food) Oral: ~1.5 hours (delayed by subjects, a secondary Cmax 2 hours with high-fat meal) occurs ~0.4 to 3 hours after the first maxC Distribution Vz/F: 155 L Vss: 1.1 L/kg Vz/F: 968–2,140 L Minimal beyond GI tissues Metabolism CYP3A Conversion to methyl-6- CYP3A Carbonyl reductase naltrexol isomers and methylnaltrexone sulfate Elimination t½: 11 hours t½: 8 hours t½: 6–11 hours M3 t½: 0.9–1.4 hours Side Effects • Abdominal pain • Abdominal pain • Abdominal pain • Abdominal pain • Diarrhea • Flatulence • Diarrhea • Diarrhea • Nausea • Nausea • Nausea • Nausea • Gastroenteritis • Dizziness • Flatulence • Flatulence *Low systemic availability of lubiprostone after oral administration, with concentrations below the level of quantitation (10 pg/mL). Pharmacokinetic parameters of M3 (its only measurable active metabolite) have been characterized. Cmax = peak concentrations, Vz/F = mean apparent volume of distribution during terminal phase, Vss = steady-state volume of distribution, t½ = half-life. PHARMACOKINETICS UGT1A3 to form naldemedine 3-G. Both and renal (estimated creatinine clearance A summary of the pharmacokinetic metabolites have shown antagonistic ≥ 90 mL/min) function were similar to characteristics of the FDA-approved activity for opioid receptors but to a lesser those in subjects with mild (estimated treatments for OIC can be found in Table extent than naldemedine. Naldemedine glomerular filtration rate [eGFR] of 60 to 2.9,11-14 is also cleaved to benzamidine and nalde- 89 mL/min/1.73 m2), moderate (eGFR, medine carboxylic acid within the GI 30 to 59 mL/min/1.73 m2), or severe Absorption and Distribution tract.9,11 When [14C]-labeled naldemedine (eGFR < 30 mL/min/1.73 m2) renal When taken orally, naldemedine is was taken orally, nor-naldemedine was impairment, subjects with end-stage renal absorbed from the GI tract, with peak the primary metabolite in plasma, with disease requiring hemodialysis, and sub- concentrations (Cmax) occurring at approximately 9% to 13% relative exposure jects with mild (Child-Pugh Class A) or approximately 0.75 hours (Tmax) in the compared to naldemedine. As a minor moderate (Child-Pugh Class B) hepatic fasted state. There is a dose-proportional, metabolite in plasma, naldemedine 3-G impairment. No adjustments are required or near dose-proportional, increase for had a relative exposure of less than 3%.9 when dosing naldemedine for patients both Cmax and the area-under the-plasma- with mild to moderate hepatic impair- concentration-time curve (AUC) and mul- Elimination ment, although there have been no stud- tiple daily doses of naldemedine result in When [14C]-labeled naldemedine was ies of the effect on the pharmacokinetic minimal accumulation. A high-fat meal taken orally, 57% and 35% of the radio- properties of naldemedine in subjects decreases Cmax by approximately 35% labeled dose was excreted in the urine with severe hepatic impairment (Child- and Tmax is extended to approximately and feces, respectively. In the urine, Pugh Class C) and use should be avoided 2.5 hours when taken with food; however, approximately 16% to 18% of the admin- in these types of patients.9,11 the AUC does not experience a signifi- istered dose of naldemedine was excreted cant change as high-fat meals lower the unchanged. There is no estimate at this CLINICAL TRIALS speed, but not the degree, of naldemedine time for the degree of change in nalde- A summary of the clinical trials leading absorption.9,11 Naldemedine is 93% to 94% medine excreted in the feces. As the pri- to the approval of naldemedine can be bound to human plasma proteins when mary metabolite excreted in the urine and found in Table 3.11,15, 17-20 taken orally and has a mean apparent feces, benzamidine represented approxi- volume of distribution of 155 L.9,11 mately 32% and 20% of the administered NCT01122030 dose of naldemedine, respectively.9,11 Webster et al. conducted a single- Metabolism center, randomized, double-blind, pla- Naldemedine undergoes hepatic Hepatic and Renal Impairment cebo-controlled, single ascending-dose metabolism via CYP3A to nor-nalde- The pharmacokinetic properties of phase 2a study evaluating the safety and medine.