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DRUG FORECASTNaldemedine (Symproic) for the TreatmentOf Opioid-Induced ConstipationKenneth Hu, PharmD; and Mary Barna Bridgeman, PharmD, BCPS, BCGPINTRODUCTIONPain, pain management, and the complications associated with interventionsintended to mitigate pain are associatedwith significant direct and indirect healthcare costs. Beyond the direct costs associated with medications, hospitalizations,provider visits, physical therapy, andrehabilitation, chronic pain places anenormous indirect burden on the affectedindividual’s productivity, quality of life,and mental health. More than 100 million Americans are estimated to sufferfrom chronic pain, with an estimated 3%of adults in the United States receivinglong-term opioid therapy for chronicnon-cancer pain, at a national annual estimated cost of approximately 560 billionto 630 billion.1-4Opioid analgesics are commonly prescribed for the treatment of chronic painmanagement. In 2012, prescriptions foropioid pain medications were written byhealth care providers 259 million times.5While opioids can be useful for alleviatingsevere pain, the clinical utility of opioidsmay be limited by an association withadverse effects. Severe adverse effectsattributed to opioid use may include physical dependence, respiratory and centralnervous system depression, tolerance,and hyperalgesia.2 Adverse effects relatedto sedation, pruritus, nausea and vomiting, and constipation may be perceivedAt the time of writing, Dr. Hu was a PharmDCandidate at the Ernest Mario School ofPharmacy at Rutgers, The State University ofNew Jersey; he is now a Global RegulatoryAffairs Postdoctoral Fellow at Sanofi inBridgewater, New Jersey. Dr. Bridgemanis a Clinical Associate Professor at RutgersUniversity and an Internal Medicine ClinicalPharmacist at Robert Wood Johnson Hospitalin New Brunswick, New Jersey. Drug Forecastis a regular column coordinated by Alan Caspi,PhD, PharmD, MBA, President of Caspi andAssociates in New York, New York.Disclosure: The authors report no commercialor financial interests in regard to this article.as less severe, but potentially bothersome, and can ultimately contribute tonon-compliance with the prescribed regimen. In particular, gastrointestinal (GI)side effects, including nausea, abdominal pain, bloating, abdominal cramping,and constipation, can have an impact onthe quality of life, dignity, and health ofpatients utilizing these agents for chronicpain management. Opioid-induced constipation (OIC), new or worsening constipation occurring when initiating, changing,or increasing opioid use, represents themost common of these GI effects (seeTable 1 for a depiction of the ROME IVdefinition of OIC).6Since tolerance does not develop tothe constipating effects of this class,OIC may occur at any point after initiation of the opioids and can be directlyattributed to the peripheral effects of theopioid interacting with receptors foundwithin the GI tract. The frequency of OICincreases with prolonged use of opioids,and many patients may reduce the doseor discontinue their opioid treatment dueto the effects of constipation, resulting indecreased treatment satisfaction.7Although there are several treatmentoptions for OIC, an unmet clinical needcontinues to exist for patients utilizingopioids chronically for pain management.Several novel treatment methods are indevelopment.8 This review focuses on thesafety and efficacy of naldemedine (Symproic, Shionogi), a peripherally acting mu(µ)-opioid receptor antagonist approvedby the Food and Drug Administration(FDA) in March of 2017 for the treatmentof OIC in adult patients with chronic noncancer pain.9PHARMACOLOGYThe mu (µ)-, delta (δ)-, and kappa(κ)-opioid receptors are common inthe central nervous system (CNS), butthey are also involved with GI function.While the δ- and κ-receptors are primarilyfound in the proximal colon and stomach,the µ-receptors are widely distributedthroughout the GI tract. OIC is largelydue to enteric µ-opioid receptor activation, leading to non-peristaltic contractions of the esophagus, reduced gastricmotility and emptying, decreased GIsecretions, inhibited intestinal propulsion, and greater absorption of water frombowel contents.10As a peripheral µ-opioid receptor antagonist, naldemedine works by binding tothe µ-, δ-, and κ-opioid receptors and specifically reduces the constipating effectsof opioids through its action as an antagonist at the µ-opioid receptors in GI tracttissue.9,11 Naldemedine shares a similarchemical structure to that of naltrexone,with an additional side chain increasingthe molecular weight and polar surfacearea.11 Naldemedine also acts as a substrate of the P-glycoprotein (P-gp) effluxtransporter. These properties reduce thepossibility of naldemedine interferingwith centrally mediated opioid analgesiaby decreasing its penetration into theCNS at recommended dose levels.9Table 1 Characteristics of OIC According to the ROME IV Criteria6New or worsening symptoms when initiating, changing, or increasing opioid therapy that mustinclude two or more of the following in 25% of defecations: Straining to pass a bowel movement Passing lumpy or hard stools Experiencing the sensation of incomplete evacuation, obstruction, or blockage of stool Requiring manual maneuvers to facilitate evacuation of stool Fewer than three spontaneous bowel movements per weekANDRarely experiencing loose stools without laxative useVol. 43 No. 10 October 2018 P&T 601

DRUG FORECASTTable 2 Comparison of FDA-Approved Medications for the Treatment of OIC9, xegol13Lubiprostone14*Mechanismµ-, δ-, and κ-opioid receptor µ-opioid receptor antagonist µ-opioid receptor antagonistantagonistChloride channel activatorRoute of Administration OralSubcutaneous; OralOralOralAbsorption(Time to Peak)0.75 hours; 2.5 hours (withfood)Subcutaneous: 30 minutes;Oral: 1.5 hours (delayed by2 hours with high-fat meal) 2 hours; in majority ofsubjects, a secondary Cmaxoccurs 0.4 to 3 hours afterthe first CmaxM3: 1.1 hoursDistributionVz/F: 155 LVss: 1.1 L/kgVz/F: 968–2,140 LMinimal beyond GI tissuesMetabolismCYP3AConversion to methyl-6naltrexol isomers andmethylnaltrexone sulfateCYP3ACarbonyl reductaseEliminationt½: 11 hourst½: 8 hourst½: 6–11 hoursM3 t½: 0.9–1.4 hoursSide Effects Abdominal painDiarrheaNauseaGastroenteritisAbdominal painFlatulenceNauseaDizzinessAbdominal painDiarrheaNauseaFlatulenceAbdominal painDiarrheaNauseaFlatulence*Low systemic availability of lubiprostone after oral administration, with concentrations below the level of quantitation (10 pg/mL). Pharmacokinetic parameters ofM3 (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.PHARMACOKINETICSA summary of the pharmacokineticcharacteristics of the FDA-approvedtreatments for OIC can be found in Table2.9,11-14Absorption and DistributionWhen taken orally, naldemedine isabsorbed from the GI tract, with peakconcentrations (Cmax) occurring atapproximately 0.75 hours (Tmax) in thefasted state. There is a dose-proportional,or near dose-proportional, increase forboth Cmax and the area-under the-plasmaconcentration-time curve (AUC) and multiple daily doses of naldemedine result inminimal accumulation. A high-fat mealdecreases Cmax by approximately 35%and Tmax is extended to approximately2.5 hours when taken with food; however,the AUC does not experience a significant change as high-fat meals lower thespeed, but not the degree, of naldemedineabsorption.9,11 Naldemedine is 93% to 94%bound to human plasma proteins whentaken orally and has a mean apparentvolume of distribution of 155 L.9,11MetabolismNaldemedine undergoes hepaticmetabolism via CYP3A to nor-naldemedine. Naldemedine also undergoesmetabolism to a lesser degree through602 P&T October 2018 Vol. 43 No. 10UGT1A3 to form naldemedine 3-G. Bothmetabolites have shown antagonisticactivity for opioid receptors but to a lesserextent than naldemedine. Naldemedineis also cleaved to benzamidine and naldemedine carboxylic acid within the GItract.9,11 When [14C]-labeled naldemedinewas taken orally, nor-naldemedine wasthe primary metabolite in plasma, withapproximately 9% to 13% relative exposurecompared to naldemedine. As a minormetabolite in plasma, naldemedine 3-Ghad a relative exposure of less than 3%.9EliminationWhen [14C]-labeled naldemedine wastaken orally, 57% and 35% of the radiolabeled dose was excreted in the urineand feces, respectively. In the urine,approximately 16% to 18% of the administered dose of naldemedine was excretedunchanged. There is no estimate at thistime for the degree of change in naldemedine excreted in the feces. As the primary metabolite excreted in the urine andfeces, benzamidine represented approximately 32% and 20% of the administereddose of naldemedine, respectively.9,11Hepatic and Renal ImpairmentThe pharmacokinetic properties ofnaldemedine given once at a dose of0.2 mg in subjects with normal hepaticand renal (estimated creatinine clearance 90 mL/min) function were similar tothose in subjects with mild (estimatedglomerular filtration rate [eGFR] of 60 to89 mL/min/1.73 m2), moderate (eGFR,30 to 59 mL/min/1.73 m2), or severe(eGFR 30 mL/min/1.73 m2) renalimpairment, subjects with end-stage renaldisease requiring hemodialysis, and subjects with mild (Child-Pugh Class A) ormoderate (Child-Pugh Class B) hepaticimpairment. No adjustments are requiredwhen dosing naldemedine for patientswith mild to moderate hepatic impairment, although there have been no studies of the effect on the pharmacokineticproperties of naldemedine in subjectswith severe hepatic impairment (ChildPugh Class C) and use should be avoidedin these types of patients.9,11CLINICAL TRIALSA summary of the clinical trials leadingto the approval of naldemedine can befound in Table 3.11,15, 17-20NCT01122030Webster et al. conducted a singlecenter, randomized, double-blind, placebo-controlled, single ascending-dosephase 2a study evaluating the safety andefficacy of naldemedine at doses of 0.01mg, 0.03 mg, 0.1 mg, 0.3 mg, 1.0 mg,