Cardiovascular Safety of the Selective µ-Opioid Receptor Antagonist Naloxegol: A Novel Therapy for Opioid-Induced Constipation.

BACKGROUND: Naloxegol is a novel selective, peripherally acting µ-opioid receptor antagonist for treating opioid-induced constipation (OIC) in patients with chronic pain syndromes. We analyzed the cardiovascular (CV) safety of naloxegol based on data from its development program prior to approval by the US Food and Drug Administration in 2015. METHODS: Comprehensive CV safety analyses were performed in 4 clinical studies of naloxegol (12.5 and/or 25 mg) in patients with noncancer pain and OIC: two 12-week, double-blind, randomized studies; a 12-week, double-blind, extension study; and a 52-week, randomized, open-label study versus usual care. Evaluations of baseline CV risk were obtained from medical histories and clinical findings at the time of study initiation. RESULTS: Across the 4 studies (N = 2135), 68% of patients had ≥1 CV risk factor and 41% had a history of CV disease, diabetes, or ≥2 other CV risk factors. There were no increases in blood pressure, heart rate, or the rate-pressure product with naloxegol versus placebo. The rates of major adverse cardiovascular events (MACE) per 100 patient-years of exposure were 1.13 (95% confidence interval [CI], 0.31-2.89) for placebo/usual care and 0.75 (95% CI, 0.24-1.75) for naloxegol. The relative risk of MACE for all doses of naloxegol versus placebo was 0.67 (95% CI, 0.14-3.36). CONCLUSION: These data demonstrate that naloxegol has a CV safety profile comparable to placebo/usual care in patients with OIC. Although the observed number of events was low, the data show no CV signal in patients with OIC treated with naloxegol.

Treatment with Naloxegol Versus Placebo: Pain Assessment in Patients with Noncancer Pain and Opioid-Induced Constipation.

OBJECTIVE: To summarize results from pain and opioid use assessments with naloxegol in adults with opioid-induced constipation (OIC) and chronic noncancer pain. METHODS: Two phase 3 randomized, double-blind, 12-week studies evaluated the efficacy and safety of oral naloxegol (12.5 or 25 mg daily) in adults (18 to < 85 years) with confirmed OIC and chronic noncancer pain: KODIAC-04 (NCT01309841) and KODIAC-05 (NCT01323790). Pain level was assessed daily (11-point numeric rating scale [NRS]; 0 = no pain, 10 = worst imaginable pain). Changes from baseline in mean weekly pain scores and opioid dose (weeks 1 through 12) were analyzed using mixed-model repeated measures. RESULTS: At baseline, mean daily NRS average pain scores ranged from 4.5 to 4.8 for all groups in KODIAC-04 (N = 652) and were 4.6 for each group in KODIAC-05 (N = 700). Respective mean ± SD changes from baseline average pain for placebo, naloxegol 12.5 mg, and naloxegol 25 mg were -0.2 ± 1.07, -0.3 ± 1.05 (P = 0.773 vs. placebo), and 0.2 ± 0.95 (P = 0.837 vs. placebo; KODIAC-04) and -0.1 ± 0.94, -0.1 ± 0.87 (P = 0.744), and 0.0 ± 1.18 (P = 0.572; KODIAC-05). At baseline, mean daily opioid doses ranged from 135.6 to 143.2 morphine equivalent units (MEUs)/day in KODIAC-04, and from 119.9 to 151.7 MEUs/day in KODIAC-05. Respective mean ± SD changes from baseline dose were -1.8 ± 30.19, -2.3 ± 20.52 (P = 0.724 vs. placebo), and 0.4 ± 13.01 (P = 0.188 vs. placebo; KODIAC-04) and -0.3 ± 17.14, -1.3 ± 17.11 (P = 0.669 vs. placebo), and 0.1 ± 8.54 (P = 0.863 vs. placebo; KODIAC-05). Changes in maintenance opioid dose were few; reasons for such changes were similar across treatment groups. CONCLUSION: Centrally mediated opioid analgesia was maintained during treatment with naloxegol in patients with noncancer pain and OIC.

Pharmacologic Profile of Naloxegol, a Peripherally Acting µ-Opioid Receptor Antagonist, for the Treatment of Opioid-Induced Constipation.

Opioid-induced constipation (OIC) is a common side effect of opioid pharmacotherapy for the management of pain because opioid agonists bind to µ-opioid receptors in the enteric nervous system (ENS). Naloxegol, a polyethylene glycol derivative of naloxol, which is a derivative of naloxone and a peripherally acting µ-opioid receptor antagonist, targets the physiologic mechanisms that cause OIC. Pharmacologic measures of opioid activity and pharmacokinetic measures of central nervous system (CNS) penetration were employed to characterize the mechanism of action of naloxegol. At the human µ-opioid receptor in vitro, naloxegol was a potent inhibitor of binding (Ki = 7.42 nM) and a neutral competitive antagonist (pA2 - 7.95); agonist effects were <10% up to 30 µM and identical to those of naloxone. The oral doses achieving 50% of the maximal effect in the rat for antagonism of morphine-induced inhibition of gastrointestinal transit and morphine-induced antinociception in the hot plate assay were 23.1 and 55.4 mg/kg for naloxegol and 0.69 and 1.14 mg/kg by for naloxone, respectively. In the human colon adenocarcinoma cell transport assay, naloxegol was a substrate for the P-glycoprotein transporter, with low apparent permeability in the apical to basolateral direction, and penetrated the CNS 15-fold slower than naloxone in a rat brain perfusion model. Naloxegol-derived radioactivity was poorly distributed throughout the rat CNS and was eliminated from most tissues within 24 hours. These findings corroborate phase 3 clinical studies demonstrating that naloxegol relieves OIC-associated symptoms in patients with chronic noncancer pain by antagonizing the µ-opioid receptor in the ENS while preserving CNS-mediated analgesia.

When People with Opioid-Induced Constipation Speak: A Patient Survey.

INTRODUCTION: Opioid-induced constipation (OIC) is a common consequence of opioid use for chronic pain. OIC creates problems for patients independent of their pain syndromes, in addition to threatening pain treatment effectiveness. Healthcare practitioners need to be alert to how patients talk about OIC so that it is not missed. Using a survey mechanism, we sought patient expressions of the personal impact OIC imposes on how they are able to live their lives and on meanings that symptom relief would produce. METHODS: We used an online survey asking adults with OIC about quality of life implications of OIC and focused on open-ended text responses to questions about personal impacts of straining and meanings attached to OIC symptom relief. Participants were from the US, Canada, UK, Germany, Sweden, and Norway. RESULTS: A survey of 513 people with OIC produced 280 text responses concerning the impacts of straining on quality of life and 469 text responses on the meaning OIC symptom relief would confer. Text responses about the quality of life impacts of straining often included explicit descriptions conveying physical, psychological, or practical problems. Text responses about the meaning conferred from OIC symptom relief primarily concentrated around freedom from the constraints that OIC can impose. CONCLUSIONS: Patients are willing and able to comment on the problems OIC cause them, using a variety of terms and phrases. Their comments concerning impacts on their lives will often refer to physical consequences, psychological effects, or practical implications. These insights provide healthcare practitioners guidance on how to engage patients about OIC.

Translating Clinical Findings into the Patient's Perspective: Post-hoc Pooled Analysis of Bowel Movement Changes as a Predictor of Improvement in Patients' Opioid-induced Constipation Symptoms and Outcomes.

PURPOSE: Opioid-induced constipation (OIC) is a bothersome side effect of opioid use for the management of noncancer pain, affecting patients' health-related quality of life and chronic-pain management. The objective of this study was to examine the relationship between changes in the frequency of spontaneous bowel movements (SBMs) and changes in patient-reported outcomes (PROs) among patients with OIC treated with naloxegol. METHODS: Post hoc analyses were conducted using pooled data from two Phase III 12-week, placebo-controlled trials of naloxegol for the treatment of OIC (NCT01309841 and NCT01323790). Patients completed the Patient Assessment of Constipation-Quality of Life (PAC-QOL) and PAC-Symptoms (PAC-SYM) at each study visit, and the Straining Scale and Bristol Stool Scale (BSS) with each bowel movement for the study duration. Four subgroups were created based on improvements from baseline in mean frequency of SBMs per week: 0 or worse (no change), +1 SBM, +2 SBMs, and +≥3 SBMs. Spearman correlations assessed the association between mean SBM changes from baseline and mean changes from baseline in PROs; analysis of covariance was used to compare changes from baseline. FINDINGS: A total of 1337 patients with mean (SD) age of 52.2 (11.0) years were included in this analysis. The patient population was predominantly white (79.0%) and female (62.4%). At baseline, mean SBM frequency was 1.4 (1.0) per week. At study end, all 4 SBM-change subgroups experienced improvements in PAC-QOL, PAC-SYM, Straining Scale, and BSS scores, and these changes were significantly correlated with mean changes from baseline in SBMs per week. The subgroup of patients with an increase in SBMs of ≥3 per week experienced the greatest improvements in PROs. IMPLICATIONS: In these patients with OIC, an improvement in the frequency of SBMs by ≥3 per week was associated with consistent improvements in PROs, providing support for the use of improvements in SBMs as a clinical outcome surrogate for managing patients with OIC. Further research is needed to determine a threshold for change in SBMs that is clinically meaningful in both research and clinical settings. A key limitation was the post hoc nature of the study, which was not powered prospectively to examine these relationships.

The effect of quinidine, a strong P-glycoprotein inhibitor, on the pharmacokinetics and central nervous system distribution of naloxegol.

Naloxegol is a PEGylated, oral, peripherally acting µ-opioid receptor antagonist approved in the United States for treatment of opioid-induced constipation in patients with noncancer pain. Naloxegol is metabolized by CYP3A, and its properties as a substrate for the P-glycoprotein (PGP) transporter limit its central nervous system (CNS) permeability. This double-blind, randomized, 2-part, crossover study in healthy volunteers evaluated the effect of quinidine (600 mg PO), a CYP3A/PGP transporter inhibitor, on the pharmacokinetics and CNS distribution of naloxegol (25 mg PO). In addition, the effects of quinidine on morphine (5 mg/70 kg IV)-induced miosis and exposure to naloxegol were assessed. Coadministration of quinidine and naloxegol increased naloxegol's AUC 1.4-fold and Cmax 2.5-fold but did not antagonize morphine-induced miosis, suggesting that PGP inhibition does not increase the CNS penetration of naloxegol. Naloxegol pharmacokinetics was unaltered by coadministration of morphine and either quinidine or placebo; conversely, pharmacokinetics of morphine and its metabolites (in the presence of quinidine) were unaltered by coadministration of naloxegol. Naloxegol was safe and well tolerated, alone or in combination with quinidine, morphine, or both. The observed increase in exposure to naloxegol in the presence of quinidine is primarily attributed to quinidine's properties as a weak CYP3A inhibitor.

Population pharmacokinetics of naloxegol in a population of 1247 healthy subjects and patients.

AIMS: Naloxegol, a polyethylene glycol conjugated derivative of the opioid antagonist naloxone, is in clinical development for treatment of opioid-induced constipation (OIC). The aim of the study was to develop a population pharmacokinetic model describing the concentration vs. time profile of orally administered naloxegol, and determine the impact of pre-specified demographic and clinical factors and concomitant medication on population estimates of apparent clearance (CL/F) and apparent central compartment volume of distribution (Vc /F). METHODS: Analysis included 12,844 naloxegol plasma concentrations obtained from 1247 healthy subjects, patients with non-OIC and patients with OIC in 14 phase 1, 2b and 3 clinical studies. Pharmacokinetic analysis used the non-linear mixed effects modelling program. Goodness of fit plots and posterior predictive checks were conducted to confirm concordance with observed data. RESULTS: The final model was a two compartment disposition model with dual absorptions, comprising one first order absorption (ka1 4.56 h(-1) ) and one more complex absorption with a transit compartment (ktr 2.78 h(-1) ). Mean (SE) parameter estimates for CL/F and Vc /F, the parameters assessed for covariate effects, were 115 (3.41) l h(-1) and 160 (27.4) l, respectively. Inter-individual variability was 48% and 51%, respectively. Phase of study, gender, race, concomitant strong or moderate CYP3A4 inhibitors, strong CYP3A4 inducers, P-glycoprotein inhibitors or inducers, naloxegol formulation, baseline creatinine clearance and baseline opioid dose had a significant effect on at least one pharmacokinetic parameter. Simulations indicated concomitant strong CYP3A4 inhibitors or inducers had relevant effects on naloxegol exposure. CONCLUSIONS: Administration of strong CYP3A4 inhibitors or inducers had a clinically relevant influence on naloxegol pharmacokinetics.

Effects of CYP3A Modulators on the Pharmacokinetics of Naloxegol.

Naloxegol, a peripherally acting µ-opioid receptor antagonist, was recently approved in the United States for the treatment of opioid-induced constipation. This study evaluated the effects of CYP3A inhibition and induction on the pharmacokinetics, safety, and tolerability of naloxegol. Separate open-label, nonrandomized, fixed-sequence, 3-period, 3-treatment, crossover studies of naloxegol (25 mg by mouth [PO]) in the absence or presence of the inhibitors ketoconazole (400 mg PO) and diltiazem extended release (240 mg PO), or the inducer rifampin (600 mg PO) were conducted in healthy volunteers. Area under the curve (AUC∞ ) for naloxegol was increased with coadministration of either ketoconazole (12.9-fold) or diltiazem (3.4-fold) and decreased by 89% with coadministration of rifampin compared with AUC∞ for naloxegol alone. Naloxegol was generally safe and well tolerated when given alone or coadministered with the respective CYP3A modulators; 1 subject discontinued because of elevations in liver enzymes attributed to rifampin. The exposure of naloxegol was affected substantially by ketoconazole, diltiazem, and rifampin, suggesting that it is a sensitive in vivo substrate of CYP3A4.

Efficacy and safety of naloxegol in patients with opioid-induced constipation and laxative-inadequate response.

BACKGROUND: Treatment options for patients with opioid-induced constipation (OIC) and inadequate response to laxatives (LIR) are few. OBJECTIVE: Assess the efficacy and safety of orally administered naloxegol in patients with prospectively confirmed OIC and LIR. METHODS: We analyzed pooled data from two identical randomized, double-blind, placebo-controlled, Phase 3 trials of naloxegol in patients with non-cancer pain, OIC and LIR in which naloxegol (12.5 mg, n = 240; 25 mg, n = 241) or placebo (n = 239) were administered daily. We assessed the response rates, time to first post-dose laxation, spontaneous bowel movements (SBMs), OIC symptoms and patient-reported outcomes over 12 weeks. RESULTS: OIC response rates for the naloxegol 25-mg (p < 0.001) and the 12.5-mg (p = 0.005) LIR dose groups were higher than placebo. Median times to first post-dose SBM were 7.6, 19.2 and 41.1 hours for the naloxegol 25 mg, naloxegol 12.5 mg and placebo groups, respectively. Other SBM measures, daily symptoms of OIC, and both the Patient Assessment of Constipation - Symptoms and Patient Assessment of Constipation-Quality of Life scores improved from baseline with naloxegol treatment. Changes from baseline in opioid dose, pain scores and opioid withdrawal scores were similar among treatment groups. CONCLUSIONS: Naloxegol was efficacious, generally safe and well tolerated in the patients with OIC and LIR, while preserving opioid analgesia. ClinicalTrials.gov identifiers: NCT01309841; NCT01323790.

Absorption, distribution, metabolism, and excretion of [14C]-labeled naloxegol in healthy subjects.

OBJECTIVE: To characterize the absorption, distribution, metabolism, and excretion of naloxegol, a PEGylated derivative of the µ-opioid antagonist naloxone, in healthy male subjects. MATERIALS AND METHODS: [14C]-Labeled naloxegol (27 mg, 3.43 MBq) was administered as an oral solution to 6 fasted subjects. Blood, fecal, and urine samples were collected predose and at various intervals postdose. Naloxegol and its metabolites were quantified or identified by liquid chromatography with radiometric or mass spectrometric detection. Pharmacokinetic parameters were calculated for each subject, and metabolite identification was performed by liquid chromatography with parallel radioactivity measurement and mass spectrometry. RESULTS: Naloxegol was rapidly absorbed, with a maximum plasma concentration (geometric mean) of 51 ng/mL reached before 2 hours after dosing. A second peak in the observed naloxegol and [14C] plasma concentration-time profiles was observed at ~3 hours and was likely due to enterohepatic recycling of parent naloxegol. Distribution to red blood cells was negligible. Metabolism of [14C]-naloxegol was rapid and extensive and occurred via demethylation and oxidation, dealkylation, and shortening of the polyethylene glycol chain. Mean cumulative recovery of radioactivity was 84.2% of the total dose, with ~68.9% recovered within 96 hours of dosing. Fecal excretion was the predominant route of elimination, with mean recoveries of total radioactivity in feces and urine of 67.7% and 16.0%, respectively. Unchanged naloxegol accounted for ~1/4 of the radioactivity recovered in feces. CONCLUSIONS: Naloxegol was rapidly absorbed and cleared via metabolism, with predominantly fecal excretion of parent and metabolites.

Treatment patterns, healthcare utilization, and costs of chronic opioid treatment for non-cancer pain in the United States.

OBJECTIVES: To evaluate treatment patterns, healthcare resource utilization, and costs among patients within a large managed care population chronically using opioids for non-cancer pain. STUDY DESIGN: Retrospective cohort study. METHODS: Patients aged ≥18 years with ≥1 prescription initiating opioids between January 1, 2007, and December 31, 2011, who also had 12 months of continuous pre-index health plan enrollment, were identified. Patients with pre-index opioid use or cancer diagnosis were excluded. Opioid exposure was stratified by treatment duration-short-term (30-182 days) versus chronic (≥183 days)-and by index opioid type (weak vs strong). RESULTS: A total of 2.9 million patients initiating opioids were identified, of which 257,602 had at least 30 days of continuous use and were included in the study. The mean age was 51 years and 52% were female. Overall, 239,998 (93%) patients had short-term opioid use, and 17,604 (7%) had chronic use; 215,424 (84%) initiated treatment with a weak opioid, and 44,712 (17%) with a strong opioid. The specialty most associated with the use of less potent opioids was general/family practice (28%), and for more potent opioids it was surgery (22%). Large increases in health-care utilization were reported between the pre-index and first 6-month post initiation periods for chronic users. Utilization rates decreased after the first 6 months but never reverted to baseline levels. Costs mirrored utilization trends, more than doubling between baseline and the first 6 months of treatment for pharmacy ($2029 vs $4331) and all-cause medical ($11,430 vs $27,365). Costs declined after the first 6 months of opioid use but remained above pre-index levels. CONCLUSIONS: These results demonstrated that healthcare resource utilization and costs increased during the first 6 months following clinical scenarios that necessitated opioid initiation and subsequently declined, suggesting the need to monitor patients beyond the acute care period.

Safety, tolerability, pharmacokinetics, and pharmacodynamic effects of naloxegol at peripheral and central nervous system receptors in healthy male subjects: A single ascending-dose study.

This randomized, double-blind, placebo-controlled, ascending-dose, crossover study evaluated single oral doses of naloxegol (NKTR-118; 8, 15, 30, 60, 125, 250, 500, and 1000 mg), a PEGylated derivative of naloxone, for safety and tolerability, antagonism of peripheral and central nervous system (CNS) effects of intravenous morphine, and pharmacokinetics. Healthy men were randomized 1:1 to naloxegol or naloxegol-matching placebo administered with morphine and lactulose in a 2-period crossover design. Periods were separated by a 5- to 7-day washout. Assessments included safety, tolerability, orocecal transit time (OCTT), pupillary miosis, and pharmacokinetics. The study was completed by 46 subjects. The most common adverse events were somnolence, dizziness, headache, and nausea. Greater reversal of morphine-induced delay in OCTT occurred with increasing naloxegol dose, demonstrating dose-ordered antagonism of morphine's peripheral gastrointestinal effects. Forty-four subjects showed no reversal of pupillary miosis; 2 showed potential partial reversal at 250 and 1000 mg, indicating negligible antagonism of morphine's CNS effects at doses ≤ 125 mg. Rapid absorption, linear pharmacokinetics up to 1000 mg, and low to moderate between-subject pharmacokinetic variability was observed. The pharmacokinetics of morphine or its glucuronide metabolites were unaltered by concurrent naloxegol administration. Naloxegol was generally safe and well tolerated at single doses up to 1000 mg.

Safety, tolerability, and pharmacokinetics of multiple ascending doses of naloxegol.

Opioid-induced constipation (OIC) is the most common and often a treatment-limiting adverse event (AE) of opioid therapy for chronic pain. Naloxegol (previously NKTR-118), a PEGylated derivative of naloxone that has minimal penetration of the central nervous system, has received regulatory approval as an oral therapy for OIC. This randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation study was performed to assess safety, tolerability, and pharmacokinetics of multiple doses of naloxegol in healthy volunteers. Four cohorts, each with 4 male and 4 female volunteers, were randomized 3:1 to a twice-daily naloxegol solution (25, 60, 125, and 250 mg) or matching placebo solution. Doses were given every 12 hours for 7 days, with a single final dose on the morning of day 8. All 32 subjects completed the study. The incidence of most AEs was similar in the naloxegol and placebo groups; no AE led to study discontinuation. Naloxegol was rapidly absorbed. Plasma naloxegol pharmacokinetics showed dose proportionality, negligible accumulation at steady state, and no sex differences. Naloxegol in doses up to 250 mg every 12 hours was generally safe and well tolerated in this healthy volunteer population.

Patient preferences for change in symptoms associated with opioid-induced constipation.

INTRODUCTION: While opioids have become a standard treatment option for those experiencing moderate to severe chronic pain, side effects of constipation and related symptoms have interfered with their usage in as many as 40-50% of treated patients. Prior research has elucidated the range of these symptoms, but no study has determined which of these symptoms patients most desire improving or whether improving constipation itself by as little as one more bowel movement per week is deemed an important change. METHODS: We conducted an online patient survey of 513 participants residing in one of six countries who reported having chronic pain, were taking opioids, and experiencing opioid-induced constipation (OIC) to address these questions. RESULTS: Respondents rank ordered their preferences and the following eight symptoms generated >80% endorsement as important to improve: improvement in having bowel movements without rectal pain, soft stools that are not loose or watery, regular bowel movements, a reduction in rectal straining, relief from feeling bloated, feeling less fear about having OIC when following their opioid medication regime, a desire to worry less overall about having a bowel movement, and with less 'stomach' area pain. When asked 'how important is it you to have 1 more bowel movement per week", over 90% endorsed it was 'somewhat', 'very', or 'extremely important' with nearly 70% (n = 354) endorsing the 'extremely' or 'very important' response options. In multivariate models, being in more overall pain or reporting fewer than 3 bowel movements per week were found to be independent predictors of the importance. CONCLUSIONS: These results highlight the notable range of OIC symptoms most desired by patients to improve and demonstrate that bowel movements of only one more per week were important to register a meaningful improvement. The latter is particularly helpful for those assessing the minimal clinically important difference in treating this condition.

A description of clinical characteristics and treatment patterns observed within prescribed opioid users in Germany and the UK.

AIMS: To describe a cohort of new opioid users (adult noncancer patients) in terms of clinical characteristics and treatment patterns in the UK and Germany. MATERIAL & METHODS: Data used were extracted from electronic medical records databases (UK: Clinical Practice Research Database-Hospital Episode Statistics; Germany: IMS Disease Analyzer) covering the 2008-2012 period. RESULTS: Most eligible patients were treated with opioids for less than 6 months (UK: 78.7% and Germany: 93.7%) and indexed on weak opioids (UK: 89.5% and Germany: 88.6%). Most prescribed opioids were codeine (UK) and tramadol (Germany). Most prevalent comorbidities were dorsalgia/depression. Constipation was observed in 16.8%/17.4% (UK/Germany) of chronic users (>6 months). CONCLUSION: While both populations were highly morbid populations largely initiated on weak opioids, chronic use was less common in Germany.

Description of cardiovascular event rates in patients initiating chronic opioid therapy for noncancer pain in observational cohort studies in the US, UK, and Germany.

INTRODUCTION: Previous observational studies in the US suggest that opioid analgesic use increases the risk of cardiovascular (CV) events. The current study provides additional background event rates for five prespecified CV outcomes of interest in patients from three countries. METHODS: Three observational cohort studies were conducted in patients from the US (N = 17,604), the UK (N = 9,823), and Germany (N = 9,412). Patients were new opioid users who had undergone ≥6 months of chronic, continuous therapy. De-identified data were collated from electronic healthcare databases in the respective countries. Demographics, clinical characteristics, and opioid use were examined. Overall rates, prevalence rates in patients with established CV disease, and incidence rates in patients without established CV disease were determined for myocardial infarction (MI), stroke, transient ischemic attack, unstable angina, and congestive heart failure (CHF). RESULTS: Cardiovascular disease at baseline was more prevalent in US and German patients. Back pain and depression were prevalent preexisting comorbidities. The majority of patients were using various weak opioids (based on receptor affinities), CV medications, and antidepressants. Overall rates by individual CV outcome per 1,000 patient-years by country were greatest for CHF (US 37.2, 95% CI 24.1-40.5), unstable angina (UK 8.2, 95% CI 7.0-9.6), and stroke (Germany 5.3, 95% CI 4.1-6.7). Overall rates for MI were: US, 10.7 (95% CI 9.1-12.5), UK, 6.7 (95% CI 5.6-8.0), and Germany, 2.7 (95% CI 1.9-3.7). Overall rates for each CV outcome, prevalence rates in patients with preexisting CV disease, and incidence rates in patients without established CV disease differed by country. Rates were higher in patients with preexisting CV disease. CONCLUSIONS: CV risk for new opioid users with ≥6 months of therapy was increased in patients with established CV disease compared with those without established CV disease, and the risk for specific outcomes differed by country. Assessment of CV safety events of new therapies introduced to chronic opioid users should consider sample size and population heterogeneity in the design of an observational study.

The effects of mild or moderate hepatic impairment on the pharmacokinetics, safety, and tolerability of naloxegol.

Naloxegol is a peripherally acting µ-opioid receptor antagonist (PAMORA) in development for the treatment of opioid-induced constipation (OIC). The pharmacokinetics of a single oral 25-mg dose of naloxegol in plasma was assessed in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment and compared with healthy volunteers. Participants were matched for sex, age, and body mass index. Hepatically impaired patients exhibited a 17%-18% decrease in area under the plasma concentration versus time curve (AUC) despite similar maximum plasma concentrations (Cmax ). This was an unexpected finding given that naloxegol is primarily cleared by the hepatic route. Time to Cmax was shorter in patients with moderate impairment (0.6 hours) versus those with mild impairment (2.3 hours) or normal subjects (2.0 hours). Mean apparent terminal half-life (t½ ) was shorter in patients with mild (9.6 hours) and moderate (7.5 hours) hepatic impairment versus healthy subjects (11.3 hours). Reductions in enterohepatic recycling of naloxegol because of hepatic impairment may explain the observed decreases in AUC and t½ observed in these patients. Naloxegol was generally well tolerated, and mild or moderate hepatic impairment appeared to have minimal effect on its pharmacokinetics and safety.

The effects of renal impairment on the pharmacokinetics, safety, and tolerability of naloxegol.

The impact of renal impairment on the pharmacokinetics of a 25-mg oral dose of naloxegol was examined in patients with renal impairment classified as moderate, severe, or end-stage renal disease (ESRD) and compared with healthy subjects (n = 8/group). Geometric mean area under the plasma concentration-time curve (AUC) was increased in patients with moderate (1.7-fold) or severe (2.2-fold) impairment, and maximum plasma concentrations (Cmax ) were elevated in patients with moderate (1.1-fold) or severe (1.8-fold) impairment. These findings were driven by higher exposures in two patients in each of the moderate and severe impairment groups; exposures in all other patients were similar to the control group. Overall exposures in ESRD patients were similar and Cmax was 29% lower versus normal subjects. Renal impairment minimally affected other plasma pharmacokinetic parameters. As renal clearance was a minor component of total clearance, exposure to naloxegol was unaffected by the degree of renal impairment, with no correlation between either AUC or Cmax and estimated glomerular filtration rate (eGFR). Hemodialysis was an ineffective means to remove naloxegol. Naloxegol was generally well tolerated in all groups. Renal impairment could adversely affect clearance by hepatic and gut metabolism, resulting in the increased exposures observed in outliers of the moderate and severe renal impairment groups.

Naloxegol for opioid-induced constipation in patients with noncancer pain.

BACKGROUND: Opioid-induced constipation is common and debilitating. We investigated the efficacy and safety of naloxegol, an oral, peripherally acting, µ-opioid receptor antagonist, for the treatment of opioid-induced constipation. METHODS: In two identical phase 3, double-blind studies (study 04, 652 participants; study 05, 700 participants), outpatients with noncancer pain and opioid-induced constipation were randomly assigned to receive a daily dose of 12.5 or 25 mg of naloxegol or placebo. The primary end point was the 12-week response rate (≥3 spontaneous bowel movements per week and an increase from baseline of ≥1 spontaneous bowel movements for ≥9 of 12 weeks and for ≥3 of the final 4 weeks) in the intention-to-treat population. The key secondary end points were the response rate in the subpopulation of patients with an inadequate response to laxatives before enrollment, time to first postdose spontaneous bowel movement, and mean number of days per week with one or more spontaneous bowel movements. RESULTS: Response rates were significantly higher with 25 mg of naloxegol than with placebo (intention-to-treat population: study 04, 44.4% vs. 29.4%, P=0.001; study 05, 39.7% vs. 29.3%, P=0.02; patients with an inadequate response to laxatives: study 04, 48.7% vs. 28.8%, P=0.002; study 05, 46.8% vs. 31.4%, P=0.01); in study 04, response rates were also higher in the group treated with 12.5 mg of naloxegol (intention-to-treat population, 40.8% vs. 29.4%, P=0.02; patients with an inadequate response to laxatives, 42.6% vs. 28.8%, P=0.03). A shorter time to the first postdose spontaneous bowel movement and a higher mean number of days per week with one or more spontaneous bowel movements were observed with 25 mg of naloxegol versus placebo in both studies (P<0.001) and with 12.5 mg of naloxegol in study 04 (P<0.001). Pain scores and daily opioid dose were similar among the three groups. Adverse events (primarily gastrointestinal) occurred most frequently in the groups treated with 25 mg of naloxegol. CONCLUSIONS: Treatment with naloxegol, as compared with placebo, resulted in a significantly higher rate of treatment response, without reducing opioid-mediated analgesia. (Funded by AstraZeneca; KODIAC-04 and KODIAC-05 ClinicalTrials.gov numbers, NCT01309841 and NCT01323790, respectively.).

Evaluation of the effect of Naloxegol on cardiac repolarization: a randomized, placebo- and positive-controlled crossover thorough QT/QTc study in healthy volunteers.

BACKGROUND: Opioid-induced constipation (OIC) is a common adverse effect associated with opioid use. Naloxegol is a PEGylated derivative of naloxone in clinical development as a once-daily oral treatment of OIC. OBJECTIVES: A thorough QT/QTc study was conducted, according to International Conference on Harmonisation E14 guidelines, to characterize the effect of naloxegol on cardiac repolarization. METHODS: In this randomized, positive- and placebo-controlled crossover study, healthy men received a single dose of naloxegol 25 mg (therapeutic dose), naloxegol 150 mg (supratherapeutic dose), moxifloxacin 400 mg (positive control), or placebo in 1 of 4 sequences (Williams Latin square design). The washout time between treatment periods was at least 5 days. Digital 12-lead ECGs were recorded at baseline and at 10 time points over 24 hours after dosing in each treatment period. QT intervals were corrected for heart rate using the Fridericia formula (QTcF) and the Bazett formula (QTcB). RESULTS: A total of 52 subjects were enrolled (mean age, 28 years), and 45 received all 4 treatments. The placebo-corrected, baseline-adjusted, mean increases in QTcF with naloxegol 25 and 150 mg were both <5 msec at each time point, and all upper limits of the 2-sided 90% CI were <10 msec. Similar findings were observed using QTcB; the upper limits of the 2-sided 90% CI were <10 msec at all time points after dosing with naloxegol 25 or 150 mg. With moxifloxacin 400 mg, mean QTcF was increased by a maximum of 11.1 msec (90% CI, 9.3-12.9 msec), supporting assay sensitivity. CONCLUSION: Naloxegol at 25 and 150 mg was not associated with QT/QTc interval prolongation in these healthy men, and at the proposed therapeutic dose of 25 mg/d, naloxegol is not expected to have a clinically relevant effect on cardiac repolarization in patients with OIC. ClinicalTrials.gov identifier: NCT01325415.