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Mark Sostek - One of the best experts on this subject based on the ideXlab platform.
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treatment with Naloxegol versus placebo pain assessment in patients with noncancer pain and opioid induced constipation
Pain Practice, 2018Co-Authors: Lynn R Webster, Raj Tummala, Ulysses Diva, Mark SostekAbstract: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.
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cardiovascular safety of the selective μ opioid receptor antagonist Naloxegol a novel therapy for opioid induced constipation
Journal of Cardiovascular Pharmacology and Therapeutics, 2018Co-Authors: William B. White, Mark Sostek, Ulysses Diva, Peter R Kowey, Raj TummalaAbstract: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 c...
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Supplemental Material, JCPT_Oct_2016_225_revised_CV_effect_revised_supplemental_materials_24_Jan_2018 - Cardiovascular Safety of the Selective μ-Opioid Receptor Antagonist Naloxegol: A Novel Therapy for Opioid-Induced Constipation
2018Co-Authors: William B. White, Mark Sostek, Ulysses Diva, Peter Kowey, Raj TummalaAbstract:Supplemental Material, JCPT_Oct_2016_225_revised_CV_effect_revised_supplemental_materials_24_Jan_2018 for Cardiovascular Safety of the Selective μ-Opioid Receptor Antagonist Naloxegol: A Novel Therapy for Opioid-Induced Constipation by William B. White, Peter Kowey, Ulysses Diva, Mark Sostek, and Raj Tummala in Journal of Cardiovascular Pharmacology and Therapeutics
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pharmacologic profile of Naloxegol a peripherally acting µ opioid receptor antagonist for the treatment of opioid induced constipation
Journal of Pharmacology and Experimental Therapeutics, 2017Co-Authors: Eike Floettmann, Khanh Bui, Mark Sostek, Kemal Payza, Michael A EldonAbstract: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.
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effects of cyp3a modulators on the pharmacokinetics of Naloxegol
The Journal of Clinical Pharmacology, 2016Co-Authors: Khanh Bui, Fahua She, Mark Sostek, Diansong Zhou, Nidal AlhunitiAbstract: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.
Khanh Bui - One of the best experts on this subject based on the ideXlab platform.
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pharmacometric modeling of Naloxegol efficacy and safety impact on dose and label
Clinical Pharmacology & Therapeutics, 2017Co-Authors: Nidal Alhuniti, Khanh Bui, Diansong Zhou, Sergej V Aksenov, R Fox, Gabriel Helmlinger, Donald R StanskiAbstract:Naloxegol is a peripherally acting μ-opioid receptor antagonist that was developed for the treatment of opioid-induced constipation. Modeling and simulation of Naloxegol efficacy and tolerability informed selection of doses for phase III studies and provided comprehensive dosage recommendations for the Naloxegol US package insert.
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population exposure response modeling supported selection of Naloxegol doses in phase iii studies in patients with opioid induced constipation
CPT: Pharmacometrics & Systems Pharmacology, 2017Co-Authors: Nidal Alhuniti, Diansong Zhou, Sergey Aksenov, Robert Fox, Khanh BuiAbstract:Naloxegol is approved for the treatment of opioid-induced constipation (OIC) in adults with chronic noncancer pain. Population exposure-response models were developed using data from a phase II study comprising 185 adults with OIC. The weekly probability of response defined as having ≥3/week spontaneous bowel movements (SBMs) and ≥1 SBM/week increase over baseline was characterized by a longitudinal mixed-effects logistic regression dose-response model, and the probability of time to discontinuation was modeled with a Weibull distribution function. The predicted probability of SBM in a given week increased with increasing Naloxegol dose. The model predicted that 12.5, 25, and 37.5 mg doses would produce median response rates of 40%, 50%, and 60%, and dropout rates of 13.3%, 16.7%, and 23.3%, respectively. The large overlap of predicted difference of the response rate between placebo and the 25 or 37.5 mg doses suggested little utility of using a 37.5 mg dose in phase III studies.
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an open label randomized bioavailability study of alternative methods of oral administration of Naloxegol in healthy subjects
Clinical pharmacology in drug development, 2017Co-Authors: Khanh Bui, Ulysses Diva, Bruce K Birmingham, Bruce BergerAbstract:Naloxegol is a peripherally acting μ-opioid receptor antagonist approved as an orally administered tablet for the treatment of opioid-induced constipation. Patients with swallowing difficulties may benefit from alternative approaches to the oral administration of the whole-tablet formulation of Naloxegol. This open-label, randomized, 4-period, 4-treatment, crossover, single-dose study (NCT02446171) evaluated the pharmacokinetic (PK) characteristics of crushed Naloxegol 25-mg tablets (suspended in water) administered orally or by nasogastric tube and a Naloxegol solution compared with the commercially available 25-mg tablet formulation in healthy volunteers. The PK profiles for the crushed tablet, whether administered orally or by nasogastric tube, and the 25-mg oral solution were similar to that of the 25-mg tablet administered orally. Compared with Naloxegol commercial tablets, the relative bioavailability of Naloxegol using 3 alternative methods of administration was approximately 100%. For each pairwise treatment comparison of the 3 alternative methods with the approved whole tablet, the geometric least-squares mean ratio ranges were 94.37%-100.04%, 94.83%-100.44%, and 97.05%-102.05% for area under the curve (AUC), AUC0-t , and maximum plasma concentration, respectively, and their 90% confidence intervals were entirely within the predefined 80% to 125% bioequivalence limits. Naloxegol was well tolerated when administered in both liquid and solid form.
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clinical pharmacokinetics and pharmacodynamics of Naloxegol a peripherally acting µ opioid receptor antagonist
Clinical Pharmacokinectics, 2017Co-Authors: Khanh Bui, Diansong Zhou, Eike Floettmann, Nidal AlhunitiAbstract:Naloxegol is a peripherally acting µ-opioid receptor antagonist approved for use as an orally administered tablet (therapeutic doses of 12.5 and 25 mg) for the treatment of opioid-induced constipation. Over a wide dose range (i.e. single supratherapeutic doses up to 1000 mg in healthy volunteers), the pharmacokinetic properties of Naloxegol appear to be time- and dose-independent. Naloxegol is rapidly absorbed, with mean time to maximum plasma concentration of <2 h. Following once-daily administration, steady state is achieved within 2–3 days and minimal accumulation is observed. The primary route of Naloxegol elimination is via hepatic metabolism, with renal excretion playing a minimal role. In clinical studies, six metabolites were found in feces, urine or plasma, none of which have been identified as unique or disproportionate human metabolites. The major plasma circulating species is Naloxegol. There are small effects of mild and moderate renal impairment, age, race, and body mass index on the systemic exposure of Naloxegol; however, gender has no effect on the pharmacokinetics of this agent. Naloxegol is a sensitive substrate of cytochrome P450 (CYP) 3A4 and its exposure can be significantly altered by strong or moderate CYP3A modulators. Food increases the bioavailability of Naloxegol, and the relative bioavailability of the tablet formulation was not limited by dissolution. Naloxegol in the dose range of 8–125 mg can antagonize morphine-induced peripheral effects without impacting the effect of morphine on the central nervous system, consistent with a peripheral mode of action.
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pharmacologic profile of Naloxegol a peripherally acting µ opioid receptor antagonist for the treatment of opioid induced constipation
Journal of Pharmacology and Experimental Therapeutics, 2017Co-Authors: Eike Floettmann, Khanh Bui, Mark Sostek, Kemal Payza, Michael A EldonAbstract: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.
Nidal Alhuniti - One of the best experts on this subject based on the ideXlab platform.
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pharmacometric modeling of Naloxegol efficacy and safety impact on dose and label
Clinical Pharmacology & Therapeutics, 2017Co-Authors: Nidal Alhuniti, Khanh Bui, Diansong Zhou, Sergej V Aksenov, R Fox, Gabriel Helmlinger, Donald R StanskiAbstract:Naloxegol is a peripherally acting μ-opioid receptor antagonist that was developed for the treatment of opioid-induced constipation. Modeling and simulation of Naloxegol efficacy and tolerability informed selection of doses for phase III studies and provided comprehensive dosage recommendations for the Naloxegol US package insert.
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population exposure response modeling supported selection of Naloxegol doses in phase iii studies in patients with opioid induced constipation
CPT: Pharmacometrics & Systems Pharmacology, 2017Co-Authors: Nidal Alhuniti, Diansong Zhou, Sergey Aksenov, Robert Fox, Khanh BuiAbstract:Naloxegol is approved for the treatment of opioid-induced constipation (OIC) in adults with chronic noncancer pain. Population exposure-response models were developed using data from a phase II study comprising 185 adults with OIC. The weekly probability of response defined as having ≥3/week spontaneous bowel movements (SBMs) and ≥1 SBM/week increase over baseline was characterized by a longitudinal mixed-effects logistic regression dose-response model, and the probability of time to discontinuation was modeled with a Weibull distribution function. The predicted probability of SBM in a given week increased with increasing Naloxegol dose. The model predicted that 12.5, 25, and 37.5 mg doses would produce median response rates of 40%, 50%, and 60%, and dropout rates of 13.3%, 16.7%, and 23.3%, respectively. The large overlap of predicted difference of the response rate between placebo and the 25 or 37.5 mg doses suggested little utility of using a 37.5 mg dose in phase III studies.
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clinical pharmacokinetics and pharmacodynamics of Naloxegol a peripherally acting µ opioid receptor antagonist
Clinical Pharmacokinectics, 2017Co-Authors: Khanh Bui, Diansong Zhou, Eike Floettmann, Nidal AlhunitiAbstract:Naloxegol is a peripherally acting µ-opioid receptor antagonist approved for use as an orally administered tablet (therapeutic doses of 12.5 and 25 mg) for the treatment of opioid-induced constipation. Over a wide dose range (i.e. single supratherapeutic doses up to 1000 mg in healthy volunteers), the pharmacokinetic properties of Naloxegol appear to be time- and dose-independent. Naloxegol is rapidly absorbed, with mean time to maximum plasma concentration of <2 h. Following once-daily administration, steady state is achieved within 2–3 days and minimal accumulation is observed. The primary route of Naloxegol elimination is via hepatic metabolism, with renal excretion playing a minimal role. In clinical studies, six metabolites were found in feces, urine or plasma, none of which have been identified as unique or disproportionate human metabolites. The major plasma circulating species is Naloxegol. There are small effects of mild and moderate renal impairment, age, race, and body mass index on the systemic exposure of Naloxegol; however, gender has no effect on the pharmacokinetics of this agent. Naloxegol is a sensitive substrate of cytochrome P450 (CYP) 3A4 and its exposure can be significantly altered by strong or moderate CYP3A modulators. Food increases the bioavailability of Naloxegol, and the relative bioavailability of the tablet formulation was not limited by dissolution. Naloxegol in the dose range of 8–125 mg can antagonize morphine-induced peripheral effects without impacting the effect of morphine on the central nervous system, consistent with a peripheral mode of action.
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effects of cyp3a modulators on the pharmacokinetics of Naloxegol
The Journal of Clinical Pharmacology, 2016Co-Authors: Khanh Bui, Fahua She, Mark Sostek, Diansong Zhou, Nidal AlhunitiAbstract: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.
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population exposure response modeling of Naloxegol in patients with noncancer related pain and opioid induced constipation
CPT: Pharmacometrics & Systems Pharmacology, 2016Co-Authors: Nidal Alhuniti, Jaakko Lappalainen, J C Nielsen, M M Hutmacher, K Cantagallo, Mark SostekAbstract:Naloxegol is a polyethylene glycol derivative of naloxone approved in the US as a once-daily oral treatment for opioid-induced constipation (OIC) in adults with chronic noncancer pain. Population exposure-response models were constructed based on data from two phase III studies comprising 1,331 adults with noncancer pain and OIC. In order to characterize the protocol-defined Naloxegol responder rate, the number of daily spontaneous bowel movements (SBMs) was characterized by a longitudinal ordinal nonlinear mixed-effects logistic regression dose-response model, and the incidence of diary entry discontinuation was described by a time-to-event model. The mean number of SBMs per week increased with increasing Naloxegol dose. The predicted placebo-adjusted responder rates (90% confidence interval) were 10.4% (4.6-13.4%) and 11.1% (4.8-14.4%) for Naloxegol 12.5 and 25 mg/day, respectively. Model-predicted response to Naloxegol was influenced by the baseline SBM frequency and characteristics of the opioid treatment.
Jaakko Lappalainen - One of the best experts on this subject based on the ideXlab platform.
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a 12 week extension study to assess the safety and tolerability of Naloxegol in patients with noncancer pain and opioid induced constipation
Journal of opioid management, 2016Co-Authors: Lynn R Webster, Raj Tummala, Ulysses Diva, Jaakko LappalainenAbstract:Objective: To compare the long-term safety and tolerability of Naloxegol with placebo in patients with opioid-induced constipation (OIC) and noncancer pain. Design: Twelve-week, multicenter, randomized, double-blind, parallel-group phase 3 extension study (KODIAC-07, NCT01395524). Setting: Clinical investigation centers in the United States. Patients: Adult outpatients (N = 302) with confirmed OIC who had completed a 12-week pivotal phase 3 study (KODIAC-04, NCT01309841). Interventions: Daily oral administration of Naloxegol (12.5 and 25 mg) or placebo. Main Outcome Measures: Adverse events (AEs), including treatment-related AEs, serious AEs, and AEs of special interest; changes from baseline to week 12 in pain scores, daily opioid dose, and symptoms and quality-of-life measurements. Results: No important new AEs occurred during this extension study compared with KODIAC-04. AEs occurred more frequently with Naloxegol 25 mg (41.2 percent) versus Naloxegol 12.5 mg (34.0 percent) and placebo (33.0 percent). Treatment-emergent AEs occurring in >5 percent of patients in either Naloxegol group during the treatment period were arthralgia (25 mg; 5.2 percent) and diarrhea (12.5 mg; 5.3 percent); two reported AEs attributable to opioid withdrawal syndrome in Naloxegol groups were deemed unrelated to study medication. None of the gastrointestinal serious AEs was adjudicated as bowel perforation; one patient (Naloxegol 12.5 mg) had an event adjudicated as a major cardiovascular event and was unrelated to study medication. Pain scores and daily opioid dose were unchanged, and improvements in symptoms and quality-of-life observed in KODIAC-04 were maintained throughout the extension study. Conclusion: Naloxegol was generally safe and well tolerated in this 12-week extension study in patients with noncancer pain and OIC.
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population exposure response modeling of Naloxegol in patients with noncancer related pain and opioid induced constipation
CPT: Pharmacometrics & Systems Pharmacology, 2016Co-Authors: Nidal Alhuniti, Jaakko Lappalainen, J C Nielsen, M M Hutmacher, K Cantagallo, Mark SostekAbstract:Naloxegol is a polyethylene glycol derivative of naloxone approved in the US as a once-daily oral treatment for opioid-induced constipation (OIC) in adults with chronic noncancer pain. Population exposure-response models were constructed based on data from two phase III studies comprising 1,331 adults with noncancer pain and OIC. In order to characterize the protocol-defined Naloxegol responder rate, the number of daily spontaneous bowel movements (SBMs) was characterized by a longitudinal ordinal nonlinear mixed-effects logistic regression dose-response model, and the incidence of diary entry discontinuation was described by a time-to-event model. The mean number of SBMs per week increased with increasing Naloxegol dose. The predicted placebo-adjusted responder rates (90% confidence interval) were 10.4% (4.6-13.4%) and 11.1% (4.8-14.4%) for Naloxegol 12.5 and 25 mg/day, respectively. Model-predicted response to Naloxegol was influenced by the baseline SBM frequency and characteristics of the opioid treatment.
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efficacy and safety of Naloxegol in patients with opioid induced constipation and laxative inadequate response
United European gastroenterology journal, 2015Co-Authors: Jan Tack, Jaakko Lappalainen, Ulysses Diva, Raj Tummala, Mark SostekAbstract: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 (12.5mg, n ¼240; 25mg, n ¼241) or placebo (n ¼239) 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 ¼0.005) 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 25mg, Naloxegol 12.5mg 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
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randomised clinical trial the long term safety and tolerability of Naloxegol in patients with pain and opioid induced constipation
Alimentary Pharmacology & Therapeutics, 2014Co-Authors: Lynn R Webster, Jan Tack, Jaakko Lappalainen, Ulysses Diva, William D Chey, Mark SostekAbstract:SummaryBackground Opioid-induced constipation (OIC) is a common adverse effect of opioid therapy. Aim To evaluate the long-term safety and tolerability of Naloxegol, an oral, peripherally acting μ-opioid receptor antagonist (PAMORA), in patients with noncancer pain and OIC. Methods A 52-week, multicenter, open-label, randomised, parallel-group phase 3 study was conducted in out-patients taking 30–1000 morphine-equivalent units per day for ≥4 weeks. Patients were randomised 2:1 to receive Naloxegol 25 mg/day or usual-care (UC; investigator-chosen laxative regimen) treatment for OIC. Results The safety set comprised 804 patients (Naloxegol, n = 534; UC, n = 270). Mean exposure duration was 268 days with Naloxegol and 297 days with UC. Frequency of adverse events (AEs) was 81.8% with Naloxegol and 72.2% with UC. Treatment-emergent AEs occurring more frequently for Naloxegol vs. UC were abdominal pain (17.8% vs. 3.3%), diarrhoea (12.9% vs. 5.9%), nausea (9.4% vs. 4.1%), headache (9.0% vs. 4.8%), flatulence (6.9% vs. 1.1%) and upper abdominal pain (5.1% vs. 1.1%). Most Naloxegol-emergent gastrointestinal AEs occurred early, resolving during or after Naloxegol discontinuation and were mild or moderate in severity; 11 patients discontinued due to diarrhoea and nine patients owing to abdominal pain. Pain scores and mean daily opioid doses remained stable throughout the study; no attributable opioid withdrawal AEs were observed. Two patients in each group had an adjudicated major adverse cardiovascular event unrelated to study drug; no AEs were reported nor adjudicated as bowel perforations. Conclusion In patients with noncancer pain and opioid-induced constipation, Naloxegol 25 mg/day up to 52 weeks was generally safe and well tolerated.
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Naloxegol for opioid induced constipation in patients with noncancer pain
The New England Journal of Medicine, 2014Co-Authors: William D Chey, Mark Sostek, Jaakko Lappalainen, Lynn R Webster, Peter Barker, Jan TackAbstract:Background Opioid-induced constipation is common and debilitating. We investigated the efficacy and safety of Naloxegol, an oral, peripherally acting, I¼-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. R...
Jan Tack - One of the best experts on this subject based on the ideXlab platform.
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Naloxegol for patients with cancer pain diagnosed with opioid induced constipation oic nacasy observational study
Journal of Clinical Oncology, 2020Co-Authors: Andrew Davies, Jan Tack, Ana Maria Arance Fernandez, J S Chambers, Juan Luis SanzAbstract:e19350Background: Opioids have been the cornerstone of analgesic treatment for severe chronic pain. OIC is the most commonly reported adverse effect associated with opioids, and compromises patient...
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efficacy and safety of Naloxegol in patients with opioid induced constipation and laxative inadequate response
United European gastroenterology journal, 2015Co-Authors: Jan Tack, Jaakko Lappalainen, Ulysses Diva, Raj Tummala, Mark SostekAbstract: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 (12.5mg, n ¼240; 25mg, n ¼241) or placebo (n ¼239) 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 ¼0.005) 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 25mg, Naloxegol 12.5mg 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
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Naloxegol the first orally administered peripherally acting mu opioid receptor antagonist approved for the treatment of opioid induced constipation
Drugs of Today, 2015Co-Authors: Maura Corsetti, Jan TackAbstract:Treatment of opioid-induced constipation (OIC) is becoming a relevant clinical challenge as most of the treatments demonstrated to be more effective than placebo in treating OIC have safety issues limiting a broad clinical application. Naloxegol is the first orally administered, peripherally acting, µ opioid receptor antagonist approved by the FDA and EMA specifically for the treatment of noncancer patients with OIC. This review summarizes the results of the studies regarding the effects of Naloxegol in OIC. Pharmacodynamic studies have demonstrated that Naloxegol was able to inhibit gastrointestinal opioid effects while preserving central analgesic actions. Phase II and phase III studies in patients with noncancer OIC have confirmed the efficacy of Naloxegol to inhibit OIC, and the most consistent efficacy was seen with the 25-mg dose once daily. Side effects were mainly gastrointestinal in origin (and usually transient and mild) and there were no signs of opioid withdrawal in the studies. Safety and tolerability were shown in a long-term safety study. Considering its efficacy, safety, route of administration and the limitations of most of the other available treatments, Naloxegol has the potential to become the first-line treatment for noncancer patients with OIC.
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Naloxegol a new drug for the treatment of opioid induced constipation
Expert Opinion on Pharmacotherapy, 2015Co-Authors: Maura Corsetti, Jan TackAbstract:Introduction: With increasing chronic opioid use, opioid-induced constipation (OIC) is becoming a relevant clinical challenge. Presently, only few treatments have been demonstrated to be more effective than placebo in treating OIC but most of them have a restricted clinical application because of side effects. Naloxegol, an orally administered, peripherally acting, μ-opioid receptor antagonist (PAMORA), was developed for the treatment of OIC.Area covered: This review summarizes published information and presentations at meetings on the effects of Naloxegol in OIC. Pharmacodynamic studies have demonstrated that Naloxegol inhibits gastrointestinal opioid effects while preserving central analgesic actions. Phase II and Phase III studies in patients with non-cancer OIC have confirmed the efficacy of Naloxegol to inhibit OIC, and the most consistent efficacy was seen with the 25 mg dose once daily. Adverse events were mainly gastrointestinal in origin and usually transient and mild. There were no signs of opio...
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Naloxegol for the treatment of opioid induced constipation
Expert Review of Gastroenterology & Hepatology, 2014Co-Authors: Jan Tack, Maura CorsettiAbstract:With increasing chronic opioid use, opioid-induced constipation (OIC) is a rapidly increasing clinical challenge. Naloxegol, an orally administered, peripherally-acting, µ-opioid receptor antagonist, was developed for the treatment of OIC. This drug profile summarizes published information and presentations at meetings on the effects of Naloxegol in OIC. In animal studies, Naloxegol was able to inhibit gastrointestinal opioid effects while preserving central analgesic actions and human pharmacodynamic studies were in agreement with such mode of action. Phase II and Phase III studies in patients with non-cancer OIC confirmed the efficacy of Naloxegol to inhibit OIC, and the most consistent efficacy was seen with the 25 mg dose once daily. There were no signs of opioid withdrawal in these studies. Side effects were mainly gastrointestinal in origin, and usually transient and mild. A long-term safety study showed no new adverse events. The US FDA and EMA are currently evaluating the use of Naloxegol in OIC.
