Clinical utility of naloxegol in the treatment of opioid-induced constipation

Figures & data

Table 1 Details of relevant naloxegol studies

Author/year	Phase	N and population studied in	Study design and dosing	Toxicities	Efficacy measures and outcomes
Bui et al (2014)^Citation20	I	N=28 with renal impairment and eight with normal renal function	Dual center, open-label, non-randomized parallel-group study. Renal function defined by MDRD equation for eGFR: normal >80 mL/min/1.73 m^2, moderate renal impairment 30–59 mL/min/1.73 m^2, severe renal impairment <30 mL/min/1.73 m^2. Naloxegol 25 mg PO ×1 for all participants. Patients with ESRD two doses: 2 hours before dialysis and 2 hours after dialysis, 7-day washout period.	No related serious AE were reported	AUC were 1.7× greater in moderate and 2.2× greater in severe compared to normal. Cmax was 1.8× greater in severe compared to normal. No good correlation between renal clearance and total clearance as renal minor route of elimination. 1.2% removed during IHD
Bui et al (2014)^Citation19	I	N=8 normal hepatic function and eight with mild hepatic impairment	Single-dose, non-randomized, open-label, parallel-group conducted at a single center. Hepatic function defined by Child-Pugh class: class A considered mild and class B moderate. Naloxegol 25 mg PO ×1 for all participants.	No related serious AE were reported	AUC in mild hepatic 82.9% and 82.3% in moderate hepatic impairment
Webster et al (2013)^Citation17	II	N=207; ≥18 yo, receiving 30–1,000 mg of oral morphine equivalent per day for nonmalignant or cancer-related pain on stable regimen with documented OIC; exclusions: renal, hepatic or cardiovascular disease, prognosis <6 mos, Hx of GI bleeding, or GI disorder making bowel movements hard to quantify	Multicenter, randomized, DB, placebo-controlled, dose-escalation; 5 mg, 25 mg, 50 mg orally in sequential cohorts with placebo-control.	Abdominal pain, diarrhea and nausea with increased frequency and severity in 50 mg group; no evidence of opioid withdrawal or worsening pain	Primary endpoint: change in spontaneous BMs/week over baseline at the end of week 1 statistically significantly improved compared to placebo at 25 mg and 50 mg doses; secondary endpoints: change over baseline across weeks 2, 3, and 4; change over baseline at the end of week 4; time after first dose of naloxegol to first laxation; improvement over baseline compared to placebo maintained in 25 mg and 50 mg cohort over 4 weeks
Chey et al (2014)^Citation2	III	KODIAC-04: N=652; KODIAC-05: N=700; outpatients 18–84 yo on stable dose of 30–1,000 mg of oral morphine equivalents for >4 weeks with good pain control and no cancer diagnosis, GI obstruction or increased risk for bowel perforation who had confirmed, active OIC	Multicenter, randomized, DB, parallel-group, placebo-controlled; received naloxegol 12.5 mg or 25 mg or placebo for 12 weeks.	More common in 25 mg group; diarrhea, abdominal pain, nausea, vomiting; no evidence of opioid withdrawal or worsening pain	Primary endpoint: 12-week response rate (≥3 spontaneous BMs/week and inc of ≥1 spontaneous BMs over baseline for ≥9/12 weeks and ≥3/4 of the final weeks); higher response for 25 mg group over placebo for both trials and for 12.5 mg group over placebo in KODIAC-04 trial
Webster et al (2014)^Citation21	III	KODIAC-08: N=804; outpatients 18–84 yo on stable dose of 30–1,000 mg of oral morphine equivalents for >4 weeks with good pain control and no cancer diagnosis, GI obstruction or increased risk for bowel perforation who had confirmed, active OIC; some were rolled over from prior KODIAC studies	Multicenter, open-label, randomized, parallel-group; received naloxegol 25 mg or placebo.	Abdominal pain, diarrhea, nausea, headache, and flatulence; no evidence of opioid withdrawal or worsening pain	Eleven patients stopped due to diarrhea and nine due to abdominal pain; no incidences of bowel perforation or cardiovascular events considered drug-related; no evidence of opioid withdrawal or worsening pain; minimal use of bisacodyl rescue doses in treatment group

Abbreviations: AE, adverse event; AUC, area under the plasma concentration curve; BMs, bowel movements; C_max, maximum plasma concentration; DB, double blind; eGFR, estimate glomerular filtration rate; ESRD, end-stage renal disease; GI, gastrointestinal; IHD, intermittent hemodialysis; MDRD, modification of diet in renal disease; OIC, opioid-induced constipation; PO, by mouth; yo, years old; Hx, history; inc, including; mos, months.

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BuiKSheFSostekMThe effects of mild or moderate hepatic impairment on the pharmacokinetics, safety, and tolerability of naloxegolJ Clin Pharmacol201454121368137424945932

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CheyWDWebsterLSostekMLappalainenJBarkerPNTackJNaloxegol for opioid-induced constipation in patients with noncancer painN Engl J Med2014370252387239624896818

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WebsterLCheyWDTackJLappalainenJDivaUSostekMRandomised clinical trial: the long-term safety and tolerability of naloxegol in patients with pain and opioid-induced constipationAliment Pharmacol Ther201440777177925112584

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