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

Abstract

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 (K_i = 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.

Fig. 1.

Chemical structure of naloxegol, a PEGylated derivative of naloxol, which is derived from naloxone. The box encompasses the low molecular weight polyethylene glycol (PEG) chain that is covalently bound to the morphinan ring-based structure of naloxone.

Fig. 2.

Competitive antagonism of naloxegol at the human µ-opioid receptor. The effects of 3 different concentrations of naloxegol (A) and methylnaltrexone (B) on morphine agonist concentration-response curves, as measured by guanosine 5-O-(3-[³⁵S]thio)triphosphate ([³⁵S]GTPγS binding) (1 of 3 independent experiments) are shown. Each compound elicited a rightward shift in the morphine concentration-response curve with no reduction in E_max.

Fig. 3.

Naloxegol is a competitive neutral antagonist of morphine at the human µ-opioid receptor. This Schild plot depicts the effects of naloxegol (♦) and methylnaltrexone (▪) on morphine agonist concentration-response curves at the human µ-opioid receptor, as measured by [³⁵S]GTPγS binding (pooled results of 3 independent experiments for each compound). Note the respective Schild slopes: –1.03 for naloxegol and –0.982 for methylnaltrexone. DR, dose ratio.

Fig. 4.

Quantitative whole body autoradiogram of sections through a male pigmented rat at 1 hour after the administration of a single oral dose of [¹⁴C]naloxegol (50 mg/kg). Note the absence of radioactivity in the brain.

Fig. 5.

Predicted plasma concentration-time profile for oral naloxegol 25 mg. At this maximum clinically approved dose, naloxegol exposure is predicted to be insufficient to antagonize the δ-opioid receptor. The light blue area represents the 90% confidence interval (N = 500 simulations from phase 3 studies).