Chemical formula: C₃₄H₅₃NO₁₁ Molecular mass: 651.794 g/mol PubChem compound: 56959087
Naloxegol is a PEGylated derivative of the mu-opioid receptor antagonist naloxone. PEGylation reduces naloxegol’s passive permeability and also renders the compound a substrate for the P-glycoprotein transporter. Due to poorer permeability and increased efflux of naloxegol across the blood-brain barrier, related to P-gp substrate properties, the CNS penetration of naloxegol is minimal.
In vitro studies demonstrate that naloxegol is a full neutral antagonist at the mu-opioid receptor. Naloxegol acts by binding to mu-opioid receptors in the GI tract targeting the underlying causes of OIC (i.e. reduced GI motility, hypertonicity and increased fluid absorption resulting from long-term opioid treatment).
Naloxegol functions as a peripherally-acting mu-opioid receptor antagonist in the gastrointestinal tract, thereby decreasing the constipating effects of opioids without impacting opioid-mediated analgesic effects on the central nervous system.
Following oral administration, naloxegol is absorbed rapidly, with peak concentrations (Cmax) achieved at less than 2 hours. In a majority of subjects, a secondary plasma concentration peak of naloxegol was observed approximately 0.4 to 3 hours after the first peak. Enterohepatic recirculation may be an explanation as extensive biliary excretion was seen in the rat.
A high-fat meal increased the extent and rate of naloxegol absorption. The Cmax and area under the plasma concentration-time curve (AUC) were increased by approximately 30% and 45%, respectively.
Naloxegol as a crushed tablet mixed in water, given orally or administered through a nasogastric tube into the stomach, is bioequivalent to the whole tablet, with a median tmax of 0.75 and 1.50 hours (range 0.23 to 5.02 hours) for the crushed tablet given orally and the crushed tablet given via NG tube, respectively.
The mean apparent volume of distribution during the terminal phase (Vz/F) in healthy volunteers ranged from 968 to 2,140 L across dosing groups and studies. Results from a QWBA (Quantitative Whole Body Autoradiography) study in the rat and the lack of antagonism of CNS opiate effects in humans at naloxegol doses less than 250 mg, indicate minimal distribution of naloxegol into the CNS. Plasma protein binding of naloxegol in humans was low and the fraction unbound ranged from 80% to 100%.
In a mass balance study in humans, a total of 6 metabolites were identified in plasma, urine and faeces. These metabolites represented more than 32% of the administered dose and were formed via N-dealkylation, O-demethylation, oxidation and partial loss of the PEG chain. None of the metabolites were present in > 10% of the plasma concentrations of parent or total parent and metabolite related material.
Following oral administration of radiolabelled naloxegol, 68% and 16% of total administered dose were recovered in the faeces and urine, respectively. Parent naloxegol excreted in the urine accounted for less than 6% of the total administered dose. Thus renal excretion is a minor clearance pathway for naloxegol. In clinical pharmacology studies, the half-life of naloxegol at therapeutic dose ranged from 6–11 hours.
Across the range of doses evaluated peak plasma concentration and AUC increased in a dose-proportional, or approximately dose proportional, manner.
There is a small effect of age on the pharmacokinetics of naloxegol (approximately 0.7% increase in AUC for every year increase in age). No dose adjustment is recommended for elderly patients. Patients over 65 years of age have been represented in the phase III studies. Clinical studies of naloxegol did not include sufficient numbers of patients aged 75 years or over to determine whether they respond differently than younger patients, however, based on the mode of action of the active substance there are no theoretical reasons for any requirement for dose adjustments in this age group. For dose recommendations for patients with moderate or severe renal insufficiency. There is no gender effect on the PK of naloxegol.
The effect of race on the pharmacokinetics of naloxegol is small (approximately 20% decrease in the AUC of naloxegol when other groups are compared to Caucasian) and, therefore, no dose adjustment is necessary.
Naloxegol exposure was found to increase with increased weight, however, the differences in exposure were not considered clinically relevant.
As renal clearance is a minor route of elimination for naloxegol, regardless of severity (i.e. moderate, severe and end stage renal failure), the impact of renal impairment on the pharmacokinetics of naloxegol was minimal in most subjects. However, in 2 out of 8 patients (in both the moderate and severe renal impairment groups but not in the end stage renal failure group) up to 10-fold increases in the exposure of naloxegol were observed. In these patients renal impairment may adversely affect other clearance pathways (hepatic/gut drug metabolism, etc.) resulting in higher exposure. The starting dose for patients with moderate or severe renal insufficiency is 12.5 mg. If side effects impacting tolerability occur, naloxegol should be discontinued. The dose can be increased to 25 mg if 12.5 mg is well tolerated by the patient. Exposure of naloxegol in end-stage renal disease (ESRD) patients on haemodialysis was similar to healthy volunteers with normal renal function.
Less than 20% decrease in AUC and 10% decrease in Cmax were observed in patients with mild and moderate hepatic impairment (Child-Pugh Class A and B). Effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of naloxegol was not evaluated. Use in patients with severe hepatic impairment is not recommended.
The pharmacokinetics of naloxegol in the paediatric population has not been studied.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and fertility.
Embryo-foetal development studies were conducted in rats and rabbits. A potentially treatment-related increased incidence of the skeletal variant bipartite vertebral centrum and a single foetus with anorchism was seen at the highest dose tested in the rat embryo-foetal development study. A possible treatment-related foetal skeletal malformation of fused arches was noted at highest dose tested in the rabbit embryo-foetal development study, in the absence of maternal toxicity. In a separate pre- and post-natal development study in rats, body weights were lower for male pups following maternal administration at the high dose. All these effects were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Carcinogenicity studies of naloxegol were conducted in rats and mice. In male rats, a dose-related increase in Leydig cell adenomas and interstitial cell hyperplasia was observed at exposures considered sufficiently in excess of the maximum human exposure. The observed neoplastic changes are well known hormonal and centrally mediated effects in the rat which are not relevant for humans.
Studies in suckling rats have shown that naloxegol is excreted in the milk.
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