e CNS. Plasma protein binding of naloxegol in humans was low and the fraction unbound ranged from 80% to 100%.
Biotransformation
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.
Elimination
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.
Linearity/non-linearity
Across the range of doses eva luated peak plasma concentration and AUC increased in a dose-proportional, or approximately dose proportional, manner.
Special populations
Age and gender
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, see section 4.2. There is no gender effect on the PK of naloxegol.
Race
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.
Body weight
Naloxegol exposure was found to increase with increased weight, however, the differences in exposure were not considered clinically relevant.
Renal impairment
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 (see section 4.2). Exposure of naloxegol in end-stage renal disease (ESRD) patients on haemodialysis was similar to healthy volunteers with normal renal function.
Hepatic impairment
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). Effe |
