Clinical Pharmacokinetics and Pharmacodynamics of Naloxegol, a Peripherally Acting µ-Opioid Receptor Antagonist

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.