Effects of CYP3A Modulators on the Pharmacokinetics of Naloxegol

Naloxegol, a peripherally acting μ-opioid receptor antagonist, was recently approved in the United States for the treatment of opioid-induced constipation. This study evaluated the effects of CYP3A inhibition and induction on the pharmacokinetics, safety, and tolerability of naloxegol. Separate open-label, nonrandomized, fixed-sequence, 3-period, 3-treatment, crossover studies of naloxegol (25 mg by mouth [PO]) in the absence or presence of the inhibitors ketoconazole (400 mg PO) and diltiazem extended release (240 mg PO), or the inducer rifampin (600 mg PO) were conducted in healthy volunteers. Area under the curve (AUC∞ ) for naloxegol was increased with coadministration of either ketoconazole (12.9-fold) or diltiazem (3.4-fold) and decreased by 89% with coadministration of rifampin compared with AUC∞ for naloxegol alone. Naloxegol was generally safe and well tolerated when given alone or coadministered with the respective CYP3A modulators; 1 subject discontinued because of elevations in liver enzymes attributed to rifampin. The exposure of naloxegol was affected substantially by ketoconazole, diltiazem, and rifampin, suggesting that it is a sensitive in vivo substrate of CYP3A4.