Simulation and Prediction of the Drug-Drug Interaction Potential of Naloxegol by Physiologically Based Pharmacokinetic Modeling.
Naloxegol, a peripherally acting μ-opioid receptor antagonist for the treatment of opioid-induced constipation, is a substrate for cytochrome P450 (CYP) 3A4/3A5 and the P-glycoprotein (P-gp) transporter. By integrating in silico, preclinical, and clinical pharmacokinetic (PK) findings, minimal and full physiologically based pharmacokinetic (PBPK) models were developed to predict the drug-drug interaction (DDI) potential for naloxegol. The models reasonably predicted the observed changes in naloxegol exposure with ketoconazole (increase of 13.1-fold predicted vs. 12.9-fold observed), diltiazem (increase of 2.8-fold predicted vs. 3.4-fold observed), rifampin (reduction of 76% predicted vs. 89% observed), and quinidine (increase of 1.2-fold predicted vs. 1.4-fold observed). The moderate CYP3A4 inducer efavirenz was predicted to reduce naloxegol exposure by ∼50%, whereas weak CYP3A inhibitors were predicted to minimally affect exposure. In summary, the PBPK models reasonably estimated interactions with various CYP3A modulators and can be used to guide dosing in clinical practice when naloxegol is coadministered with such agents.
AstraZeneca Pharmaceuticals, Waltham, Massachusetts, USA.
D
D
Zhou
AstraZeneca Pharmaceuticals, Waltham, Massachusetts, USA.
K
K
Bui
AstraZeneca Pharmaceuticals, Gaithersburg, Maryland, USA.
M
M
Sostek
AstraZeneca Pharmaceuticals, Waltham, Massachusetts, USA.
N
N
Al-Huniti
D000284:Administration, Oral; D003198:Computer Simulation; D065701:Cytochrome P-450 CYP3A Inducers / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions / Q000502:physiology; D005544:Forecasting; D006801:Humans; D008954:Models, Biological; D009019:Morphinans / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors
D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D009019:Morphinans; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D011092:Polyethylene Glycols; C000589308:naloxegol