Managing Drug–Drug Interactions Involving the Non‐Prescription Opioid Loperamide Through Physiologically Based Pharmacokinetic Modeling

Loperamide is a widely used nonprescription peripherally acting opioid indicated for diarrhea. Loperamide undergoes extensive first-pass metabolism, primarily by cytochrome (CYP) 3A and CYP2C8, with minor contributions from CYP2B6 and CYP2D6, and intestinal efflux by P-glycoprotein (P-gp). Increasing case reports have described exaggerated peripheral opioid effects and cardiac toxicities when ultra-high doses (> 70 mg) of loperamide are consumed alone and with CYP or P-gp inhibitors. A physiologically based pharmacokinetic (PBPK) model for loperamide was developed, verified, and applied by simulating interactions with select inhibitor drugs. The model successfully described the pharmacokinetics of loperamide (4, 8, 16 mg loperamide•HCl) in healthy adults. The predicted area under the plasma concentration-time curve (AUC) and maximum concentration (C_max) at all three doses were within 0.61-1.41-fold of observed values obtained from 10 clinical studies. The model independently well-captured the loperamide pharmacokinetic profile obtained from each of seven drug-drug interaction (DDI) studies. The inhibitor drugs tested included quinidine (P-gp), ritonavir (CYP3A/P-gp), gemfibrozil (CYP2C8), itraconazole (CYP3A/P-gp), gemfibrozil+itraconazole, and abemaciclib (CYP1A). Predicted AUC and C_max for loperamide from each DDI study were within 0.78-1.45-fold of observed values. Predicted AUC ratios (AUC of loperamide in the presence to absence of inhibitor) were within 0.78-1.09-fold of observed ratios. This novel PBPK model for loperamide could be used to guide loperamide dosing under untested DDI scenarios when the drug is coadministered with certain CYP/transporter inhibitors to minimize toxicity risk.