Managing Drug Interactions Involving the Over-the-Counter Opioid Loperamide through Physiologically Based Pharmacokinetic Modeling

Abstract ID 26621 Poster Board 384 Background: Loperamide is a widely used over-the-counter opioid that is indicated for the treatment of diarrhea. The recommended dose is not to exceed 16 mg/day. Loperamide is a substrate for the efflux transporter P-glycoprotein (P-gp), which prevents loperamide entry into the brain and subsequent central opioid effects. Loperamide undergoes extensive first-pass metabolism, primarily by cytochrome (CYP) 3A and CYP2C8, with minor contributions by CYP2B6 and CYP2D6. Loperamide oral bioavailability is further limited by P-gp in the intestine. Increasing case reports have described opioid and cardiac toxicities when supratherapeutic doses of loperamide are consumed alone and in combination with CYP or P-gp inhibitors. The objective of this work was to develop and verify a physiologically based pharmacokinetic (PBPK) model of loperamide that could be used to guide loperamide dosing under various drug-drug interaction (DDI) scenarios that have not been assessed clinically and thereby minimize potential toxicities. Methods: A dose proportionality assessment of loperamide was first conducted at clinically relevant doses (4-16 mg loperamide•HCl). A PBPK model for loperamide in the absence and presence of select inhibitor drugs was next developed using the Simcyp™ simulator (v21). Physicochemical and pharmacokinetic properties for loperamide were collected from the literature or generated experimentally. Then the model was verified with data from published clinical DDI studies. Results: Loperamide exhibited linear pharmacokinetics at clinically relevant doses. The PBPK model successfully described the pharmacokinetics of loperamide in healthy adult participants at 4, 8, and 16 mg loperamide•HCl. The predicted AUC and C_max at all three doses were within 0.61- to 1.27-fold of the observed values obtained from ten clinical studies. The PBPK model independently well-captured the loperamide pharmacokinetic profile obtained from each of the eight 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). The predicted AUC and C_max for loperamide from each DDI study were within 0.78- to 1.29-fold of observed values. The predicted AUC ratios (AUC of loperamide in the presence to absence of the inhibitor) were within 0.76- to 1.03-fold of observed ratios. Conclusions: A PBPK model for loperamide was successfully developed and verified, enabling future applications. First, the model could be used to predict loperamide systemic and tissue exposure in combination with other enzyme/transporter inhibitors to assess potential safety issues at supratherapeutic exposures, including opioid and cardiac toxicities. Second, the model could be extended to assess loperamide systemic and tissue exposure in special populations, including older adults, who are particularly at risk for DDIs due to polypharmacy and co-morbidities. This work was supported by the NIH/NIGMS (R16 GM146679), NIH/NCCIH (U54 AT008909), and PSC-CUNY Award.