Prediction of Drug-Drug Interaction Potentials among Clarithromycin, Amoxicillin, Clavulanate, and Loxoprofen Using Physiologically Based Pharmacokinetic Modeling

Lower respiratory tract infections are prevalent in South Korea, and clarithromycin, amoxicillin, clavulanate, and loxoprofen are frequently prescribed for these infections.In addition, co-administration of these small molecule drugs and Korean traditional medicine (KTM) are common.Despite a growing number of patients administering these drugs in combination, their drug-drug interaction (DDI) potentials have not been examined.Therefore, our goal was to assess the potential DDIs among clarithromycin, amoxicillin, clavulanate, and loxoprofen when administered together using physiologically based pharmacokinetic (PBPK) modeling approach.The PBPK models of the drugs were constructed and validated based on the previously reported studies using SimCYP TM .Subsequently, the DDI potentials were evaluated in scenarios with one drug as the substrate (clarithromycin 250 mg, amoxicillin 250 mg, clavulanate 125 mg, and loxoprofen 60 mg) and the others as inhibitors.The simulated pharmacokinetic parameters were validated against observed data, showing good agreement within predefined criteria (0.5-2.0).The observed data fell within the 5th to 95th confidence interval of the simulated data, indicating accurate description of plasma concentration-time profiles.Assessing DDI potentials through AUC ratios (with inhibitors/without inhibitors), the predicted AUC ratios ranged from 0.89 to 1.03, indicating no significant DDIs (criteria: 0.80-1.25).In summary, our study supports the safe use of a combination of clarithromycin, amoxicillin, clavulanate, and loxoprofen.