Prediction of herb–drug interaction between hyperforin and sedative hypnotics (zolpidem, alprazolam, and midazolam) using physiologically-based pharmacokinetic modeling

Background This study investigates the interactions between various doses of hyperforin, a key compound in St. John’s Wort, and sedative hypnotics such as zolpidem, alprazolam, and midazolam. Since St John’s Wort is known to be an inducer of cytochrome P450 (CYP) 3A4, co-administration with drugs metabolized by CYP3A4 has been contraindicated. Objective We studied the risks of combination use and the possibility of safe combination by simulating the interaction of hyperforin, a key compound in St. John’s Wort, with drugs metabolized by CYP3A4 that can be used to relieve various symptoms of depression. Understanding these interactions is crucial for optimizing the treatment of depression and associated symptoms. Results The hyperforin physiologically based pharmacokinetic (PBPK) model was validated against clinical data, and PBPK models for zolpidem, alprazolam, and midazolam were used to predict herb–drug interactions. The simulations with a two-week co-administration scenario showed that hyperforin potentially acts as a weak inducer (hyperforin dose 2–20 mg, 3 times a day, AUC ratio 0.8–0.68) of 10 mg zolpidem metabolism, with sex-dependent interactions largely unaffected. However, the pharmacokinetics of alprazolam at doses of 0.25, 0.5, and 1 mg were minimally impacted (hyperforin dose 1–20 mg, 3 times a day, AUC ratio 0.96–0.87). In the case of 7.5 mg midazolam, hyperforin acted as a moderate to strong inducer (hyperforin dose 1–20 mg, 3 times a day, AUC ratio 0.26–0.20), even at low doses. Conclusions These findings emphasize the importance of careful monitoring and dose adjustments when using hyperforin and sedative hypnotics together. This study provided insights into co-administration of hyperforin and sedative hypnotics, facilitating the safe and effective use of these medications. Based on these results, it is necessary to know the possibility of safer drug combination, and to conduct clinical research and verification on this.