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Lemborexant, a recently approved dual orexin receptor antagonist for treatment of adults with insomnia, is eliminated primarily by cytochrome P450 (CYP)3A metabolism. The recommended dose of lemborexant is 5 mg once per night, with a maximum recommended dose of 10 mg once daily. A physiologically-based pharmacokinetic (PBPK) model for lemborexant was developed and applied to integrate data obtained from in vivo drug-drug interaction (DDI) assessments, and to further explore lemborexant interaction with CYP3A inhibitors and inducers. The model predictions were in good agreement with observed pharmacokinetic data and with DDI results from clinical studies with CYP3A inhibitors, itraconazole and fluconazole. The model further predicted that DDI effects of weak CYP3A inhibitors (fluoxetine and ranitidine) are weak, and effects of moderate inhibitors (erythromycin and verapamil) are moderate. Based on the PBPK simulations and clinical efficacy and safety data, the maximum daily recommended lemborexant dose when administered with weak CYP3A inhibitors is 5 mg; co-administration of moderate and strong inhibitors should be avoided except in countries where 2.5 mg has been approved., (© 2021 Eisai Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: To evaluate the time course of changes in perampanel levels when co-administered with carbamazepine, and following carbamazepine discontinuation, using a physiologically based pharmacokinetic (PBPK) model., Methods: The PBPK model was developed, verified using clinical PK data, and used to simulate the effect of abrupt discontinuation and down-titration (75 mg twice daily [bid]/wk) of co-administered carbamazepine 300 mg bid on the PK of perampanel once daily (qd). Perampanel dose tapering (8-4 mg) and up-titration (2-6 mg) were simulated during abrupt carbamazepine 300 mg bid discontinuation to identify a titration schedule that minimizes changes in perampanel plasma concentrations., Results: The PBPK model accurately reproduced perampanel plasma concentration-time profiles from clinical studies in single- and multiple-dose regimen simulations, including multiple-dose carbamazepine co-administration. The time course of return to pre-induced perampanel levels occurred more slowly following carbamazepine down-titration (~48 days after first down-titration) vs abrupt discontinuation (~25 days). Perampanel dose tapering (8-4 mg) at abrupt carbamazepine discontinuation produced minimal changes in steady-state concentrations, which returned to the levels observed during carbamazepine co-administration in ~15 days from the time of carbamazepine discontinuation. When perampanel was up-titrated in the presence of carbamazepine, return to steady state occurred more slowly when carbamazepine was down-titrated weekly (~45 days) vs abrupt discontinuation (~24 days)., Conclusion: This PBPK model simulated and predicted optimal perampanel dose tapering and up-titration schedules for maintaining perampanel levels during conversion to monotherapy. These results may guide physicians when managing conversion from perampanel polytherapy with concomitant enzyme-inducing anti-seizure medications to monotherapy., (© 2020 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

This work provides a perspective on the qualification and verification of physiologically based pharmacokinetic (PBPK) platforms/models intended for regulatory submission based on the collective experience of the Simcyp Consortium members. Examples of regulatory submission of PBPK analyses across various intended applications are presented and discussed. European Medicines Agency (EMA) and US Food and Drug Administration (FDA) recent draft guidelines regarding PBPK analyses and reporting are encouraging, and to advance the use and acceptability of PBPK analyses, more clarity and flexibility are warranted., (© 2018, The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug discovery and development process. A survey focusing on preclinical pharmacokinetic/pharmacodynamics (PK/PD) analysis was conducted across pharmaceutical companies that are members of the International Consortium for Quality and Innovation in Pharmaceutical Development. Based on survey responses, ~68% of companies use preclinical PK/PD analysis in all therapeutic areas indicating its broad application. An important goal of preclinical PK/PD analysis in all pharmaceutical companies is for the selection/optimization of doses and/or dose regimens, including prediction of human efficacious doses. Oncology was the therapeutic area with the most PK/PD analysis support and where it showed the most impact. Consistent use of more complex systems pharmacology models and hybrid physiologically based pharmacokinetic models with PK/PD components was less common compared to traditional PK/PD models. Preclinical PK/PD analysis is increasingly being included in regulatory submissions with ~73% of companies including these data to some degree. Most companies (~86%) have seen impact of preclinical PK/PD analyses in drug development. Finally, ~59% of pharmaceutical companies have plans to expand their PK/PD modeling groups over the next 2 years indicating continued growth. The growth of preclinical PK/PD modeling groups in pharmaceutical industry is necessary to establish required resources and skills to further expand use of preclinical PK/PD modeling in a meaningful and impactful manner.