Search

Introduction: Drug-drug interaction (DDI) is one of the major concerns for the clinical use of NOACs in the older adults considering that coexistence of multiple diseases and comorbidity were common. Current guidelines on the DDI management were established based on clinical studies conducted in healthy adults and mainly focus on the Caucasians, whereas systemic and ethnic differences may lead to distinct management in the Chinese older adults., Objectives: To investigate the impact of aging on the DDI magnitude between P-gp and/or CYP3A4 inhibitors with dabigatran etexilate and rivaroxaban in older adults, providing additional information for the use in clinical practice., Results: Compared with the simulated adult, the AUC of the simulated older adults increased by 42-88% (DABE) and 21-60% (rivaroxaban), respectively, during NOACs monotherapy. Simulation on DDIs predicted that verapamil and clarithromycin further increase the exposure of dabigatran by 29-72% and 40-47%, whereas clarithromycin, fluconazole, and ketoconazole increase the exposure of rivaroxaban by 21-30%, 16-24%, and 194-247% in the older adults. Overall, our simulation result demonstrated that aging and DDIs both increased the exposure of NOACs. However, aging does not have a drastic impact on the extent of DDIs. The DDI ratios of young and old older adults were similar to the adults and were also similar between Caucasians and Chinese., Discussion: We further simulated the interactions under steady-state based on the EHRA guideline (2021). Our simulation results revealed that recommended reduced dosing regimen of dabigatran etexilate during comedication with verapamil and clarithromycin (110 and 75 mg BID for Chinese young and old older adults) will result in exposure (trough concentration) that was either slightly higher or similar to the trough concentration of patients with any bleeding events. Routine monitoring of bleeding risk is encouraged. Further studies on the use of rivaroxaban in Chinese older adults are warranted., Conclusion: Aging and DDI increases exposure of drug in Chinese older adults. However, aging does not have a drastic impact on the extent of DDIs. Clinical management of DDIs in Chinese older adults in the absence of complex polypharmacy can a priori be similar to the EHRA guideline but routine monitoring of bleeding risk is encouraged when dabigatran etexilate given with verapamil and clarithromycin., Competing Interests: Declaration of Competing Interest Valerie Sia Jie En, Xuan Lai, Xinyi Wu, Fan Zhang, Haiyan Li, Cheng Cui and Dongyang Liu declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript., (Copyright © 2023. Published by Elsevier B.V.)

The objective for the present analyses was to evaluate the utility of physiologically-based pharmacokinetic (PBPK) modeling for prediction of the pharmacokinetics (PK) in Chinese and Japanese populations with a panel of Pfizer internal compounds. Twelve compounds from Pfizer internal development pipeline with available Westerner PK data and available PK data in at least one of the subpopulations of Japanese and Chinese populations were identified and included in the current analysis. These selected compounds represent various elimination pathways across different therapeutic areas. The Simcyp ® PBPK simulator was used to develop and verify the PBPK models of individual compounds. The developed models for these compounds were verified by using the clinical PK data in Westerners. The verified PBPK models were further used to predict the PK of these compounds in Chinese and Japanese populations and the predicted PK parameters were compared with the observed PK parameters. Ten of the 12 compounds had PK data in Chinese, and all the 12 compounds had PK data in Japanese. In general, the PBPK models performed well in predicting PK in Chinese and Japanese, with 8 of 10 drugs in Chinese and 7 of 12 drugs in Japanese has AAFE values less than 1.25-fold. PBPK-guided predictions of the relative PK difference were successful for 75% and 50%, respectively, between Chinese and Western and between Japanese and Western of the tested drugs using 0.8-1.25 as criteria. In conclusion, well verified PBPK models developed using data from Westerners can be used to predict the PK in Chinese and Japanese populations., Competing Interests: Competing Interests: YY, JL, CM, YL, YM, RKM, ST, JL, BKG, and JL are employees of Pfizer Inc. and own stock in Pfizer Inc., (© The author(s).)

Aims: This study aims to develop and verify a physiologically based pharmacokinetic (PBPK) population model for the Chinese geriatric population in Simcyp., Methods: Firstly, physiological information for the Chinese geriatric population was collected and later employed to develop the Chinese geriatric population model by recalibration of corresponding physiological parameters in the Chinese adult population model available in Simcyp (i.e., Chinese healthy volunteer model). Secondly, drug-dependent parameters were collected for six drugs with different elimination pathways (i.e., metabolized by CYP1A2, CYP3A4 or renal excretion). The drug models were then developed and verified by clinical data from Chinese adults, Caucasian adults and Caucasian elderly subjects to ensure that drug-dependent parameters are correctly inputted. Finally, the tested drug models in combination with the newly developed Chinese geriatric population model were applied to simulate drug concentration in Chinese elderly subjects. The predicted results were then compared with the observations to evaluate model prediction performance., Results: Ninety-eight per cent of predicted AUC, 95% of predicted C max , and 100% of predicted CL values were within two-fold of the observed values, indicating all drug models were properly developed. The drug models, combined with the newly developed population model, were then used to predict pharmacokinetics in Chinese elderly subjects aged 60-93. The predicted AUC, C max , and CL values were all within two-fold of the observed values., Conclusion: The population model for the Chinese elderly subjects appears to adequately predict the concentration of the drug that was metabolized by CYP1A2, CYP3A4 or eliminated by renal clearance., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)