Exploration And Application Of Physiologically Based Pharmacokinetic Model In Clinical Medication For The Elderly Population In Chin

China’s population is aging increasingly,and it is expected that by 2050,the elderly population in China will reach 31%of the total population,entering a stage of severe aging.As the elderly age,complex pathophysiological and organ functional changes can affect the absorption,distribution,metabolism,and excretion(ADME)processes of drugs in the body,leading to increased differences in drug efficacy and safety among the elderly population.At the same time,due to the significant increase in the incidence of multiple medication and adverse drug reactions,there is generally a higher risk of medication use among the elderly population.However,in stark contrast to the complexity of medication among the elderly population,there is a general lack of evidence for the dosage of medication given to the elderly population in China.Therefore,clarifying the in vivo pharmacokinetics and potential drug-drug interactions in the elderly,developing reasonable medication plans,and achieving personalized and precise treatment are the fundamental ways to solve the problem of individualized medication in the elderly population.Physiologically based pharmacokinetic(PBPK)model can integrate physicochemical properties of drugs and human physiological parameters into the dynamic model,which can predict the pharmacokinetics(PK)characteristics of drugs in vivo.This paper intends to establish PBPK models in Chinese elderly population to evaluate exposure of commonly used drugs in the elderly and explore important physiological affecting factors,so as to provide scientific support for rational use of drugs in the elderly population.The full text of this paper is divided into three parts:(1)The first part established PBPK models of 50 drugs commonly used in the elderly:Fifty common drugs for the elderly were selected,physicochemical property parameters,pharmacokinetic parameters and clinical pharmacokinetic data were collected.And then,PBPK models of 50 drugs in Chinese elderly population were established and applied to simulate the PK characteristics of the elderly under common clinical administration schemes,providing guidance for clinical dose optimization,therapeutic drug monitoring(TDM)and individualized drug administration.(2)The second part explored the application of PBPK model in therapeutic drug monitoring:As an important method in patient management,TDM is widely used in clinical monitoring of multiple drugs.In this part,four representative drugs in the first part were taken as targets:sertraline,moclobemide(anti-depressant drug),ilaprazole(sedative-hypnotic drug),and amantadine(anti-parkinson drug).The PBPK models were used to predict the reasonable dosages,so that the drug concentrations in vivo could be within the therapeutic reference range.Finally,such predictions could provide reference for individualized drug use in the elderly population.(3)The third part is the expansion of PBPK model in special preparation:a semimechanistic PBPK model of varenicline nasal spray was established to explore the systemic and nasal PK characteristics in Chinese and American populations with different ages after intranasal administration,so as to support the clinical development and marketing of varenicline nasal spray in China.And then,the model was used to predict drug exposure in the Chinese elderly population.