Population Pharmacokinetics And Pharmacodynamics Of Aspirin In Healthy Elderly Volunteers And Elderly Patients With Coronary Heart Disease

Background and Objective:Aspirin is one of the most widely used antiplatelet drugs. The clinicaleffectiveness of aspirin in the first and secondary prevention of cardiovascular eventshas been well established. In the elderly, there is a high incidence of aspirin resistanceand bleeding. It is necessary to establish an early warning system. Populationpharmacokinetics/population pharmacodynamics (PPK/PPD), was proposed as a wayto utilize sparse data and investigate the fixed effect factors(eg.height, weight, age,comorbidities, and drug combination) which affect the pharmacokinetics orpharmacodynamics parameters. In this study, we explored the populationpharmacokinetics (PPK) of aspirin in healthy elderly volunteers and elderly patientswith coronary heart disease. The fixed effect factors(Age, gender, body weight index,comorbidities) were analysed. Meanwhile, the pharmacodynamics of aspirin and theeffects of covariates were determined. In addition, the understanding of aspirinresistance was improved.Methods:23healthy elderly volunteers aged over60years who received aspirin100mgdaily more than7days were enrolled in Hebei community. Blood samples wereobtained at the eighth day before administration and1,2,3,4,5,6,8,9,10,12h afteradministration of aspirin.210senile patients with coronary heart disease who receivedaspirin were enrolled in Geriatric Cardiology unit. Blood samples were randomlyobtained at the0-24h after administration of aspirin,1-4point every patient.Salicylate concentration was measured using a validated high-performance liquidchromatographic–electrospray tandem mass spectrometry assay method. AA, ADP were measured by turbidimetric method. PAC-1, CD62P were detected by flowcytometry method. Population pharmacokinetics analysis was performed bynon-linear mixed-effect modelling and VPC method for internal validation. Partialcorrelation and Logistic methods were used in pharmacodynamics analysis.Results:The final pharmacokinetic model was a one-compartment model with first-orderabsorption and elimination. The population estimates (interindividual variability;coefficient of variation) for salicylic acid were: a clearance of6.69L/h (range5.15-8.23), a absorption rate constant of1.05h (range0.83-28.6) and a total volume ofdistribution of41.2(range26.0-56.4). The total volume of distribution in patients waslower than in healthy individuals(0.646times). Age, gender, body weight index,comorbidities has not been included in the model. However, the only covariateinfluencing the clearance was ACEI combination. VPC verification were consistentwith the model calculation.In PPD analysis, a linear correlation was found between AA、ADP、PAC-1andsalicylic acid concentration. The correlation coefficient is-1.46，-0.379，-0.059,respectively. A exponential correlation was found between CD62P and salicylic acidconcentration. ADP and PAC-1are negatively correlated with salicylic acidconcentration using partial correlation method. There was no significant correlationbetween AA, ADP, CD62p and other factors and salicylic acid concentration was theprotective factors of PAC-1in healthy elderly group. There was no significantcorrelation between the four pharmacodynamic index and salicylic acid concentrationin all enrolled cases using partial correlation analysis. Logistic regression analysesshowed diabetes and cerebral infarction history as significant predictors of AA≥20%;clopidogrel as protective factor of ADP≥70%, PAC-1≥40%and CD62P≥20%; ageand herbal drugs as risk factors of CD62P≥20%; statin as risk factors ofPAC-1≥40%. Aspirin resistance rate was4.35%, semi aspirin resistance rates were4.35%(AA≥20%),73.91%(ADP≥70%) by measuring at different time points inhealthy elderly group. Conclusion:1.The total volume of distribution in patients was lower than healthyindividuals(0.646times)2. ACEI was significantly affected aspirin clearance. Aspirin clearance is lower incombination with ACEI(0.668times)3. There was a weak linear correlation between AA、ADP、PAC-1and salicylic acidconcentration. A feeble exponential correlation was found between CD62P andsalicylic acid concentration.4. Diabetes and cerebral infarction history were the significant predictors of AA≥20%;clopidogrel was a protective factor of ADP≥70%, PAC-1≥40%and CD62P≥20%;Age and herbal drugs combination were the risk factors of CD62P≥20%; Statin wasthe risk factors of PAC-1≥40%.5.The definition of biochemical aspirin resistance needs to be furtherimproved. Single-point evaluation of platelet aggregation was unilateral. Accordingto this single-point result to change antithrombotic strategies was dangerous.