Supervisors info:
Αριστείδης Δοκουμετζίδης, Επίκουρος Καθηγητής, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Σοφία Μαρκαντώνη-Κυρούδη, Καθηγήτρια, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Μαρία Βερτζώνη, Επίκουρη Καθηγήτρια, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Summary:
Introduction:
Clopidogrel is an antiplatelet medicine widely used nowadays in order to prevent cardiovascular event, primarily and secondary, in patients suffering from acute coronary syndrome or with previous history of myocardial infraction. Metabolized extensively from the first-pass effect, about 85% of the absorbed drug is metabolized in an inactive-carboxylic acid derivate and about 2% of the total dose prescribed is metabolized in to an active metabolite who acts as an antiplatelet agent. However, due to significant inter-individual variability, there is, in a significant number of patients, resistance in treatment with clopidogrel which is shown as reduced antiplatelet activity. There are a number of factors contributing in the development of the inter-individual variability, such as demographic factors, drug-drug interactions, presence of comorbidities and genetic polymorphisms, primarily the presence of the CYP2C19 genetic mutation of reduced activity.
Objectives:
Considering all the above, the objectives of this study is to investigate the pharmacokinetic profile of the inactive metabolite clopidogrel so as to deduce conclusions regarding clopidogrel΄s pharmacokinetics in plasma in direct correlation with the genetic profile of patients, their individual characteristics and the different bioequivalence products.
Methods: Clopidogrel΄s inactive metabolite plasma concentration (C) – time (t) data was obtained from the B Cardiology Clinic of Attikon University Hospital after the initial administration of 75, 300 or 600mg of clopidogrel the first day of the study and 75 mg dose per day for the rest of the study, a total period of 6 months or 1 year. Data were analyzed using a validated HPLC/UV methodology. Nonlinear mixed effect modeling was applied in order to describe the kinetics of inactive metabolite of clopidogrel through the usage of Monolix 2019R2 version. During the analysis, it was conducted the investigation of structural model (number of compartments, investigation of absorption kinetics) and residual error model, the possibility of non-linear elimination and the investigation of the initial estimates of the population parameters. The correlations of pharmacokinetic parameters were assessed for their impact on clopidogrel΄s inactive metabolite kinetics. Potential variables evaluated as potential covariates were sex, age, weight, height, genetic characteristics (presence of CY2PC19 reduced activity genetic mutation) and different bioequivalence clopidogrel products. Evaluation of the results was based on goodness-of-fit plots, statistical information criteria (-2LL, Akaike and Bayesian information criteria), and the physiological soundness of the derived parameters. The entire computational task was performed in Monolix 2019R2. The final model was tested for its credibility with Visual Predictive Check, the Bootstrap method and the new ability of Final Model’s Assessment provided by Monolix.
Results:
A two-compartment model with first-order absorption and linear elimination and with proportional residual error was found to describe best the C-t profiles of the carboxylic metabolite of clopidogrel. The use of one compartment or three compartments models or the option of non-linear elimination were rejected due to poor fitness in our data. The usage of the same estimation, led to the rejection of the other possible models for the residual error. The following estimates were found for the pharmacokinetic parameters: first-order absorption constant ka:0,538hr-1, total clearance Cl:1,19L/hr, apparent volume of distribution of central and peripheral compartment V1 and V2:18,4 and 1250 L and between compartments clearance Q:42,9L/hr. The majority of the values of population parameters estimated in final model had significant inter-individual variability with the exception of the between compartments clearance. Moreover, strong correlation was found between ka and central and peripheral apparent volume of distribution V1, V2 and between the two apparent volumes of distribution. The presence of CYP2C19 genetic mutation of reduced activity (GENOTYPE 1) was found to contribute significantly to total clearance Cl and between the compartment clearance Q and the option of bioequivalent clopidogrel product (DRUG 1 or 2) to peripheral apparent volume of distribution. Consequently, they introduced as covariates in the final model. Finally, the results of the final model were validated by the Bootstrap method, since its values were contained in the 90% confidence intervals and by the new assessment ability provided by Monolix since its simulated values were close to those estimated with the final model.
Conclusions:
A population pharmacokinetic model was developed for the description of the inactive-carboxylic metabolite of clopidogrel. Significant inter-individual variability was found in the majority of pharmacokinetics parameters, with the sole exception of the between the compartment’s clearance Q, which it may be attributed to the presence of comorbidities. Strong correlation was found between ka and central and peripheral apparent volume of distribution V1, V2 and between the two apparent volumes of distribution. The presence of CYP2C19 genetic mutation of reduced activity (GENOTYPE 1) was found to contribute significantly to total clearance Cl and between the compartment clearance Q and the option of bioequivalent clopidogrel product (DRUG 1 or 2) to peripheral apparent volume of distribution, with last one being important as it may affect loading doses. Further research which could introduce comorbidities as additional covariates or confirm the variability of peripheral distribution volume depending on the bioequivalent form of clopidogrel, may contribute in the confirmation of our findings and the optimization of safety and effectiveness of clopidogrel, through the conduction of indirect conclusions from the pharmacokinetics of the inactive metabolite.
Keywords:
Coronary disease, Clopidogrel, inactive-carboxylic metabolite of Clopidogrel, population pharmacokinetic model, nonlinear mixed effect analysis, bootstrap.
