Supervisors info:
Αριστείδης Δοκουμετζίδης Αναπληρωτής Καθηγητής Τμήμα Φαρμακευτικής ΕΚΠΑ,
Βαλσαμή Γεωργία Καθηγήτρια Τμήμα Φαρμακευτικής ΕΚΠΑ,
Βερτζώνη Μαρία Επίκουρη Καθηγήτρια Τμήμα Φαρμακευτικής ΕΚΠΑ
Summary:
Parkinson's disease is the second most common, chronic, progressive brain disease after Alzheimer's. Τhe disease is mainly due to the degeneration of dopamine-producing brain cells and ultimately to its lack in the brain. Ropinirole is a non-ergoline dopamine antagonist and is one of the methods to fight the symptoms of Parkinson's disease. In particular, it stimulates dopaminergic receptors and mimics the action of dopamine in the brain. It is used either as a single treatment or in combination with other drugs. In this study, experimental data on the concentration of ropinirole in the blood over time were
used. Thirty healthy volunteers (men and women, aged 19 - 44y, BMI = 19.4 - 29.8 kg/m2) who participated in a 2 × 2 bioequivalence crossover study received orally by simple administration both the original and the potentially generic 2 mg ropinirole prolonged-release tablet, in conditions of fasting. The population pharmacokinetic model was developed for each of the two formulations, to provide information on the pharmacokinetics of ropinirole and to analyze their model-based bioequivalence. The population pharmacokinetic model for both formulations was developed with nonlinear mixed effects modeling using the Monolix computer program. The models were selected based on diagnostic charts, such as observation value charts (Observation, OBS) as a function of Individual Predicted (IPRED) values, information criteria (AIC, BIC) and statistical criteria (likelihood ratio test). For the prototype product, the pharmacokinetic model is an one-compartment dual-peak absorption model, the first and the second peak follow first-order kinetics with lag time delay, the removal from the body is linear. The multiplier was selected as the error model. The between subject variability of all parameters was estimated. Age had a significant effect on the dose fraction absorbed by
the first absorption (F1) and added as a covariate to it. The same structural model presented the potentially generic product with a multiplier error model. The between subject variability was calculated for all parameters. In the product under study, age has a significant effect on both the fraction of the drug absorbed by the first absorption and the clearance (Cl) and was added as a covariate of these two parameters. The bioequivalence indices (AUC, Cmax) for both products were calculated using the results of the model via Simulx, an R function of the mlxR package, in which pharmacokinetic models from Monolix can be inserted. The indices were also calculated with the classical non-compartmental analysis. Bioequivalence analysis was performed using the calculated indices from non-compartmental analysis
and the indices based on the model. In both cases the bioequivalence of the two formulations was proved. Bioequivalence studies using model-based indicators are studied so that they can be used in cases where non-compartmental analysis fails, such as in studies with sparse data and in studies involving ethical barriers. In addition, by first developing the pharmacokinetic model, rich information is obtained regarding the drug-organism system.
Keywords:
pharmacokinetics, population pharmacokinetics, bioequivalence, non compartmental analysis, ropinirole, Monolix
