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Title: Development of quantitative framework for the estimation of antiparkinsonian drug exposure in elderly patients
Abstract:
Patients are recruited in clinical trials based on the strict inclusion and exclusion criteria. Despite there are strong reasoning behind such a recruitment process, the sample population in clinical trials is often less heterogenous than the real-file patients which administer the drug after its approval on a routine basis. For example, elderly patients for ethical reasons are often underrecruited in clinical trials despite the fact that most of the diseases start to develop or advance with age. The older demographics are typical for such diseases as neurodegenerative diseases, hepatic/renal impairment, or cancer. Not accounting for interindividual variability of physiological parameters which affect the drug exposure in the patients might lead to the situation when the dosing regimen established in the clinical conditions might not fit all the patients. Additionally, there are several complex clinical scenarios which are not typically tested in clinical trials. One of such examples is inhibition of one of the metabolic pathways involved in drug of interest metabolism by the coadministered drug, reduced rate of elimination by another metabolic pathway because the patient is a poor metabolizer and reduced renal elimination because of the renal impairment. Such a complex scenario might lead to the drug accumulation and result in toxicity. Another extremum is insufficient plasma ; concentration due to coadministration of enzymatic inducers and not accounting for the patient lifestyle and environmental factors affecting drug exposure. The prevalence of Parkinson’s disease is much higher after the age of 60 and elderly subjects are the target users of antiparkinsonian drugs. The precise dosing in Parkinson’s disease is directly related to the quality of patients’ life considering the fact that the disease is associated with a number of movement symptoms which should be controlled by a patienttailored therapy. At the same time, elderly are more prone to exposure-related adverse events due to the age-related decline in key physiological parameters influencing drug pharmacokinetics. Physiologically based pharmacokinetic modeling (PBPK) is a quantitative tool which might be used as a base in precision dosing for the prediction of patient-specific exposure while taking into account different clinical scenarios and patient covariates. The PBPK framework consists of three components such as drug data, systems data, and the trial design which allow to separate and study the interactions between drug- and the system-related parameters. At the same time, it allows to estimate the unknown physiological or drug parameters when having enough confidence in other drug-or system-related parameters. While the use of PBPK for the prediction of CYP-mediated drug-drug interac ; tions in healthy volunteers has become a standard practice for the internal decision making and to support regulatory approvals, there is less confidence in modeling the drug exposure in specific populations such as elderly. The purpose of this research was to develop PBPK models for two antiparkinsonian drugs with different routes of elimination: ropinirole (predominantly hepatic metabolism) and amantadine (predominantly renal excretion of the unchanged compound) and consequently apply the models for the prediction of drug exposure in elderly patients. The models were developed using middle out approach and verified based on clinical data in healthy volunteers, Parkinson’s disease patients, and healthy elderly subjects. The PBPK models have not been developed previously for these two drugs and for the first time their pharmacokinetics have been mechanistically described. The ropinirole model allowed to confirm the in vitro findings on drug metabolic pathways and their rates. In addition, the model for the prolonged release formulation allowed to confirm the assumption on biopredictiveness of the quality control dissolution data. Amantadine model for the first time described the mechanism of amantadine renal excretion, including the transporters involved in the compound’s active transport in proximal tubular cells. The developed and verified models can be applied to predict exp ; osure in different clinical scenarios, such as older age, potential inhibition of drug eliminating enzymes or transporters. The drug clearance tends to decrease with age however, several mechanistic components of such decline are still quantitatively undefined. The example of such components are metabolic enzyme or drug transporters levels and activity in elderly patients. The ropinirole PBPK model successfully extrapolated from the young healthy to elderly subjects without any modification in the absolute enzyme abundance/activity demonstrated that the parameters contributing to the metabolic clearance decline in elderly are changes in the hepatic blood flow, amount of microsomal protein in the liver, and liver weight. Therefore, the decline in the enzyme abundance appears to be related to the listed above parameters and not to the changes in the enzyme activity. For amantadine, it has been shown that the active secretion decreases almost in parallel with glomerular filtration rate which indicates that there is no decrease in transporter activity with age and it is rather the total number of nephrons which is being reduced. Such findings, especially regarding the active secretion, are filling the knowledge gaps and will hopefully accelerate the development of similar PBPK models in elderly population.
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Rada Dyscypliny Nauki farmaceutyczne
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Last modified:
Feb 27, 2025
In our library since:
Feb 27, 2025
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http://dl.cm-uj.krakow.pl:8080/publication/5223
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| Edition name | Date |
|---|---|
| ZB-142197 | Feb 27, 2025 |
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