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Pharmacokinetic Evaluation and Modeling of Clinically Significant Drug MetabolitesDrug metabolism is a part of the absorption-desorption processes, activation-detoxification, distribution, elimination, safety and therapeutic efficacy of practically all drugs. The kinetics of plasma metabolites are correlated with the release, absorption, metabolism and elimination of administered (“parent”) drugs, quality, rate and extent of therapeutic effect.
To prevent drug failure at later stages of development as a result of toxic metabolites, drug-drug interactions, and polymorphic metabolism, preclinical and clinical pharmacology studies are conducted for identification and modelling of metabolic profiles. The interplay between drug transport and metabolism in oral bioavailability are evaluated to obtain information on the pharmacokinetic/pharmacodynamic (PK/PD) mechanisms underlying drug bioavailability and response, or for evaluation of the bioequivalence of different formulations. The in vitro - in vivo correlations are used for predicting pharmacokinetics and/or biowaiver of bioequivalence studies.
Clinical implications of genetic polymorphisms in drug metabolism are studied for elaboration of general and personalized therapeutic schemes, especially in case of active metabolites.
The pharmacokinetics of metabolites is highly variable due to the unpredictable in-vivo release and absorption of parent drugs, the inter-subjects variability (the two extremes being extensive and poor metabolizers), drug-drug interactions, and interactions with efflux transport systems.
The use of PK of metabolites in the evaluation of bioequivalence is a difficult challenge. There are critical situations that cannot be solved without evaluation of metabolites if: (a) the parent drug levels in plasma are too low to allow accurate analytical measurements, (b) the parent drug is unstable in the biological matrix, (c) the parent drug is an inactive prodrug, (d) the formation of the metabolite occurs rapidly, and (e) the metabolite contributes significantly to the net activity.
Correlations between in-vitro dissolution and in-vivo pharmacokinetics, as well as pharmacokinetics with pharmacodynamics for drugs with significant metabolism, fail to lead to reliable relationships.
New advances in metabolite PK modelling and valorization were recently proposed. The first proposed direction is metabolite modelling in plasma as diffusion from reservoirs, coupled with distribution, further extends metabolization and elimination. The other proposed direction is studying the correlation between the dissolution kinetics of a parent drugs in-vitro, and the kinetics of its metabolites in plasma, estimated by deconvolution of their pharmacokinetic data that could permit waivers of in-vivo studies for bioequivalence. Correlation of these results with results obtained by usual methods could promote progress in evaluation, modeling and estimation of part played by major and/or active metabolites in prediction of safety and efficacy of drugs.
Last but not least, recommendations concerning adjustment of treatment in case of drugs with active metabolites for particularly poor or extensive metabolizers are hoped.
In this Research Topic, the editorial team welcome contributions concerning:
- Correlation between in-vitro dissolution of parent drugs and pharmacokinetic of metabolites and possibility of biowaiver,
- PK of metabolites in evaluation of bioequivalence (BE)
- PK of metabolites in case of prodrugs
- Bioanalytical methods for concomitant evaluation of PD and major or active metabolites
- Modelling of the PK of metabolites, of enterohepatic circulation
- Development of biorelevant dissolution tests in-vitro for drugs with extensive metabolism
- in silico - in vitro- in vivo correlation and modelling
- Presystemic metabolism
- Extensive first pass metabolism
- Physiologically-based pharmacokinetic
- Personalization of treatment schedules based on metabolism