Pharmacokinetics

Summary

Pharmacokinetics (from Ancient Greek pharmakon "drug" and kinetikos "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as: pharmaceutical drugs, pesticides, food additives, cosmetics, etc. It attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is completely eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, whereas pharmacodynamics (PD) is the study of how the drug affects the organism. Both together influence dosing, benefit, and adverse effects, as seen in PK/PD models. Overview Pharmacokinetics describes how the body affects a specific xenobiotic/chemical after administration through the mechanisms of absorption and distribution, as

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Protein pharmacokinetics : single-loop binders to albumin

Florian Formica

2012

Antibiotic resistance, defined as the ability of a bacteria to survive an antibiotic drug to which it was initially sensitive, has become increasingly worrying. While the discovery of antibiotics is considered to be one of the most important of all biomedical advances of the twentieth century, bacterial infections are still problematic, and the medical and financial costs that they entail are a great burden to society. In the last 30 years the number of new antibiotic approvals has been decreasing dramatically, leading to a lack of replacements for antibiotics whose effectiveness has been compromised. The drug discovery pipeline is very long and expensive with high rates of attrition at each stage of the process. Massive economic investments have attempted to address this problem but they will bear little fruit if methods are not improved to make the process faster, less expensive, and more efficient. One of the fundamental steps in the evaluation of any new compound is the characterization of the relationship between its pharmacokinetic (PK) and pharmacodynamic (PD) parameters, which will ultimately determine the optimal dosing regimen to be used in clinical trials. A more detailed understanding of these parameters can make a critical difference in early go/no-go decisions, thereby increasing the effectiveness of the drug discovery process. The use of novel assays with single-cell resolution has demonstrated how conventional measurements, taken at the population level, can hide important underlying dynamics of cellular behavior. Since none of the PK/PD models available today allow single-cell measurements, this thesis is focused on the development and implementation of new tools that address this need by enabling the study of essential parameters of antibiotic effectiveness at the single-cell level. We first assessed the effect of different isocratic concentrations of antibiotic by exposing Mycobacterium smegmatis to various concentrations of isoniazid. We find that the higher number of surviving bacteria at lower concentrations of antibiotic is entirely due to increased division rates, as killing rates remain constant. Second, in order to study more realistic pharmacokinetic profiles, we construct a novel microfluidic platform that uses computer-controlled microvalves to enable the administration of time-dependent antibiotic concentration gradients. These gradients serve as input to an array of 960 microchambers in which the cells are imaged by time-lapse microscopy. By studying uropathogenic Escherichia coli (UPEC) treated with ampicillin, we evaluated dosing regimens of intermittently dosed patients. As a proof-of-principle, we accurately predict the pharmacokinetic driver for dose-optimization. Finally, we employ quantitative phase microscopy to complement our single-cell analyses with dry-mass measurements, which give us deeper insights into fundamental processes. Interestingly, we find that this technique can be used as a more rigorous tool to identify dead cells by microscopy.

EPFL2018

Microdevice-integrated immunoassays for Point-of-Care Therapeutic Drug Monitoring

Elena-Diana Bojescu

A significant number of drugs exhibit narrow therapeutic windows and high inter-individual pharmacokinetic variability. In such cases, Therapeutic Drug Monitoring (TDM) is compulsory in order to optimize the efficacy of the drug while avoiding adverse effects. Concentration measurements required for dose-adjustments are however complex and are therefore only performed at specialized facilities. The development of a device for accurate whole-blood quantification of critical drugs at the Point-of-Care (POC) would enable fast time-to-result and provide a more convenient solution to patients. This thesis aimed at the design of sample-to-result devices comprising microstructures that allowed for the quantification of small molecules in blood. The designs were based on the development and use of miniaturized fluorescence polarization immunoassays (FPIA). The main feature offered by the FP assay format was the ability to perform homogeneous measurements with no separation or washing steps required. An important result of this thesis is the demonstration that the concentration of small drugs can be quantified in whole blood within paper-like membranes using Fluorescence Polarization Immunoassay (FPIA). Different types of paper-like materials such as glass microfibers, cellulose and filter paper were screened for artefacts such as scattering or autofluorescence. Accurate determination of the fluorescence polarization of red-emitting fluorophores at sub-nanomolar concentrations was found possible within glass fiber membranes. This enabled the development of a competitive immunoassay for the quantification of the antibiotic tobramycin using only 1 ïL of plasma in glass fiber micro-chambers. Furthermore, the same membrane was used for transversal separation of blood cells followed by accurate FPIA read-out at the bottom part of the micro-chamber. Within the therapeutic window, coefficients of variation were around 20% and recoveries between 80-105%, demonstrating the ability to run quantitatively both clinical chemistry and sample preparation by incorporating FPIA in glass fiber membranes. Another important step towards a POC device was the design of a compact, bench-top FP-based analyzer. In this case, glass capillaries were used as detection chambers as they cause little light scattering and for reasons of convenience. Furthermore, the new optical system was employed for tobramycin quantification previously spiked in plasma samples showing good analytical performance in terms of coefficients of variation and recoveries within the therapeutic range of the drug. A more challenging class of drugs are the immunosuppressants, administered in cases of organ transplantation. Here, several fluorescent derivatives of tacrolimus at different wavelengths were synthesized. Their affinity for various biorecognition molecules were tested allowing the choice of a ligand-receptor pair for the development of a FPIA for tacrolimus quantification in buffer. Next, attempts were undertaken to adapt the immunoassay for analysis in whole blood samples. Considerable challenges due to the complexity of the matrix were revealed and initiated efforts to improve the whole blood preparation techniques with the aim of quantifying tacrolimus within its therapeutic range. With the aim of paving the way towards personalized therapies, this thesis makes the realisation of a POC for TDM a realistic goal.

EPFL2018

Microdevice-integrated immunoassays for Point-of-Care Therapeutic Drug Monitoring

Elena-Diana Bojescu

EPFL2018