ADME Pharmacokinetics Studies
Pharmacokinetic studies are based on the exploration of drug absorption, tissue distribution, metabolism, and elimination (ADME) in the body. These different parameters give a precise idea of the distribution of the substance in the body.
Absorption: The arrival of the substance in the bloodstream. It occurs mainly in the digestive tract when administered orally. The bioavailability depends on the absorption, it will be total by intravenous route.
Distribution: Distribution into the tissues from the bloodstream. A good distribution in the appropriate tissues ensures the effectiveness of the drug. Some tissue barriers are difficult to cross, e.g., drugs that must reach the central nervous system will have to cross the blood-brain barrier, which can be a major issue in drug design. Distribution is affected by the volume of distribution.
Metabolism: This is the transformation of the substance into a metabolite. It occurs primarily in the liver and is mediated by cytochrome enzymes. It can give active or inactive forms. Oral drugs require a first pass through the liver, which can be a real problem if the drug is extensively metabolized.
Excretion: The elimination of the drug from the body takes place mainly through 3 pathways: renal for small hydrophilic molecules often, biliary for larger or hydrophobic molecules, and pulmonary for volatile substances. Elimination is assessed by clearance and elimination half-life.
sb-PEPTIDE offers to assist its partners in the realization of pharmacokinetic studies by quantifying peptide substances in specific matrix (the matrices generally used in pharmacokinetic studies are blood, plasma, serum, saliva and urine).
The data from ADME studies are taken into account by sb-PEPTIDE which provides a detailed report of the different parameters crucial in pharmacokinetic studies: C0 (initial plasma concentration), Cmax (maximum plasma concentration), tmax (time to Cmax), t1/2 (elimination half life), ke (constant elimination rate), Volume of distribution, AUC (Area Under the Curve), clearance, bioavailability, absorbed fraction
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Di L. AAPS J. (2015)
Development of peptide drugs is challenging but also quite rewarding. Five blockbuster peptide drugs are currently on the market, and six new peptides received first marketing approval as new molecular entities in 2012. Although peptides only represent 2% of the drug market, the market is growing twice as quickly and might soon occupy a larger niche. Natural peptides typically have poor absorption, distribution, metabolism, and excretion (ADME) properties with rapid clearance, short half-life, low permeability, and sometimes low solubility. Strategies have been developed to improve peptide drugability through enhancing permeability, reducing proteolysis and renal clearance, and prolonging half-life. In vivo, in vitro, and in silico tools are available to evaluate ADME properties of peptides, and structural modification strategies are in place to improve peptide developability
Vermeulen E, van den Anker JN, Della Pasqua O, Hoppu K, van der Lee JH. J Pharm Pharmacol. (2017)
How to optimise drug study design: pharmacokinetics and pharmacodynamics studies introduced to paediatricians
In children, there is often lack of sufficient information concerning the pharmacokinetics (PK) and pharmacodynamics (PD) of a study drug to support dose selection and effective evaluation of efficacy in a randomised clinical trial (RCT). Therefore, one should consider the relevance of relatively small PKPDstudies, which can provide the appropriate data to optimise the design of an RCT.
Based on the experience of experts collaborating in the EU‐funded Global Research in Paediatrics consortium, we aimed to inform clinician‐scientists working with children on the design of investigator‐initiated PKPD studies.
The importance of the identification of an optimal dose for the paediatric population is explained, followed by the differences and similarities of dose‐ranging and efficacy studies. The input of clinical pharmacologists with modelling expertise is essential for an efficient dose‐finding study.
The emergence of new laboratory techniques and statistical tools allows for the collection and analysis of sparse and unbalanced data, enabling the implementation of (observational) PKPD studies in the paediatric clinic. Understanding of the principles and methods discussed in this study is essential to improve the quality of paediatric PKPD investigations, and to prevent the conduct of paediatric RCTs that fail because of inadequate dosing.
Diao, Lei & Meibohm, Bernd. Clinical pharmacokinetics (2013)
Peptides, defined as polymers of less than 50 amino acids with a molecular weight of less than 10 kDa, represent a fast-growing class of new therapeutics which has unique pharmacokinetic characteristics compared to large proteins or small molecule drugs. Unmodified peptides usually undergo extensive proteolytic cleavage, resulting in short plasma half-lives. As a result of their low permeability and susceptibility to catabolic degradation, therapeutic peptides usually have very limited oral bioavailability and are administered either by the intravenous, subcutaneous, or intramuscular route, although other routes such as nasal delivery are utilized as well. Distribution processes are mainly driven by a combination of diffusion and to a lesser degree convective extravasation dependent on the size of the peptide, with volumes of distribution frequently not larger than the volume of the extracellular body fluid. Owing to the ubiquitous availability of proteases and peptidases throughout the body, proteolytic degradation is not limited to classic elimination organs. Since peptides are generally freely filtered by the kidneys, glomerular filtration and subsequent renal metabolism by proteolysis contribute to the elimination of many therapeutic peptides. Although small peptides have usually limited immunogenicity, formation of anti-drug antibodies with subsequent hypersensitivity reactions has been described for some peptide therapeutics. Numerous strategies have been applied to improve the pharmacokinetic properties of therapeutic peptides, especially to overcome their metabolic instability, low permeability, and limited tissue residence time. Applied techniques include amino acid substitutions, modification of the peptide terminus, inclusion of disulfide bonds, and conjugation with polymers or macromolecules such as antibody fragments or albumin. Application of model-based pharmacokinetic-pharmacodynamic correlations has been widely used for therapeutic peptides in support of drug development and dosage regimen design, especially because their targets are often well-described endogenous regulatory pathways and processes.