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Model-Informed Drug Development
Published in Wei Zhang, Fangrong Yan, Feng Chen, Shein-Chung Chow, Advanced Statistics in Regulatory Critical Clinical Initiatives, 2022
There are two major drug clearance routes in the human body: liver clearance and renal clearance. At present, four models for describing the drug clearance in liver are developed including: well-stirred model, parallel tube model and dispersion model [43]. In the well-stirred model, the liver is conceived to be a single well-stirred compartment with intimate mixing between portal and hepatic arterial blood in the sinusoids which can be described by the following equation.
Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Individuals with renal impairment will require adjustments based upon the degree of dysfunction. This is often estimated using formulae based upon measures of serum creatinine; however direct measures of renal function, such as creatinine or inulin clearance, are more accurate, especially in children where muscle mass may vary. In some circumstances, calculated drug clearance can be used to estimate renal dysfunction.
Neurological problems
Published in Catherine Nelson-Piercy, Handbook of Obstetric Medicine, 2020
Possible reasons for deterioration in seizure control during pregnancy include: Pregnancy itself.Poor compliance with anticonvulsant medication (due to fears regarding teratogenesis). One study using hair analysis confirmed that pregnant women commonly stop or reduce AEDs in pregnancy.Decreased drug levels related to nausea and vomiting in early pregnancy.Decreased drug levels related to increased volume of distribution and increased drug clearance through the liver and kidney. Changes in protein binding will tend to increase the free level of drugs, but this is usually outweighed by the first two factors.Lack of sleep towards term and during labour.Lack of absorption of AEDs from the gastrointestinal tract during labour.Hyperventilation during labour.
Recent advances in clearance monitoring of monoclonal antibodies in patients with inflammatory bowel diseases
Published in Expert Review of Clinical Pharmacology, 2021
Wannee Kantasiripitak, Zhigang Wang, Isabel Spriet, Marc Ferrante, Erwin Dreesen
Drug clearance is expressed as the volume of plasma in the vascular compartment that is cleared of drug per unit of time [50]. It reflects the elimination of a drug without indicating the underlying mechanisms. The elimination of mAbs occurs mainly through intracellular catabolism by lysosomal degradation to amino acids following pinocytosis (cell drinking) or receptor-mediated endocytosis [51]. Receptor-mediated endocytosis acts through Fc-gamma receptors (nonspecific elimination route) and the target antigen binding to the Fab domain (specific elimination route; target-mediated drug disposition [TMDD]) [51]. TMDD is characterized by a concentration-dependent nonlinear clearance, typically occurring at lower drug concentrations when the target is no longer saturated, resulting in an increased elimination with rapidly decreasing drug concentrations [51]. mAbs can also be cleared by binding to anti-drug antibodies [52].
Hypothesis of using albumin to improve drug efficacy in cancers accompanied by hypoalbuminemia
Published in Xenobiotica, 2021
Soghra Bagheri, Ali A. Saboury
In general, any drug is distributed in different tissues and organs after entering the bloodstream. The distribution pattern depends on physical and physiological processes. In other words, drug distribution depends on the amount of protein binding, pH, systemic and local blood flow, permeability of natural barriers (e.g. blood‐brain) and body composition (Paul 2019; Wanat 2020). In addition to the absolute amount or concentration of plasma proteins, binding to other compounds may affect binding capacity of a protein to a drug (Tesseromatis and Alevizou 2008). Only free (unbound) drug can be distributed throughout the body and have a pharmacological effect (Kok-Yong and Lawrence 2015). Of note, decreased protein binding increases the concentration of the free drug, which in fact increases the part of drug that can penetrate other parts. Of course, this also increases the drug clearance rate. In addition, the presence of larger amounts of free drug in the bloodstream causes the drug to penetrate deeper into tissues and thus increase the volume of distribution (Roberts et al. 2013). For instance, the maximum concentration of esomeprazole in the plasma of patients with hypoalbuminemia (that causes decreased protein binding) in intensive care unit has shown a significant decrease (compared to other patients) and also for these patients a larger Vd and faster clearance has been reported (Tian et al. 2018).
Drug metabolic stability in early drug discovery to develop potential lead compounds
Published in Drug Metabolism Reviews, 2021
Siva Nageswara Rao Gajula, Nimisha Nadimpalli, Rajesh Sonti
Predicting in vivo pharmacokinetic data from the in vitro drug metabolism data is of great interest in preclinical studies. Data acquired from the in vitro metabolism helps in selecting potent leads for further development. Knowledge of drug clearance provides information about the dose required to maintain steady-state plasma concentration and drug disposition description (Chiou 1982; Bardal et al. 2011). Clearance is the volume of plasma from which the drug is removed per unit of time (Chiou 1982; Bardal et al. 2011). Plasma clearance (or total systemic clearance) can be characterized by all the metabolizing and eliminating organs involved in the drug clearance (Wilkinson and Shand 1975; Dowd 2017). These organs primarily include the liver (hepatic clearance) and kidney (renal clearance). Hepatic clearance is the liver's ability to remove the drug from the blood and is related to two variables: hepatic blood flow rate and intrinsic hepatic clearance (Wilkinson and Shand 1975). On the other hand, renal clearance is the volume of blood or plasma completely cleared off the drug by the kidneys per unit time (Tucker 1981).