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Journal of Pharmacokinetics and... Apr 2019Here we characterize and summarize the pharmacokinetic changes for metabolized drugs when drug-drug interactions and pharmacogenomic variance are observed. Following... (Review)
Review
Here we characterize and summarize the pharmacokinetic changes for metabolized drugs when drug-drug interactions and pharmacogenomic variance are observed. Following multiple dosing to steady-state, oral systemic concentration-time curves appear to follow a one-compartment body model, with a shorter rate limiting half-life, often significantly shorter than the single dose terminal half-life. This simplified disposition model at steady-state allows comparisons of measurable parameters (i.e., area under the curve, half-life, maximum concentration and time to maximum concentration) following drug interaction or pharmacogenomic variant studies to be utilized to characterize whether a drug is low versus high hepatic extraction ratio, even without intravenous dosing. The characteristics of drugs based on the ratios of area under the curve, maximum concentration and half-life are identified with recognition that volume of distribution is essentially unchanged for drug interaction and pharmacogenomic variant studies where only metabolic outcomes are changed and transporters are not significantly involved. Comparison of maximum concentration changes following single dose interaction and pharmacogenomic variance studies may also identify the significance of intestinal first pass changes. The irrelevance of protein binding changes on pharmacodynamic outcomes following oral and intravenous dosing of low hepatic extraction ratio drugs, versus its relevance for high hepatic extraction ratio drugs is re-emphasized.
Topics: Area Under Curve; Drug Interactions; Half-Life; Humans; Metabolic Clearance Rate; Pharmaceutical Preparations; Pharmacogenetics
PubMed: 30911879
DOI: 10.1007/s10928-019-09626-7 -
Proceedings of the National Academy of... Nov 2019Messenger RNAs (mRNAs) encode information in both their primary sequence and their higher order structure. The independent contributions of factors like codon usage and...
Messenger RNAs (mRNAs) encode information in both their primary sequence and their higher order structure. The independent contributions of factors like codon usage and secondary structure to regulating protein expression are difficult to establish as they are often highly correlated in endogenous sequences. Here, we used 2 approaches, global inclusion of modified nucleotides and rational sequence design of exogenously delivered constructs, to understand the role of mRNA secondary structure independent from codon usage. Unexpectedly, highly expressed mRNAs contained a highly structured coding sequence (CDS). Modified nucleotides that stabilize mRNA secondary structure enabled high expression across a wide variety of primary sequences. Using a set of eGFP mRNAs with independently altered codon usage and CDS structure, we find that the structure of the CDS regulates protein expression through changes in functional mRNA half-life (i.e., mRNA being actively translated). This work highlights an underappreciated role of mRNA secondary structure in the regulation of mRNA stability.
Topics: Half-Life; HeLa Cells; Humans; Nucleic Acid Conformation; Protein Biosynthesis; Proteins; RNA Stability; RNA, Messenger
PubMed: 31712433
DOI: 10.1073/pnas.1908052116 -
Nature Biotechnology Feb 2010Improved affinity for the neonatal Fc receptor (FcRn) is known to extend antibody half-life in vivo. However, this has never been linked with enhanced therapeutic...
Improved affinity for the neonatal Fc receptor (FcRn) is known to extend antibody half-life in vivo. However, this has never been linked with enhanced therapeutic efficacy. We tested whether antibodies with half-lives extended up to fivefold in human (h)FcRn transgenic mice and threefold in cynomolgus monkeys retain efficacy at longer dosing intervals. We observed that prolonged exposure due to FcRn-mediated enhancement of half-life improved antitumor activity of Fc-engineered antibodies in an hFcRn/Rag1(-/-) mouse model. This bridges the demand for dosing convenience with the clinical necessity of maintaining efficacy.
Topics: Animals; Antibodies, Monoclonal; Half-Life; Macaca fascicularis; Mice; Mice, Inbred C57BL; Mice, Transgenic
PubMed: 20081867
DOI: 10.1038/nbt.1601 -
Journal of Thrombosis and Haemostasis :... Mar 2023With the goal of emphasizing the striking advances that materialized in hemophilia care particularly in the last 10 years, the progress of knowledge that started from... (Review)
Review
With the goal of emphasizing the striking advances that materialized in hemophilia care particularly in the last 10 years, the progress of knowledge that started from the 1970s will first be sketched as background. Subsequently, the unmet needs pertaining to therapeutic adherence and thus to prophylaxis effectiveness led to the availability of factor VIII and IX products with an extended plasma half-life as well as to emicizumab, the first nonfactor medicine for subcutaneous administration in patients with hemophilia A with or without inhibitor. The issue of a still lacking cure for the disease is approached by means of gene therapy, the first products of which were approved in 2022 for adults with both hemophilia types. Finally, views will be offered on further progress that is expected in the next few years and how patients and their care providers may make personalized choices among the wide array of therapeutic options.
Topics: Adult; Humans; Hemophilia A; Genetic Therapy; Half-Life; Hemostatics; Plasma
PubMed: 36858789
DOI: 10.1016/j.jtha.2022.12.029 -
Applied Radiation and Isotopes :... Dec 2022The half-lives of Sc and Sc were measured by following their decay rate using several measurement systems: two ionization chambers and three γ-spectrometry detectors...
The half-lives of Sc and Sc were measured by following their decay rate using several measurement systems: two ionization chambers and three γ-spectrometry detectors with digital and/or analogue electronics. For Sc, the result was the combination of seven half-life values giving a result of 4.042(7) h, which agrees with the last reported value of 4.042(3) h and confirms the near to 2% deviation from the recommended half-life of 3.97(4) h. Scandium-44 is present as an impurity in the production of Sc by cyclotron proton irradiation. Its half-life was determined by measurements performed a few days after End of Bomardment (EoB), so that the Sc decayed down to a negligible level. Seven measurements were combined to obtain an average of 58.7(3) h, which is in agreement with the recommended value of 58.6(1) h.
Topics: Half-Life; Scandium; Cyclotrons
PubMed: 36228535
DOI: 10.1016/j.apradiso.2022.110507 -
Blood Sep 2021
Topics: Amino Acid Sequence; Half-Life; P-Selectin
PubMed: 34591097
DOI: 10.1182/blood.2021012302 -
Molecules (Basel, Switzerland) May 2022Many therapeutic proteins are small in size and are rapidly cleared from circulation. Consequently, half-life extension strategies have emerged to improve...
Many therapeutic proteins are small in size and are rapidly cleared from circulation. Consequently, half-life extension strategies have emerged to improve pharmacokinetic properties, including fusion or binding to long-lasting serum proteins, chemical modifications with hydrophilic polymers such as PEGylation, or, more recently, fusion to PEG mimetic polypeptides. In the present study, two different PEG mimetic approaches, the GlycoTAIL and the FlexiTAIL, were applied to increase the hydrodynamic radius of antibody fragments of different sizes and valencies, including scFv, diabody, and scFv-EHD2 fusion proteins. The GlycoTAIL and FlexiTAIL sequences of varying lengths are composed of aliphatic and hydrophilic residues, with the GlycoTAIL furthermore comprising N-glycosylation sites. All modified proteins could be produced in a mammalian expression system without reducing stability and antigen binding, and all modified proteins exhibited a prolonged half-life and increased drug disposition in mice. The strongest effects were observed for proteins comprising a FlexiTAIL of 248 residues. Thus, the GlycoTAIL and FlexiTAIL sequences represent a flexible and modular system to improve the pharmacokinetic properties of proteins.
Topics: Animals; Antibodies; Carrier Proteins; Half-Life; Immunoglobulin Fragments; Mice; Recombinant Fusion Proteins
PubMed: 35630749
DOI: 10.3390/molecules27103272 -
Nucleic Acid Therapeutics Dec 2022Small interfering RNAs (siRNAs) with -acetylgalactosamine (GalNAc) conjugation for improved liver uptake represent an emerging class of drugs to treat liver diseases....
Small interfering RNAs (siRNAs) with -acetylgalactosamine (GalNAc) conjugation for improved liver uptake represent an emerging class of drugs to treat liver diseases. Understanding how pharmacokinetics and pharmacodynamics translate is pivotal for study design and human dose prediction. However, the literature is sparse on translational data for this modality, and pharmacokinetics in the liver is seldom measured. To overcome these difficulties, we collected time-course biomarker data for 11 GalNAc-siRNAs in various species and applied the kinetic-pharmacodynamic modeling approach to estimate the biophase (liver) half-life and the potency. Our analysis indicates that the biophase half-life is 0.6-3 weeks in mouse, 1-8 weeks in monkey, and 1.5-14 weeks in human. For individual siRNAs, the biophase half-life is 1-8 times longer in human than in mouse, and generally 1-3 times longer in human than in monkey. The analysis indicates that the siRNAs are more potent in human than in mouse and monkey.
Topics: Humans; Animals; Mice; RNA, Small Interfering; Half-Life
PubMed: 35867041
DOI: 10.1089/nat.2022.0010 -
The Journal of Clinical Psychiatry Jul 2022The half-life of a drug is most commonly defined as the time taken for the plasma or blood level of the drug to fall by half. Elimination half-life, pharmacologic...
The half-life of a drug is most commonly defined as the time taken for the plasma or blood level of the drug to fall by half. Elimination half-life, pharmacologic half-life, and biologic half-life are interchangeably used most commonly to describe the half-life of drugs that follow first-order or linear pharmacokinetics; that is, in single-compartment models, where the fall in blood level is proportionate to the concentration of the drug in blood. In 2 compartment models, where the drug equilibrates between blood and (for example) adipose tissue, during elimination there is a sharp initial fall in blood levels followed by a gradual subsequent fall; when drugs display this biphasic elimination pattern, the half-life corresponding to the second phase is what is clinically relevant, and this half-life is known as the terminal half-life. Half-life is influenced by drug distribution, drug metabolism, and drug excretion, each of which can be influenced by many factors such as age, use of concurrent medications, and presence of liver or renal disease. In order to maintain uniform blood levels and reduce the adverse effect risk, drugs with short half-lives need to be dosed more frequently. Drugs with short half-lives are more likely to be associated with withdrawal or discontinuation syndromes. The duration of action of a drug, time to steady state levels, and time to washout are each influenced by the value of the drug half-life. All these terms and concepts are defined and explained with the help of clinically relevant examples. Mental health care professionals who prescribe to patients need to know the half-lives of the drugs that they prescribe, the half-lives of active metabolites, if any, how these half-lives may differ with individual patient characteristics, and how to use this knowledge to prescribe to best advantage.
Topics: Half-Life; Humans; Metabolic Clearance Rate; Psychopharmacology
PubMed: 35900254
DOI: 10.4088/JCP.22f14584 -
Molecules (Basel, Switzerland) Aug 2022A search in PubMed revealed that 72 radionuclides have been considered for molecular or functional targeted radionuclide therapy. As radionuclide therapies increase in... (Review)
Review
A search in PubMed revealed that 72 radionuclides have been considered for molecular or functional targeted radionuclide therapy. As radionuclide therapies increase in number and variations, it is important to understand the role of the radionuclide and the various characteristics that can render it either useful or useless. This review focuses on the physical characteristics of radionuclides that are relevant for radionuclide therapy, such as linear energy transfer, relative biological effectiveness, range, half-life, imaging properties, and radiation protection considerations. All these properties vary considerably between radionuclides and can be optimised for specific targets. Properties that are advantageous for some applications can sometimes be drawbacks for others; for instance, radionuclides that enable easy imaging can introduce more radiation protection concerns than others. Similarly, a long radiation range is beneficial in targets with heterogeneous uptake, but it also increases the radiation dose to tissues surrounding the target, and, hence, a shorter range is likely more beneficial with homogeneous uptake. While one cannot select a collection of characteristics as each radionuclide comes with an unchangeable set, all the 72 radionuclides investigated for therapy-and many more that have not yet been investigated-provide numerous sets to choose between.
Topics: Half-Life; Radioisotopes
PubMed: 36080198
DOI: 10.3390/molecules27175429