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Expert Opinion on Drug Metabolism &... Dec 2007In adapting to the challenge to make more informed selection of compounds for development, the pharmaceutical industry is increasingly embracing the application of... (Review)
Review
In adapting to the challenge to make more informed selection of compounds for development, the pharmaceutical industry is increasingly embracing the application of mechanism-based models and prediction tools for prediction of pharmacokinetic parameters. This review first outlines the concepts and application of the major physiologically based prediction tools to extrapolate clearance, tissue distribution, and rate and extent of absorption from minimal in vitro or animal in vivo input data. Finally, the ability of these prediction tools, when placed within a generic whole body physiologically based model of pharmacokinetics, to predict plasma concentration-time profiles is briefly discussed.
Topics: Algorithms; Animals; Drug Industry; Humans; Metabolic Clearance Rate; Metabolic Networks and Pathways; Models, Biological; Pharmaceutical Preparations; Pharmacokinetics; Tissue Distribution
PubMed: 18028030
DOI: 10.1517/17425255.3.6.865 -
Journal of Clinical Pharmacology Feb 1988Pharmacokinetic system approaches mathematically describe a general property of a pharmacokinetic system without modeling in specific terms the kinetic processes... (Review)
Review
Pharmacokinetic system approaches mathematically describe a general property of a pharmacokinetic system without modeling in specific terms the kinetic processes responsible for the general property. Certain applications of the system approach including methods for evaluating drug delivery, drug distribution, drug secretion, and biotransformation in linear and nonlinear pharmacokinetics are presented and discussed. Linear system formulae for various mean time disposition parameters and a disposition decomposition-recomposition system approach for predicting drug levels when the drug clearance changes are presented and discussed. System approaches offer certain advantages over traditional approaches for many practical applications.
Topics: Biological Availability; Humans; Models, Biological; Pharmacokinetics
PubMed: 3283181
DOI: 10.1002/j.1552-4604.1988.tb05732.x -
British Journal of Hospital MedicinePharmacokinetic characteristics of psychotropic drugs, including their absorption, distribution, metabolism and elimination, vary greatly between drugs and between... (Review)
Review
Pharmacokinetic characteristics of psychotropic drugs, including their absorption, distribution, metabolism and elimination, vary greatly between drugs and between individual patients. Consideration of these factors is necessary for the rational prescribing of drugs in psychiatry and can prevent potentially dangerous drug interactions.
Topics: Drug Interactions; Drug Prescriptions; Humans; Intestinal Absorption; Metabolic Clearance Rate; Psychiatry; Psychotropic Drugs; Tissue Distribution
PubMed: 7952746
DOI: No ID Found -
Marine Drugs Dec 2019Fucoidan, a fucose-rich polysaccharide from brown algae, has been used for transdermalformulations targeting inflammatory skin conditions, for the treatment of...
Fucoidan, a fucose-rich polysaccharide from brown algae, has been used for transdermalformulations targeting inflammatory skin conditions, for the treatment of thrombosis, vascularpermeability diseases, subcutaneous wounds, and burns. However, the pharmacokinetics offucoidan after topical application has not been described. In this study, an ointment (OF)containing 15% fucoidan was topically applied to rats at the doses of 50-150 mg/g. The anti-Xaactivity was selected as the biomarker, and the amidolytic assay method was validated and appliedfor pharmacokinetic studies of fucoidan. Fucoidan in OF penetrated the skin and distributed intothe skin, striated muscle, and plasma with AUC0-48 = 0.94 μg·h/g, 2.22 μg·h/g, and 1.92 μg·h/mL,respectively. The longest half-life for fucoidan was observed in plasma, then in striated muscle andskin. It was found that the pharmacokinetics of fucoidan after topical OF application was linear, inthe range of 50-150 mg/kg. No accumulation of fucoidan in plasma was observed after repeatedtopical applications of 100 mg/kg during five days. Our results support the rationality of topicalapplication of formulations with fucoidan.
Topics: Administration, Cutaneous; Animals; Area Under Curve; Dermatologic Agents; Dose-Response Relationship, Drug; Half-Life; Male; Ointments; Polysaccharides; Rats; Skin Absorption; Tissue Distribution
PubMed: 31817687
DOI: 10.3390/md17120687 -
Applications and limitations of interspecies scaling and in vitro extrapolation in pharmacokinetics.Drug Metabolism and Disposition: the... Dec 1998The search for new drugs is an extremely time-consuming and costly endeavor. Much of the time and cost are expended on generating data that support the efficacy and... (Review)
Review
The search for new drugs is an extremely time-consuming and costly endeavor. Much of the time and cost are expended on generating data that support the efficacy and safety profiles of the drug. Because of ethical constraints, relevant pharmacological and toxicological assessments must be made in laboratory animals and in in vitro systems before human testing can begin. In support of the efficacy and safety evaluation during drug development, two fundamental challenges facing industrial drug metabolism scientists are (1) how to "scale-up" the pharmacokinetic data from animals to humans and (2) how to extrapolate the in vitro data to the in vivo situation. This review examines the applications and limitations of interspecies scaling and in vitro extrapolation in pharmacokinetics.
Topics: Animals; Biological Availability; Humans; Pharmacokinetics; Species Specificity
PubMed: 9860929
DOI: No ID Found -
Journal of Clinical Pharmacology Jan 2022The risk in terms of safety or diminished efficacy of switching between an originator biological product and a proposed interchangeable product is an important...
The risk in terms of safety or diminished efficacy of switching between an originator biological product and a proposed interchangeable product is an important consideration for interchangeability evaluation in the regulatory framework. This simulation study evaluated the impact of several switching study design scenarios on the pharmacokinetic (PK) assessment between a virtual originator biological product and a virtual proposed interchangeable product. Our results show that (1) at least 3 switches are needed to optimize the detection of potential PK differences, (2) the initial incidence of antidrug antibodies after treatment with the reference product in the lead-in period is a significant covariate affecting the PK results, and (3) the area under the concentration-time curve is more sensitive than peak concentration in assessing the impact of switching on PK similarity. Our simulation work illustrates that a range of factors should be carefully considered when designing a switching study for the assessment of interchangeability between 2 biological products.
Topics: Area Under Curve; Biological Products; Biosimilar Pharmaceuticals; Computer Simulation; Humans; Metabolic Clearance Rate; Models, Biological; Therapeutic Equivalency
PubMed: 34411322
DOI: 10.1002/jcph.1954 -
European Journal of Pharmaceutical... Nov 2017NNZ-2566 is a novel, small molecule being developed as a treatment for cognitive impairment in different CNS conditions, including Rett and Fragile-X syndrome, both of... (Randomized Controlled Trial)
Randomized Controlled Trial
NNZ-2566 is a novel, small molecule being developed as a treatment for cognitive impairment in different CNS conditions, including Rett and Fragile-X syndrome, both of which are associated with moderate to severe neurodevelopmental disorder. In the current study we characterise the population pharmacokinetics of NNZ-2566 after administration of single and repeated ascending doses to healthy subjects. A meta-analytical approach was used to analyse pharmacokinetic data from 3 different studies, in which a total of 61 healthy subjects (median age: 23years, range: 19 to 38) were treated with NNZ-2566. Doses of NNZ-2566 ranged from 6.0 to 100mg/kg after oral administration and from 0.1 to 30mg/kg after intravenous administration. A two-compartment model with first order absorption and elimination was found to best describe the pharmacokinetics of NNZ-2566. Inter-individual variability was identified in clearance, absorption rate, central volume of distribution, peripheral volume of distribution and inter-compartmental clearance. Population predicted clearance and central volume of distribution were 10.35L/h and 20.23L, respectively. Dose proportionality was observed across the dose range evaluated in healthy subjects. No accumulation, metabolic inhibition or induction was observed during the course of treatment. In addition, oral bioavailability appeared to vary with food intake. The relatively short half-life of 1.4h suggests the need for a twice or three times daily regimen to maintain relevant blood levels of NNZ-2566.
Topics: Administration, Intravenous; Administration, Oral; Adult; Biological Availability; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Healthy Volunteers; Humans; Male; Meta-Analysis as Topic; Metabolic Clearance Rate; Oligopeptides; Tissue Distribution; Young Adult
PubMed: 28522374
DOI: 10.1016/j.ejps.2017.05.032 -
European Journal of Drug Metabolism and... Dec 2013Physicochemical properties, such as molecular weight, size, partition coefficient, acid dissociation constant and solubility have a great impact on pharmacokinetics of... (Review)
Review
Physicochemical properties, such as molecular weight, size, partition coefficient, acid dissociation constant and solubility have a great impact on pharmacokinetics of traditional small molecule drugs and substantially used in development of small drugs. However, predicting pharmacokinetic fate (absorption, distribution, metabolism and elimination) of protein therapeutics from their physicochemical parameters is extremely difficult due to the macromolecular nature of therapeutic proteins and peptides. Their structural complexity and immunogenicity are other contributing factors that determine their biological fate. Therefore, to develop generalized strategies concerning development of therapeutic proteins and peptides are highly challenging. However, reviewing the literature, authors found that physiochemical properties, such as molecular weight, charge and structural modification are having great impact on pharmacokinetics of protein therapeutics and an attempt is made to provide the major findings in this manuscript. This manuscript will serve to provide some bases for developing protein therapeutics with desired pharmacokinetic profile.
Topics: Animals; Humans; Intestinal Absorption; Molecular Weight; Proteins; Tissue Distribution
PubMed: 23584976
DOI: 10.1007/s13318-013-0126-0 -
European Journal of Clinical... 1987The kinetic disposition of yohimbine was examined in eight young male subjects following a single oral dose of 10 mg yohimbine hydrochloride. The drug was rapidly...
The kinetic disposition of yohimbine was examined in eight young male subjects following a single oral dose of 10 mg yohimbine hydrochloride. The drug was rapidly absorbed (absorption half-time 0.17 +/- 0.11 h) and rapidly eliminated from the plasma (elimination half-life 0.60 +/- 0.26 h). This clearance of yohimbine from plasma was constant over approximately 10 elimination half-lives, suggesting that distribution into a second pharmacokinetically distinct compartment was not responsible for the rapid decline in plasma yohimbine levels. Urinary excretion and the partitioning of the drug into red blood cells (RBC) was investigated. In the 24 h following oral administration of the drug, virtually no yohimbine was eliminated in the urine (0.35 +/- 0.50% of the administered dose). Furthermore, only 20% of blood-borne yohimbine was located in RBC. These results suggest that yohimbine is eliminated primarily through metabolism since the rapid plasma clearance of yohimbine was not the result of renal elimination or sequestration by RBC.
Topics: Adult; Biological Availability; Erythrocytes; Humans; Male; Metabolic Clearance Rate; Yohimbine
PubMed: 3653227
DOI: 10.1007/BF02455991 -
JAMA May 1976The pharmacokinetic concepts introduced and defined in a preceding article are now applied to the management of drug therapy for the individual patient. The factors that...
The pharmacokinetic concepts introduced and defined in a preceding article are now applied to the management of drug therapy for the individual patient. The factors that affect the time course of drug concentrations in plasma produced by repetitive administration include the dosing rate, total clearance, biologic half-life, and systemic availability of the drug. A clinical pharmacokinetics service can monitor drug concentrations in biologic fluids, design individualized drug-dosing regimens, and carry out pharmacokinetic diagnostic work-ups to help determine the reasons for a patient's unusual response to drug therapy.
Topics: Administration, Oral; Biological Availability; Drug Therapy; Half-Life; Humans; Infusions, Parenteral; Kinetics; Metabolic Clearance Rate; Time Factors
PubMed: 946509
DOI: No ID Found