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Clinical Pharmacokinetics Jan 2022Vancomycin is widely used in pediatric patients, however, large inter- and intraindividual variability are observed in vancomycin pharmacokinetics, affecting proper... (Review)
Review
Vancomycin is widely used in pediatric patients, however, large inter- and intraindividual variability are observed in vancomycin pharmacokinetics, affecting proper therapeutic monitoring. This review aimed at providing a comprehensive synthesis of the population pharmacokinetic models of vancomycin in pediatric patients and identifying potential factors responsible for the variability observed in various subpopulations. We conducted a literature search of the PubMed and EMBASE databases to obtain population pharmacokinetic studies for vancomycin published between January 2011 and January 2020, which resulted in a total of 33 studies. Vancomycin pharmacokinetics were generally characterized using a one-compartment model (n = 27), while a two-compartment model was used in six studies. The median (interquartile range) of the typical vancomycin clearance (CL) and the total volume of distribution adjusted to the median or mean body weight of the respective study was 0.103 L/h/kg (0.071-0.125) and 0.64 L/kg (0.59-1.03), respectively. Median weight-adjusted CL between different child age groups, such as infants and adolescents, did not appear to vary significantly, although the sample size for many age groups was very small. Examples of the conditions with relatively abnormal vancomycin pharmacokinetic values include renal insufficiency, sepsis, hematological and solid malignancy, and hypothermia treatment. Factors influencing pediatric vancomycin pharmacokinetics after adjusting for size and maturation include various renal function descriptors and some case-specific variables such as dialysate flow rate, ultrafiltrate output, and hypothermia. This review was able to document possible variables explaining the high variability observed in certain subpopulations and contrast vancomycin pharmacokinetics in different pediatric subpopulations.
Topics: Adolescent; Anti-Bacterial Agents; Area Under Curve; Child; Humans; Infant; Metabolic Clearance Rate; Models, Biological; Retrospective Studies; Sepsis; Vancomycin
PubMed: 34671937
DOI: 10.1007/s40262-021-01050-w -
International Journal of Pharmaceutics Mar 2023Food-drug interactions frequently hamper oral drug development due to various physicochemical, physiological and formulation-dependent mechanisms. This has stimulated... (Review)
Review
Food-drug interactions frequently hamper oral drug development due to various physicochemical, physiological and formulation-dependent mechanisms. This has stimulated the development of a range of promising biopharmaceutical assessment tools which, however, lack standardized settings and protocols. Hence, this manuscript aims to provide an overview of the general approach and the methodology used in food effect assessment and prediction. For in vitro dissolution-based predictions, the expected food effect mechanism should be carefully considered when selecting the level of complexity of the model, together with its drawbacks and advantages. Typically, in vitro dissolution profiles are then incorporated into physiologically based pharmacokinetic models, which can estimate the impact of food-drug interactions on bioavailability within 2-fold prediction error, at least. Positive food effects related to drug solubilization in the GI tract are easier to predict than negative food effects. Preclinical animal models also provide a good level of food effect prediction, with beagle dogs remaining the gold standard. When solubility-related food-drug interactions have large clinical impact, advanced formulation approaches can be used to improve fasted state pharmacokinetics, hence decreasing the fasted/fed difference in oral bioavailability. Finally, the knowledge from all studies should be combined to secure regulatory approval of the labelling instructions.
Topics: Animals; Dogs; Models, Biological; Intestinal Absorption; Biological Availability; Models, Animal; Drug Development; Administration, Oral; Solubility; Food-Drug Interactions
PubMed: 36801481
DOI: 10.1016/j.ijpharm.2023.122758 -
Legal Medicine (Tokyo, Japan) Jul 2021Methcathinone is one of the most commonly abused designer narcotics. The pharmacokinetics and tissue distribution of methcathinone is not well understood. In this study,...
Methcathinone is one of the most commonly abused designer narcotics. The pharmacokinetics and tissue distribution of methcathinone is not well understood. In this study, methcathinone was intravenously or intragastrically administered to rabbits in order to investigate the pharmacokinetics and tissue distribution of methcathinone. The plasma concentrations of methcathinone and its metabolite cathinone at various timepoints post-methcathinone administration as well as the distribution of methcathinone and cathinone in various tissues were determined and quantified using a liquid chromatography-tandem mass spectrometry (LC-MS/MS). According to our results, the elimination of methcathinone and cathinone was faster after intravenous administration than that after intragastric administration. The methcathinone or cathinone concentration in the plasma dramatically dropped at 16-18 h post-methcathinone administration followed by a rebound. Gastric content and stomach tissue could be better samples for the identification of methcathinone abuse by oral administration while bile and stomach tissue could be ideal samples for the identification of methcathinone abuse in intravenous injection cases. The pharmacokinetic characteristics and tissue distribution pattern of methcathinone and its metabolite cathinone described in this study could benefit future study on identification and control of methcathinone abuse in forensic toxicological analysis.
Topics: Animals; Chromatography, Liquid; Propiophenones; Rabbits; Tandem Mass Spectrometry; Tissue Distribution
PubMed: 33853008
DOI: 10.1016/j.legalmed.2021.101876 -
Journal of Clinical Pharmacology Nov 2023An objective of the Precision Medicine Initiative, launched in 2015 by the US Food and Drug Administration and National Institutes of Health, is to optimize and...
An objective of the Precision Medicine Initiative, launched in 2015 by the US Food and Drug Administration and National Institutes of Health, is to optimize and individualize dosing of drugs, especially anticancer agents, with high pharmacokinetic and pharmacodynamic variability. The American Society of Clinical Oncology recently reported that 40% of obese patients receive insufficient chemotherapy doses and exposures, which may lead to reduced efficacy, and recommended pharmacokinetic studies to guide appropriate dosing in these patients. These issues will only increase in importance as the incidence of obesity in the population increases. This publication reviews the effects of obesity on (1) tumor biology, development of cancer, and antitumor response; (2) pharmacokinetics and pharmacodynamics of small-molecule anticancer drugs; and (3) pharmacokinetics and pharmacodynamics of complex anticancer drugs, such as carrier-mediated agents and biologics. These topics are not only important from a scientific research perspective but also from a drug development and regulator perspective. Thus, it is important to evaluate the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents in all categories of body habitus and especially in patients who are obese and morbidly obese. As the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents may be highly variable across drug types, the optimal dosing metric and algorithm for difference classes of drugs may be widely different. Thus, studies are needed to evaluate current and novel metrics and methods for measuring body habitus as related to optimizing the dose and reducing pharmacokinetic and pharmacodynamic variability of anticancer agents in patients who are obese and morbidly obese.
Topics: Humans; Obesity, Morbid; Antineoplastic Agents; Pharmaceutical Preparations; Neoplasms; Drug Development; Pharmacokinetics
PubMed: 37942904
DOI: 10.1002/jcph.2326 -
Journal of Veterinary Pharmacology and... Nov 2022The aim of this study was to determine the pharmacokinetics and bioavailability of danofloxacin in swan geese (Anser cygnoides) after intravenous (IV), intramuscular...
The aim of this study was to determine the pharmacokinetics and bioavailability of danofloxacin in swan geese (Anser cygnoides) after intravenous (IV), intramuscular (IM), subcutaneous (SC), and oral (PO) administrations at 10 mg/kg dose. In this study, eight clinically healthy swan geese were used. The study was performed in four periods according to a crossover design with a 15 days washout period between two administrations. The plasma concentrations of danofloxacin were analyzed using high-performance liquid chromatograph-ultraviolet detection, and pharmacokinetic parameters were estimated by non-compartmental analysis. Following IV administration, terminal elimination half-life (t ), total clearance, and volume of distribution at steady state were 6.03 h, 0.34 L/h/kg, and 2.71 L/h/kg, respectively. After IM, SC, and PO administration, t was longer than that after IV administration. The C of danofloxacin following IM, SC, and PO administrations was 3.65, 2.76, and 1.98 μg/mL at 0.63, 1, and 2 h, respectively. The bioavailability following IM, SC, and PO administrations was 87.99, 72.77, and 57.68%, respectively. This information may help in the use of danofloxacin in geese, yet the determination of optimal dosage regimen and pharmacodynamic studies are needed.
Topics: Animals; Administration, Oral; Anti-Bacterial Agents; Area Under Curve; Biological Availability; Geese; Half-Life; Injections, Intramuscular; Injections, Intravenous; Cross-Over Studies
PubMed: 35841586
DOI: 10.1111/jvp.13086 -
The Journal of Pharmacology and... Sep 2019The use of drug delivery systems (DDS) is an attractive approach to facilitate uptake of therapeutic agents at the desired site of action, particularly when free drug... (Review)
Review
The use of drug delivery systems (DDS) is an attractive approach to facilitate uptake of therapeutic agents at the desired site of action, particularly when free drug has poor pharmacokinetics/biodistribution (PK/BD) or significant off-site toxicities. Successful translation of DDS into the clinic is dependent on a thorough understanding of the in vivo behavior of the carrier, which has, for the most part, been an elusive goal. This is, at least in part, due to significant differences in the mechanisms controlling pharmacokinetics for classic drugs and DDSs. In this review, we summarize the key physiologic mechanisms controlling the in vivo behavior of DDS, compare and contrast this with classic drugs, and describe engineering strategies designed to improve DDS PK/BD. In addition, we describe quantitative approaches that could be useful for describing PK/BD of DDS, as well as critical steps between tissue uptake and pharmacologic effect.
Topics: Animals; Drug Delivery Systems; Drug Therapy; Humans; Pharmacokinetics; Pharmacology; Tissue Distribution
PubMed: 30837281
DOI: 10.1124/jpet.119.257113 -
Pharmacological Reviews Apr 2020Technology in bioanalysis, , and computation have evolved over the past half century to allow for comprehensive assessments of the molecular to whole body pharmacology... (Review)
Review
Technology in bioanalysis, , and computation have evolved over the past half century to allow for comprehensive assessments of the molecular to whole body pharmacology of diverse corticosteroids. Such studies have advanced pharmacokinetic and pharmacodynamic (PK/PD) concepts and models that often generalize across various classes of drugs. These models encompass the "pillars" of pharmacology, namely PK and target drug exposure, the mass-law interactions of drugs with receptors/targets, and the consequent turnover and homeostatic control of genes, biomarkers, physiologic responses, and disease symptoms. Pharmacokinetic methodology utilizes noncompartmental, compartmental, reversible, physiologic [full physiologically based pharmacokinetic (PBPK) and minimal PBPK], and target-mediated drug disposition models using a growing array of pharmacometric considerations and software. Basic PK/PD models have emerged (simple direct, biophase, slow receptor binding, indirect response, irreversible, turnover with inactivation, and transduction models) that place emphasis on parsimony, are mechanistic in nature, and serve as highly useful "top-down" methods of quantitating the actions of diverse drugs. These are often components of more complex quantitative systems pharmacology (QSP) models that explain the array of responses to various drugs, including corticosteroids. Progressively deeper mechanistic appreciation of PBPK, drug-target interactions, and systems physiology from the molecular (genomic, proteomic, metabolomic) to cellular to whole body levels provides the foundation for enhanced PK/PD to comprehensive QSP models. Our research based on cell, animal, clinical, and theoretical studies with corticosteroids have provided ideas and quantitative methods that have broadly advanced the fields of PK/PD and QSP modeling and illustrates the transition toward a global, systems understanding of actions of diverse drugs. SIGNIFICANCE STATEMENT: Over the past half century, pharmacokinetics (PK) and pharmacokinetics/pharmacodynamics (PK/PD) have evolved to provide an array of mechanism-based models that help quantitate the disposition and actions of most drugs. We describe how many basic PK and PK/PD model components were identified and often applied to the diverse properties of corticosteroids (CS). The CS have complications in disposition and a wide array of simple receptor-to complex gene-mediated actions in multiple organs. Continued assessments of such complexities have offered opportunities to develop models ranging from simple PK to enhanced PK/PD to quantitative systems pharmacology (QSP) that help explain therapeutic and adverse CS effects. Concurrent development of state-of-the-art PK, PK/PD, and QSP models are described alongside experimental studies that revealed diverse CS actions.
Topics: Adrenal Cortex Hormones; Animals; Computational Biology; Humans; Models, Biological; Pharmacokinetics; Pharmacology
PubMed: 32123034
DOI: 10.1124/pr.119.018101 -
Drug Metabolism Reviews Aug 2019Phthalates are a class of compounds that have been extensively used as plasticizers in different applications. Several phthalates have been recognized as substances of... (Review)
Review
Phthalates are a class of compounds that have been extensively used as plasticizers in different applications. Several phthalates have been recognized as substances of very high concern (SVHCs) in the EU, because of their toxicity for reproduction. However, high amounts of other phthalates are still produced and imported in the European Economic Area. In China and the US, recent studies show increasing concentrations of several phthalates in the air and in human urine, respectively. The understanding of phthalate absorption, distribution, metabolism, and elimination ('pharmacokinetics') in the organism is still limited. Specifically, phthalate partitioning among tissues is insufficiently understood. Here, we estimate partition coefficient (PC) values for different phthalates by using five algorithms and compare them to experimental ( and ) PC values. In addition, we review all pharmacokinetic steps for phthalates in human and rat, based on data from 133 peer-reviewed publications. We analyze the factors that determine phthalate partitioning and pharmacokinetics. Four processes are particularly relevant to phthalate distribution: protein binding, ionization, passive partitioning, and metabolism in different tissues. The interplay of these processes needs to be better represented in methods for determining the PC values of phthalates. The hydrophobicity of phthalates affects all pharmacokinetic steps. The exposure route has an influence on specific steps of phthalate pharmacokinetics but generally does not affect the pattern of metabolites in urine. The age of the organism has an influence on phthalate metabolism. More studies on the protein-bound fraction of phthalates in plasma and pharmacokinetic studies following inhalation and dermal exposure are desirable.
Topics: Animals; Humans; Phthalic Acids; Plasticizers; Rats; Tissue Distribution
PubMed: 31116073
DOI: 10.1080/03602532.2019.1620762 -
British Journal of Clinical Pharmacology Apr 2021Mycophenolic acid (MPA) is widely used in paediatric kidney transplant patients and sometimes prescribed for additional indications. Population pharmacokinetic or... (Review)
Review
Mycophenolic acid (MPA) is widely used in paediatric kidney transplant patients and sometimes prescribed for additional indications. Population pharmacokinetic or pharmacodynamic modelling has been frequently used to characterize the fixed, random and covariate effects of MPA in adult patients. However, MPA population pharmacokinetic data in the paediatric population have not been systematically summarized. The objective of this narrative review was to provide an up-to-date critique of currently available paediatric MPA population pharmacokinetic models, with emphases on modelling techniques, pharmacological findings and clinical relevance. PubMed and EMBASE were searched from inception of database to May 2020, where a total of 11 studies have been identified representing kidney transplant (n = 4), liver transplant (n = 1), haematopoietic stem cell transplant (n = 1), idiopathic nephrotic syndrome (n = 2), systemic lupus erythematosus (n = 2), and a combined population consisted of kidney, liver and haematopoietic stem cell transplant patients (n = 1). Critical analyses were provided in the context of MPA absorption, distribution, metabolism, excretion and bioavailability in this paediatric database. Comparisons to adult patients were also provided. With respect to clinical utility, Bayesian estimation models (n = 6) with acceptable accuracy and precision for MPA exposure determination have also been identified and systematically evaluated. Overall, our analyses have identified unique features of MPA clinical pharmacology in the paediatric population, while recognizing several gaps that still warrant further investigations. This review can be used by pharmacologists and clinicians for improving MPA pharmacokinetic-pharmacodynamic modelling and patient care.
Topics: Adult; Area Under Curve; Bayes Theorem; Biological Availability; Child; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid
PubMed: 33118201
DOI: 10.1111/bcp.14590 -
Pharmaceutical Research Dec 2019Intraperitoneal (IP) route of drug administration in laboratory animals is a common practice in many in vivo studies of disease models. While this route is an easy to... (Review)
Review
Intraperitoneal (IP) route of drug administration in laboratory animals is a common practice in many in vivo studies of disease models. While this route is an easy to master, quick, suitable for chronic treatments and with low impact of stress on laboratory rodents, there is a common concern that it may not be an acceptable route for drug administration in experimental studies. The latter is likely due to sparsity of information regarding pharmacokinetics of pharmacological agents and the mechanisms through which agents get systemic exposure after IP administration. In this review, we summarize the main mechanisms involved in bioavailability of IP administered drugs and provide examples of pharmacokinetic profiles for small and large molecules in comparison to other routes of administration. We conclude with a notion that IP administration of drugs in experimental studies involving rodents is a justifiable route for pharmacological and proof-of-concept studies where the goal is to evaluate the effect(s) of target engagement rather than properties of a drug formulation and/or its pharmacokinetics for clinical translation.
Topics: Animals; Biological Availability; Drug Administration Routes; Drug Compounding; Humans; Injections, Intraperitoneal; Injections, Subcutaneous; Models, Animal; Particle Size; Pharmaceutical Preparations; Pharmacokinetics; Signal Transduction
PubMed: 31873819
DOI: 10.1007/s11095-019-2745-x