DOCSLIB.ORG

Pharmacokinetics, Pharmacodynamics, and Monte Carlo Simulation EDITORIAL BOARD Co-Editors: Margaret C

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Pharmacokinetics, Pharmacodynamics, and Monte Carlo Simulation EDITORIAL BOARD Co-Editors: Margaret C ® CONCISE REVIEWS OF PEDIATRIC INFECTIOUS DISEASES CONTENTS Pharmacokinetics, Pharmacodynamics, and Monte Carlo Simulation EDITORIAL BOARD Co-Editors: Margaret C. Fisher, MD, and Gary D. Overturf, MD Editors for this Issue: John S. Bradley, MD Board Members Michael Cappello, MD Charles T. Leach, MD Geoffrey A. Weinberg, MD Ellen G. Chadwick, MD Kathleen McGann, MD Leonard Weiner, MD Janet A. Englund, MD Jennifer Read, MD Charles R. Woods, MD Leonard R. Krilov, MD Jeffrey R. Starke, MD Pharmacokinetics, Pharmacodynamics, and Monte Carlo Simulation Selecting the Best Antimicrobial Dose to Treat an Infection John S. Bradley, MD,*† Samira Merali Garonzik, PharmD,‡§ Alan Forrest, PharmD,‡§ and Sujata M. Bhavnani, PharmD, MS‡§ Key Words: Monte Carlo simulation, toxicity and the development of antimicro- failure will be different than in children with antimicrobial, pharmacokinetic, pharmacodynamics bial resistance. normal renal function. Data from popula- (Pediatr Infect Dis J 2010;29: 1043–1046) tions with organ failure are becoming more VARIABILITY IN PLASMA AND widely available, increasing our knowledge of the variability of drug elimination among hen faced with a neonate, infant, or TISSUE CONCENTRATIONS ACROSS POPULATIONS those populations. The description of the Wchild with a suspected infection, the statistical characteristics of the variability of clinician must select a specific antimicrobial Given the availability of sensitive as- antimicrobial concentrations across carefully at a specific dose for a specific duration to says to measure antibiotic concentrations in defined populations is known as “population treat that infection. Many issues require care- plasma and various tissue sites using smaller pharmacokinetics.” ful consideration, and include knowledge of quantities of blood or tissue fluids, our abil- the suspected pathogens and their suscepti- ity to assess antibiotic exposures at the tissue bility to the antimicrobials under consider- level, the actual site of infection, has in- PHARMACODYNAMICS ation, the pharmacokinetic (PK) characteris- creased. As regulatory agencies request more Our understanding of how antimicro- tics of the antimicrobials, and the clinician’s sophisticated antimicrobial exposure data for bial agents eradicate bacteria has also in- assessment of the need to achieve a cure for investigational drugs, these data are fre- creased. The relationship between the anti- that particular patient (Table 1). PK and quently collected in clinical trials and thus, microbial concentrations required at the pharmacodynamics (PD) principles together are becoming more readily available for infection site over the dosing interval to with Monte Carlo simulation can assist the analysis. As a result, our knowledge of the eradicate a pathogen and hence, achieve a 3 clinician in selecting the appropriate antimi- PK of antimicrobials (ie, concentrations in cure, is known as pharmacodynamics. crobial and dosing regimen.1 Recent ad- plasma and in different tissue sites over time) These defined exposures, indexed to the min- vances in our understanding of antimicrobial and the variability inherent between patients imum inhibitory concentration (MIC) of the PK and PD have lead to important insights in receiving the same antimicrobial agent is antimicrobial to that pathogen, have been the parameters associated with a successful better understood. Both the distribution of used to evaluate the PK-PD measure that outcome, and in ways to minimize both drug antimicrobials within tissue compartments best describes antimicrobial activity for that and drug elimination differs by pediatric age particular antimicrobial/pathogen pair. The 3 group “populations,” from the neonate to the most common PK-PD measures associated From the *University of California, San Diego, CA; adolescent. Fortunately, antimicrobial PK with efficacy are (1) the percent of the dosing †Rady Children’s Hospital San Diego, San Diego, and variability in each pediatric “population” interval that a drug concentration remains CA; ‡State University of New York at Buffalo, can also be described.2 Children with organ above the MIC (%T Ͼ MIC); (2) the ratio of Buffalo, NY; and §Institute for Clinical Pharma- dysfunction may not eliminate antimicrobi- the maximal drug concentration to the MIC codynamics, Albany, NY. Copyright © 2010 by Lippincott Williams & Wilkins als as effectively as those with normal organ (Cmax:MIC); and (3) the ratio of the area ISSN: 0891-3668/10/2911-1043 function. For example, the PK of vancomy- under the drug concentration-versus-time DOI: 10.1097/INF.0b013e3181f42a53 cin in children with some degree of renal curve (AUC) to the MIC (AUC:MIC). The Concise Reviews of Pediatric Infectious Diseases (CRPIDS) topics, authors, and contents are chosen and approved indepen- dently by the Editorial Board of CRPIDS. The Pediatric Infectious Disease Journal • Volume 29, Number 11, November 2010 www.pidj.com | 1043 Concise Reviews The Pediatric Infectious Disease Journal • Volume 29, Number 11, November 2010 TABLE 1. Considerations in Antimicrobial Management of the Infected Child Patient-specific Site(s) of infection Consideration for how important it is to cure the infection (eg what risk is the clinician willing to accept for treatment failure) Patient-specific plasma antimicrobial concentrations over time Patient-specific tissue site antimicrobial concentrations over time Pathogen-specific Documented or suspected pathogen(s) Susceptibility of pathogen(s) (if cultures are positive) Variability of the susceptibilities of pathogen(s) in specimens collected in the population of children being treated, if therapy is empiric Antibiotic-specific Antibacterial spectrum of activity Antibiotic tissue penetration characteristics Variability of antimicrobial plasma and tissue concentrations over time among children in the population being treated Antimicrobial pharmacodynamics Treatment-specific Size of dose (mg/kg) Frequency of dosing Duration of dosing For aminoglycosides (eg, gentami- have the ability to acquire mechanisms of PK-PD target. The clinician compares the cin) and fluoroquinolones (eg, ciprofloxa- resistance from other bacteria. For a popula- proportion of simulated children predicted to cin), the PK-PD measure that is most pre- tion of children who are all treated for the be cured with the proportion desired to be dictive of efficacy is one for which same infection, otitis media for example, a cured (eg, 95% of children treated for pneu- bactericidal activity is concentration-de- range of susceptibilities of otitis pathogens to mococcal pneumonia should be cured when pendent (Cmax:MIC for gentamicin, and each antimicrobial can be described. Pub- treated). Such an analysis allows the clini- AUC:MIC for ciprofloxacin). In contrast, lished data are available on the susceptibility cian to understand, given the variability in amoxicillin and other beta-lactam agents of Streptococcus pneumoniae causing ear in- the inputs, the statistical likelihood of demonstrate a time-dependent pattern of fections in children from Kentucky to Costa achieving a cure for a particular child using a bactericidal activity (%T Ͼ MIC).4 There- Rica, to Israel.5–7 These data assist us in particular dosing regimen. fore, when fluoroquinolone concentrations predicting how likely an infecting pathogen To illustrate this concept, one can ex- increase, the rate and extent of bacterial erad- will be susceptible to each of several differ- amine amoxicillin treatment of pneumococ- ication will increase. For amoxicillin, maxi- ent antimicrobials we are considering for cal pneumonia. A cure is expected if amoxi- mal bacterial eradication occurs when infec- therapy. This variability in bacterial suscep- cillin concentrations are present in lung tion site concentrations exceed the MIC for tibility to specific agents can be described tissue (epithelial lining fluid) at concentra- approximately 40% of the dosing interval. and tracked as it changes over time, provid- tions above the MIC of the infecting pneu- Eradication rates do not further increase as ing the clinician with an accurate and ongo- mococcus for approximately 40% of the dos- the amoxicillin concentration at the infection ing assessment of the likelihood of drug ing interval.8 Assuming a child is infected by site increases or as the percent of time that resistance. The distribution of MIC values a relatively resistant strain demonstrating an the amoxicillin concentration is present at for specified pathogens, considered together MIC of 2.0 mcg/mL, if the child is treated the infection site above the MIC, increases with the distribution of antimicrobial expo- with 90 mg/kg/d divided into 2 doses, then beyond 40%. For each antimicrobial/patho- sure in the population of children all given only 65% of children will achieve the PK-PD gen pair, the degree of exposure described by the same antimicrobial dose, is used in the target associated with cure; if 90 mg/kg/d is the PK-PD measure, that is associated with a Monte Carlo simulation to evaluate the prob- given, but divided into 3 doses (increasing positive outcome (eg, cure), is commonly ability of achieving a cure at that dose. the duration that amoxicillin is present in referred to as the “PK-PD target.” This can lung tissue), the chance of achieving the most easily be evaluated in a nonclinical COMPUTER MODELING AND PK-PD target increases to about 90%. To system (eg, in vitro or animal infection mod- MONTE CARLO SIMULATION achieve a 95% likelihood of cure in this els), but is increasingly
Load more

Recommended publications
  • 1: Clinical Pharmacokinetics 1
    1: CLINICAL PHARMACOKINETICS 1 General overview: clinical pharmacokinetics, 2 Pharmacokinetics, 4 Drug clearance (CL), 6 Volume of distribution (Vd), 8 The half-life (t½), 10 Oral availability (F), 12 Protein binding (PB), 14 pH and pharmacokinetics, 16 1 Clinical pharmacokinetics General overview General overview: clinical pharmacokinetics 1 The ultimate aim of drug therapy is to achieve effi cacy without toxicity. This involves achieving a plasma concentration (Cp) within the ‘therapeutic window’, i.e. above the min- imal effective concentration (MEC), but below the minimal toxic concentration (MTC). Clinical pharmacokinetics is about all the factors that determine variability in the Cp and its time-course. The various factors are dealt with in subsequent chapters. Ideal therapeutics: effi cacy without toxicity Minimum Toxic Concentration (MTC) Ideal dosing Minimum Effective Concentration (MEC) Drug concentration Time The graph shows a continuous IV infusion at steady state, where the dose-rate is exactly appropriate for the patient’s clearance (CL). Inappropriate dosing Dosing too high in relation to the patient’s CL – toxicity likely Minimum Toxic Concentration (MTC) Minimum Effective Concentration (MEC) Dosing too low in relation to the Drug concentration patient’s CL – drug may be ineffective Time Some reasons for variation in CL Low CL High CL Normal variation Normal variation Renal impairment Increased renal blood fl ow Genetic poor metabolism Genetic hypermetabolism Liver impairment Enzyme induction Enzyme inhibition Old age/neonate 2 General overview Clinical Pharmacokinetics Pharmacokinetic factors determining ideal therapeutics If immediate effect is needed, a loading dose (LD) must be given to achieve a desired 1 concentration. The LD is determined by the volume of distribution (Vd).
    [Show full text]
  • Pharmacokinetics, Biodistribution, and Pharmacodynamics of Drug Delivery Systems
    JPET Fast Forward. Published on March 5, 2019 as DOI: 10.1124/jpet.119.257113 This article has not been copyedited and formatted. The final version may differ from this version. JPET # 257113 Title: Pharmacokinetic and Pharmacodynamic Properties of Drug Delivery Systems Authors: Patrick M. Glassman, Vladimir R. Muzykantov Affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania Address: 3400 Civic Center Boulevard, Bldg 421, Philadelphia, Pennsylvania 19104-5158, United States Downloaded from jpet.aspetjournals.org at ASPET Journals on September 24, 2021 1 JPET Fast Forward. Published on March 5, 2019 as DOI: 10.1124/jpet.119.257113 This article has not been copyedited and formatted. The final version may differ from this version. JPET # 257113 Running Title: PK/PD Properties of Drug Delivery Systems Corresponding Authors: Vladimir R. Muzykantov ([email protected], (215) 898-9823) and Patrick M. Glassman ([email protected]) # of Text Pages: 22 # of Tables: 2 # of Figures: 4 Word Count – Abstract: 144 Word Count – Introduction: 350 Word Count – Discussion: N/A Downloaded from Non-Standard Abbreviations: Absorption, Distribution, Metabolism, and Elimination (ADME) Biodistribution (BD) Drug Delivery Systems (DDSs) Enhanced Permeability & Retention (EPR) jpet.aspetjournals.org Gastrointestinal (GI) Intravenously (IV) Neonatal Fc Receptor (FcRn) Monoclonal Antibody (mAb) Reticuloendothelial System (RES) at ASPET Journals on September 24, 2021 Pharmacodynamics (PD) Pharmacokinetics (PK) Physiologically-Based Pharmacokinetic (PBPK) Subcutaneously (SC) Target-Mediated Drug Disposition (TMDD) Recommended Section: Drug Discovery and Translational Medicine 2 JPET Fast Forward. Published on March 5, 2019 as DOI: 10.1124/jpet.119.257113 This article has not been copyedited and formatted.
    [Show full text]
  • Clinical Pharmacology 1: Phase 1 Studies and Early Drug Development
    Clinical Pharmacology 1: Phase 1 Studies and Early Drug Development Gerlie Gieser, Ph.D. Office of Clinical Pharmacology, Div. IV Objectives • Outline the Phase 1 studies conducted to characterize the Clinical Pharmacology of a drug; describe important design elements of and the information gained from these studies. • List the Clinical Pharmacology characteristics of an Ideal Drug • Describe how the Clinical Pharmacology information from Phase 1 can help design Phase 2/3 trials • Discuss the timing of Clinical Pharmacology studies during drug development, and provide examples of how the information generated could impact the overall clinical development plan and product labeling. Phase 1 of Drug Development CLINICAL DEVELOPMENT RESEARCH PRE POST AND CLINICAL APPROVAL 1 DISCOVERY DEVELOPMENT 2 3 PHASE e e e s s s a a a h h h P P P Clinical Pharmacology Studies Initial IND (first in human) NDA/BLA SUBMISSION Phase 1 – studies designed mainly to investigate the safety/tolerability (if possible, identify MTD), pharmacokinetics and pharmacodynamics of an investigational drug in humans Clinical Pharmacology • Study of the Pharmacokinetics (PK) and Pharmacodynamics (PD) of the drug in humans – PK: what the body does to the drug (Absorption, Distribution, Metabolism, Excretion) – PD: what the drug does to the body • PK and PD profiles of the drug are influenced by physicochemical properties of the drug, product/formulation, administration route, patient’s intrinsic and extrinsic factors (e.g., organ dysfunction, diseases, concomitant medications,
    [Show full text]
  • Pharmacology Part 2: Introduction to Pharmacokinetics
    J of Nuclear Medicine Technology, first published online May 3, 2018 as doi:10.2967/jnmt.117.199638 PHARMACOLOGY PART 2: INTRODUCTION TO PHARMACOKINETICS. Geoffrey M Currie Faculty of Science, Charles Sturt University, Wagga Wagga, Australia. Regis University, Boston, USA. Correspondence: Geoff Currie Faculty of Science Locked Bag 588 Charles Sturt University Wagga Wagga 2678 Australia Telephone: 02 69332822 Facsimile: 02 69332588 Email: [email protected] Foot line: Introduction to Pharmacokinetics 1 Abstract Pharmacology principles provide key understanding that underpins the clinical and research roles of nuclear medicine practitioners. This article is the second in a series of articles that aims to enhance the understanding of pharmacological principles relevant to nuclear medicine. This article will build on the introductory concepts, terminology and principles of pharmacodynamics explored in the first article in the series. Specifically, this article will focus on the basic principles associated with pharmacokinetics. Article 3 will outline pharmacology relevant to pharmaceutical interventions and adjunctive medications employed in general nuclear medicine, the fourth pharmacology relevant to pharmaceutical interventions and adjunctive medications employed in nuclear cardiology, the fifth the pharmacology related to contrast media associated with computed tomography (CT) and magnetic resonance imaging (MRI), and the final article will address drugs in the emergency trolley. 2 Introduction As previously outlined (1), pharmacology is the scientific study of the action and effects of drugs on living systems and the interaction of drugs with living systems (1-7). For general purposes, pharmacology is divided into pharmacodynamics and pharmacokinetics (Figure 1). The principle of pharmacokinetics is captured by philosophy of Paracelsus (medieval alchemist); “only the dose makes a thing not a poison” (1,8,9).
    [Show full text]
  • Mechanism of Action Pharmacokinetics
    NDA 21-748/S-002 Page 3 Glumetza ™, 500 mg (metformin hydrochloride extended release tablets) tablet, film coated, extended release DESCRIPTION GLUMETZA (metformin hydrochloride) extended release tablet is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride (N,N- dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula of metformin hydrochloride (metformin HCl) is as shown: Metformin HCl is a white to off-white crystalline compound with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. Metformin HCl is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. GLUMETZA tablets are modified release dosage forms that contain 500 mg or 1000 mg of metformin HCl. Each 500 mg tablet contains coloring, hypromellose, magnesium stearate, microcrystalline cellulose and polyethylene oxide. Each 1000 mg tablet contains crospovidone, dibutyl sebacate, ethylcellulose, glyceryl behenate, polyvinyl alcohol, polyvinylpyrrolidone, and silicon dioxide. GLUMETZA 500 and 1000 mg tablets both utilize polymer- based, oral drug delivery systems, which allow delivery of metformin HCl to the upper gastrointestinal (GI) tract. CLINICAL PHARMACOLOGY Mechanism of Action Metformin is an antihyperglycemic agent, which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
    [Show full text]
  • Pharmacokinetics and Pharmacology of Drugs Used in Children
    Drug and Fluid Th erapy SECTION II Pharmacokinetics and Pharmacology of Drugs Used CHAPTER 6 in Children Charles J. Coté, Jerrold Lerman, Robert M. Ward, Ralph A. Lugo, and Nishan Goudsouzian Drug Distribution Propofol Protein Binding Ketamine Body Composition Etomidate Metabolism and Excretion Muscle Relaxants Hepatic Blood Flow Succinylcholine Renal Excretion Intermediate-Acting Nondepolarizing Relaxants Pharmacokinetic Principles and Calculations Atracurium First-Order Kinetics Cisatracurium Half-Life Vecuronium First-Order Single-Compartment Kinetics Rocuronium First-Order Multiple-Compartment Kinetics Clinical Implications When Using Short- and Zero-Order Kinetics Intermediate-Acting Relaxants Apparent Volume of Distribution Long-Acting Nondepolarizing Relaxants Repetitive Dosing and Drug Accumulation Pancuronium Steady State Antagonism of Muscle Relaxants Loading Dose General Principles Central Nervous System Effects Suggamadex The Drug Approval Process, the Package Insert, and Relaxants in Special Situations Drug Labeling Opioids Inhalation Anesthetic Agents Morphine Physicochemical Properties Meperidine Pharmacokinetics of Inhaled Anesthetics Hydromorphone Pharmacodynamics of Inhaled Anesthetics Oxycodone Clinical Effects Methadone Nitrous Oxide Fentanyl Environmental Impact Alfentanil Oxygen Sufentanil Intravenous Anesthetic Agents Remifentanil Barbiturates Butorphanol and Nalbuphine 89 A Practice of Anesthesia for Infants and Children Codeine Antiemetics Tramadol Metoclopramide Nonsteroidal Anti-infl ammatory Agents 5-Hydroxytryptamine
    [Show full text]
  • Review of Pharmacokinetics and Pharmacogenetics in Atypical Long-Acting Injectable Antipsychotics
    pharmaceutics Review Review of Pharmacokinetics and Pharmacogenetics in Atypical Long-Acting Injectable Antipsychotics Francisco José Toja-Camba 1,2,† , Nerea Gesto-Antelo 3,†, Olalla Maroñas 3,†, Eduardo Echarri Arrieta 4, Irene Zarra-Ferro 2,4, Miguel González-Barcia 2,4 , Enrique Bandín-Vilar 2,4 , Victor Mangas Sanjuan 2,5,6 , Fernando Facal 7,8 , Manuel Arrojo Romero 7, Angel Carracedo 3,9,10,* , Cristina Mondelo-García 2,4,* and Anxo Fernández-Ferreiro 2,4,* 1 Pharmacy Department, University Clinical Hospital of Ourense (SERGAS), Ramón Puga 52, 32005 Ourense, Spain; [email protected] 2 Clinical Pharmacology Group, Institute of Health Research (IDIS), Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; [email protected] (I.Z.-F.); [email protected] (M.G.-B.); [email protected] (E.B.-V.); [email protected] (V.M.S.) 3 Genomic Medicine Group, CIMUS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; [email protected] (N.G.-A.); [email protected] (O.M.) 4 Pharmacy Department, University Clinical Hospital of Santiago de Compostela (SERGAS), Citation: Toja-Camba, F.J.; 15706 Santiago de Compostela, Spain; [email protected] Gesto-Antelo, N.; Maroñas, O.; 5 Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Echarri Arrieta, E.; Zarra-Ferro, I.; 46100 Valencia, Spain González-Barcia, M.; Bandín-Vilar, E.; 6 Interuniversity Research Institute for Molecular Recognition and Technological Development,
    [Show full text]
  • THE ROLE of PHARMACOGENOMICS in PHARMACOKINETICS Cheryl D
    CHAPTER 5 THE ROLE OF PHARMACOGENOMICS IN PHARMACOKINETICS Cheryl D. Cropp INTRODUCTION Recent advances in personalized medicine have demonstrated that genetic variations in genes encoding for drug metabolizing enzymes (DMEs) and drug membrane transporters (DMTs) can have an important impact on drug disposition and efficacy. These variations are integral to the explanation of differences in drug disposition between and within populations. This chapter provides a general review of the role of pharmacogenomics and its established importance in the safe and effective dosing of medications. BASIC DEFINITIONS Highlighted fields of study related to drug disposition and therapeutic outcomes include: • Pharmacodynamics: What the drug does to the body. It is the science of how the drug and drug- target interact and result in a biological effect. • Pharmacogenetics: The study of genetic causes of individual DNA variations in drug response. • Pharmacogenomics: A genome-wide analysis (DNA, RNA level) of the genetic determinants of drug efficacy and toxicity. • Pharmacokinetics: What the body does to the drug. Pharmacokinetics relates to how drug concentrations of a medication change over a dosing interval. It involves the dynamics of how the drug is absorbed, distributed, metabolized, and eliminated (ADME) by the body. • Pharmacology: An investigation of the drug action’s impact on biological systems including an understanding of chemical properties, mechanism of action, therapeutic response, and biological transformation. Overall, the pharmacokinetics, pharmacodynamics, pharmacogenetics, and pharmacogenomics related to a drug interact biologically to influence efficacy and/or toxicity and serve as a framework for improving the understanding of pharmacology and drug development in the creation of more advanced and novel approaches to treat disease and provide precision therapies for individual patients (see Figure 5-1).
    [Show full text]
  • Premarket Evaluation in Early-Phase Clinical Studies and Recommendations for Labeling
    Guidance for Industry Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase Clinical Studies and Recommendations for Labeling U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Devices and Radiological Health (CDRH) January 2013 Clinical Pharmacology Clinical/Medical 10300.fnl.doc Guidance for Industry Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase Clinical Studies and Recommendations for Labeling Additional copies are available from: Office of Communications Division of Drug Information, WO51, Room 2201 10903 New Hampshire Ave. Silver Spring, MD 20993-0002 Phone: 301-796-3400; Fax 301-847-8714 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or Office of Communication, Outreach, and Development (HFM-40) Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike, Rockville, MD 20852-1448 http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm (Tel) 800-835-4709 or 301-827-1800 or Office of Communication, Education, and Radiation Programs Division of Small Manufacturers, International and Consumer Assistance Center for Devices and Radiological Health Food and Drug Administration 10903 New Hampshire Ave. WO66, Room 4613 Silver Spring, MD 20993-0002 http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm Email: [email protected] Fax: 301-827-8149 (Tel) Manufacturers Assistance: 800-638-2041 or 301-796-7100 (Tel) International Staff: 301-796-5708 U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Devices and Radiological Health (CDRH) January 2013 Clinical Pharmacology Clinical/Medical TABLE OF CONTENTS I.
    [Show full text]
  • Absorption & Half-Life
    Slide 1 Absorption and Half-Life Nick Holford Dept Pharmacology & Clinical Pharmacology University of Auckland, New Zealand Slide 2 Objectives ➢ Understand the physiological determinants of extent and rate of absorption ➢ Be able to describe bolus, first-order and zero-order input processes ➢ Learn the definition of half-life ➢ Be able to describe the time course of drug accumulation during constant rate input and elimination after input stops ➢ Appreciate the applications of absorption and half-life concepts to clinical practice ©NHG Holford, 2021, all rights reserved. Slide Drug absorption can be described 3 by two quite distinct factors: • The extent of absorption Absorption reflects the total amount of drug entering the body. It is not time dependent. • The rate of absorption determines how quickly the ➢ Extent of Absorption drug enters the body. The rate typically changes with time. ➢ Rate of Absorption ©NHG Holford, 2021, all rights reserved. Slide The extent of oral absorption can 4 be considered in 2 parts. The first part is the fraction of drug Extent (F) absorbed across the gut wall (f). This describes how much drug gets from the gut into the portal venous system. It is determined in ➢ Fraction Absorbed (f) part by physicochemical properties. Small, unionized » into portal vein from gut molecules e.g. theophylline, are almost completely absorbed » physicochemistry across the gut wall. Large, ionized – theophylline (100%) (small,unionized) molecules like gentamicin cross – gentamicin (< 5%) (large, ionized) membranes with difficulty and only a small fraction is absorbed » metabolism/transport across the gut wall. Many drugs – simvastatin (50%?) (CYP3A4) can cross the luminal cell membrane but are then – digoxin (65%) (PGP transporter) metabolized in the gut wall (typically by CYP3A4 e.g.
    [Show full text]
  • Drug Metabolism
    Pharmacology Corner: Drug Metabolism A central aspect of pharmacokinetics (what the body does to a drug) is drug metabolism, defined as the process by which drugs are altered to facilitate their removal from the body. Ultimately, the body needs to find a way to get rid of the chemical that was just put into it. Goal of drug metabolism: Inactivate and make drugs water soluble so they leave the body. Drug metabolism is mostly enzyme-mediated. This means that it does not happen spontaneously – there are proteins in the body that process the drug and facilitate removal. Drug metabolism occurs primarily (but not exclusively) in the liver. It also occurs in target organs (where the drug is affecting the body) such as the lungs, kidney, and the heart. Usually, metabolism inactivates the drug so that it can be removed from the body. But, there are instances when metabolism can convert the drug to a more active form. When this occurs, the drug is said to be a pro-drug and the metabolite is called an active metabolite. There can be considerable variation between individuals’ ability to metabolize drugs. This can be due to many factors including the presence of other drugs, certain foods, or dietary supplements, genetics, age, disease conditions, and environmental conditions. There are two general phases of drug metabolism: phase 1 and phase 2. Phase 1 introduces reactive and polar functional groups onto the drugs. The enzymes involved in phase 1 metabolism include cytochrome P450 enzymes (CYPs), monoamine oxidases, alcohol and aldehyde dehydrogenases, and several others. Phase 2 enzymes conjugate those reactive and polar groups with groups that increase solubility (things that are easy to get out of the body).
    [Show full text]
  • Pharmacokinetics: the Absorption, Distribution, and Excretion of Drugs
    Chapter 3 Pharmacokinetics: % C The Absorption, . 789—. Distribution, and 4 5 6 X Excretion of Drugs 1 2 3 – 0 • = + OBJECTIVES After studying this chapter, the reader should be able to: • Explain the meaning of the terms absorption, distribu- tion, metabolism, and excretion. • List two physiologic factors that can alter each of the KEY TERMS processes of absorption, distribution, and excretion. • achlorhydria • adipose • Explain how bioavailability can impact drug response • albumin and product selection. • aqueous • Compare the roles of passive diffusion and carrier-medi- • bioavailability ated transport in drug absorption. • bioequivalent • biotransformation • Describe two types of drug interaction and explain how • blood-brain barrier they might affect drug response and safety. • capillary permeability • cardiac decompen- sation • carrier-mediated transport • catalyze • concentration gradient • dissolution • distribution • epithelium • equilibrium • excretion 27 28 Practical Pharmacology for the Pharmacy Technician • extracellular • lipids • prodrug • first-pass effect • metabolism • saturable process • hydrophilic • metabolite • steady state • interstitial • passive diffusion • volume of distribution • intracellular distribution The process by Safe and effective drug treatment is not only a function of the physical and chemical prop- which a drug is carried to erties of drugs, but also a function of how the human body responds to the administration sites of action throughout of medication. The study of the bodily processes that affect the movement of a drug in the the body by the blood- body is referred to as pharmacokinetics. To understand the pharmacology of drugs, the stream. pharmacy technician must also understand the four fundamental pathways of drug move- ment and modification in the body (Fig. 3.1). First, drug absorption from the site of admin- metabolism The total of all istration permits entry of the compound into the blood stream.
    [Show full text]