Progress in 7 Clinical Biochemistry and Medicine Drug Concentration Monitoring Microbial Alpha-Glucosidase Inhibitors Plasminogen Activators With Contributions by M. B. Bottorff, W. E. Evans, I. Hillebrand, B. Junge, L. Muller, W. PuIs, D. D. Schmidt, E. Truscheit, H. Will With 56 Figures Springer-Verlag Berlin Heidelberg NewY ork London Paris Tokyo ISBN-13:978-3-642-73463-2 e-ISBN-13:978-3-642-73461-8 DOl: 10.1007/978-3-642-73461-8 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks. Duplication of this publication or parts thereof is only permitted under the provisions of the German Copyright Law of September 9, 1965, in its version of June 24, 1985, and a copyright fee must always be paid. Violations fall under the prosecution act of the German Copyright Law. © Springer-Verlag Berlin Heidelberg 1988 Softcover reprint of the hardcover I st edition 1988 The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. 2151/3020-543210 Editorial Board Prof Dr. Etienne Baulieu Universite de Paris Sud, Departement de Chimie Biologique, FacuIte de Medecine de Bicetre, H6pital de Bicetre, F-94270 Bicetre/France Prof Dr. Donald T. Forman Department of Pathology, School of Medicine, University of North Carolina Chapel Hill, NC 27514/USA Prof Dr. Lothar Jaenicke Universitat Kaln, Institut fUr Biochemie An der Bottmiihle 2 D-5000 Kaln IjFRG Prof Dr. John A. Kellen Sunnybrook Medical Centre, University of Toronto, 2075 Bayview Avenue Toronto, Ontario, Canada M4N 3M5 Prof Dr. Yoshitaka Nagai Department of Biochemistry, Faculty of Medicine, The University of Tokyo Bunkyo-Ku, Tokyo/Japan Prof Dr. Georg F. Springer Immunochemistry Research, Evanston Hospital Northwestern University, 2650 Ridge Avenue, Evanston, IL 60201jUSA Prof Dr. Lothar Trager Klinikum der Johann Wolfgang Goethe Universitiit, Gustav-Embden-Zentrum Theodor Stern Kai 7 D-6000 Frankfurt a. M. 70/FRG Prof Dr. Liane Will-Shahab Akademie der Wissenschaften der DDR Zentralinstitut fUr Herz-und Kreislauf-Forschung Lindenberger Weg 70 DDR-1115 Berlin-Buch Prof Dr. James L. Wittl(!J Hormone Receptor Laboratory, James Graham Brown Cancer Center, University of Louisville Louisville, KY 40292/USA Table of Contents Drug Concentration Monitoring Michael B. Bottorff and William E. Evans Microbial Alpha-Glucosidase Inhibitors: Chemistry, Biochemistry and Therapeutic Potential Ernst Truscheit, Ingrid Hillebrand, Bodo Junge, Lutz Miiller, Walter PuIs, Delf Dieter Schmidt. . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Plasminogen Activators: Molecular Properties, Biological Cell Function and Clinical Application Horst Will. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 Author Index Volumes 1-7 ....................... 147 Drug Concentration Monitoring Michael B. Bottorff!' 2 and William E. Evans3, 4 1 Assistant Professor of Clinical Pharmacy University of Tennessee, Memphis Memphis, TN/USA 2 Director, Division of Cardiovascular Pharmacology, Mid-South Heart Institute, Methodist Hospitals of Memphis, Memphis, TN/USA 3 Department of Clinical Pharmacy and Center for Pediatric Pharmacokinetics and Therapeutics University of Tennessee, Memphis, TN/USA 4 Pharmaceutical Division St, Jude Children's Research Hospital Memphis, TN/USA The application of therapeutic drug monitoring (TDM) principles to individualize a patient's drug regimen has resulted in significant improvements in the clinical use of many drugs. Improved techniques for laboratory analysis of drug concentrations and better documentation of the pharmacokinetic and pharmacodynamic properties of drugs has led to widespread application of TDM, Appropriate utilization ofTDM requires a coordinated effort among many disciplines, including clinical chemistry, clinical pharmacy/pharmacology and medicine. Due to the demands of prospective reimbursement for payment of health care in many countries, TDM programs will likely undergo further evaluation for its cost-effectiveness through reductions in the costs of hospital care and/or improvements in clinical outcome. I Introduction. . . . . . . . . . . . . . . . . . . . 2 2 Establishing the Need for Drug Concentration Monitoring 2 2.1 "Ideal" Properties of Therapeutically Monitored Drugs 2 2.2 Pharmacokinetics and Pharmacodynamics . . . . . . 4 2.3 Pharmacokinetic Variability in Therapeutic Drug Monitoring 6 2.3.1 Influence of Disease States on Therapeutic Drug Monitoring. 6 2.3.2 Drug Interactions and Therapeutic Drug Monitoring . . 6 3 Methods for Therapeutic Drug Monitoring Services . . . . . . . 7 3.1 Integrated Approach to Therapeutic Drug Monitoring Services 7 3.2 Clinical Use of Therapeutic Drug Monitoring ....... . 7 3.3 Bayesian Methods for Therapeutic Drug Monitoring. . . . . II 4 Establishing a Need for an Organized Drug Monitoring Approach. 12 5 Impact of Therapeutic Drug Monitoring on Clinical Outcome 13 5.1 Aminoglycosides 13 5.2 Theophylline . 14 5.3 Methotrexate. 14 6 Conclusions 14 7 References. IS Progress in Clinical Biochemistry and Medicine, Vol. 7 © Springer·Verlag Berlin Heidelberg 1988 2 M. B. Bottorff and W. E. Evans 1 Introduction Therapeutic drug monitoring is a relatively young concept of individualizing drug therapy and has gained widespread clinical acceptance over the last 20 years. Thera peutic drug monitoring involves the utilization of pharmacokinetic principles that govern serum drug concentrations and couples these concentrations with pharmacolo gic and toxic effects. Proper interpretation of serum drug concentrations, therefore, requires a drug assay that is both sensitive and specific and a clinician or team with knowledge of the patient condition and TDM principles. Advances in these areas have led to the development of therapeutic drug monitoring as a customary component of drug therapy with many different drugs. One major area of advance has been in the development of more reliable, less cumbersome methods for analyzing drug concentrations in serum or plasma. In the past ten years, therapeutic drug monitoring has prospered from the development of these new technologies. Currently used drug assays, in addition to being sensitive and specific, are highly automated and provide rapid turnaround times for almost immediate assessment of drug concentration and therapeutic response. Many "dip stick" methods for serum drug analysis are being investigated and, because no special technical skills are required, may move therapeutic drug monitoring to the bedside, physician's office and patient's home. Another major area of advance in therapeutic drug monitoring has resulted from research in clinical 'Pharmacokinetics and pharmacodynamics. Pharmacokinetics is the study of the absorption and disposition of drugs in the body and the various processes which result in a given serum drug concentration-time profile, while pharma codynamics is the relation between drug concentration and pharmacologic effect. Pharmacokinetic and pharmacodynamic research with many drugs is constantly expanding the number of drugs whose clinical use in guided by drug concentration monitoring. This article will describe the current use of therapeutic drug monitoring and present data supporting the use of drug concentration monitoring for selected drugs. In addition, data are shown supporting positive cost-benefit and cost-effectiveness ratios for certain drugs. 2 Establishing the Need for Drug Concentration Monitoring 2.1 "Ideal" Properties of Therapeutically Monitored Drugs Clinicians have long realized that similar doses of the same drug in different patients often result in a wide range of clinical responses. It has been shown that interpatient variability due to many factors results in broad dispersion of serum concentrations when fixed drug doses are used. Therefore, some patients reach a 'threshold' senim drug concentration and receive therapeutic benefit from the administered drug while other patients achieve 'subtherapeutic' serum concentrations and exhibit no positive Drug Concentration Monitoring 3 30 -E toxic OJ u E c 20 .2 ~ C therapeutic u(IJ c 810 OJ o::J subtherapeutic o~--------------------------------- Fig. 1. Theoretical therapeutic range for a drug with known toxic, therapeutic and subtherapeutic serum concentrations (reproduced with permission from applied pharmacokinetics: principles of therapeutic drug monitoring, 2nd edition, edited by William E. Evans, Jerome J. Schentag, and William J. Jusko, published by applied therapeutics, Inc., Spokane, Washington, USA, 1986) response to the drug. To adjust for patient-to-patient differences in drug disposition, therapy with selected drugs is now individualized to achieve a predefined serum concentration associated with a higher probability of the desired clinical response. While all drugs are not monitored by following serum drug concentrations, therapeutic drug monitoring principles are most applicable if the drug has a narrow therapeutic range, is administered chronically, has a wide range of interpatient pharmacokinetic variability, has potentially serious toxic side effects above a certain serum concentra tion or has minimal effectiveness below a certain serum concentration. The latter two concepts result in the definition of a "therapeutic range" or window (Fig. 1). This concept is often misunderstood in that clinicians often assume that all therapeutic ranges are the result of carefully designed clinical trials involving many patients in each of several patient populations. This is not always the case, and, in fact, could be considered rare. For example, the generally accepted therapeutic range for procain amide is 4-10 mcg/mll). However, the study proposing this therapeutic range for procainamide failed to document the timing of the samples in relation to the dose 2). In addition, the definition of the therapeutic endpoint was left to the discretion of the primary physician and therefore was not always. consistent or objective. Others have documented the necessity for higher procainamide concentrations in some patient populations to achieve a positive therapeutic response, thus possibly expanding the upper end of the procainamide therapeutic window 3,4). Nevertheless, the concept of a therapeutic range for procainamide has proven useful over the years and the serum concentration objective of 4-10 mcg/ml remains a clinical target. Another common misconception is that attaining a serum concentration within the "therapeutic range" assures one of therapeutic success. In general, one should consider therapeutic ranges as probability charts describing the relative probabilities of therapeutic response and toxicity as serum concentrations increase (Fig. 2). There fore, the therapeutic range represents a spectrum of serum concentrations within which the probability of a positive clinical response to the drug is relatively high and the probability of toxic drug effects are relatively low. Although this simplistic approach can be applied to most drugs monitored by serum concentration determina- 4 M. B. Bottorff and W. E. Evans 100 Response , ,. Toxicity // / :.:ooD0 / / / ct / / / / .--," --- 20 30 Drug concentration (mg/L) Fig; 2. Graph of a theoretical drug showing the probability of a therapeutic response and toxicity with a given serum drug concentration (reproduced with permission from applied pharmacokinetics: principles of therapeutic drug monitoring, 2nd edition, edited by William E. Evans, Jerome J. Schentag, and William J. Jnsko, published by applied therapeutics, Inc., Spokane, Washington, USA, 1986) tions, it should be noted that there will be some patients (in this hypothetical example, approximately 5 %) within the low end of the therapeutic range that exhibit symptoms of toxicity and others that will not achieve any beneficial therapeutic response. On the other hand, there will be patients with serum concentrations above the desired range that fail to experience toxic drug effects, while other patients (approximately 20 % in this example) show no beneficial effects at all. Therefore, the response curve plateaus at some probability approaching the upper end of the therapeutic range, indicating that some patients will be "drug resistant" and susceptible primarily to toxic drug effects without the therapeutic effects. Unfortunately, concentration-effect charts such as the hypothetical one described above may not be the result of carefully designed, large clinical trials. In addition, the concentration-effect curve configuration may be different for certain subpopulations and inadequately defined for patients with various diseases and/or concomitant drug administration. Nevertheless, this conceptualization of a drug's therapeutic range serves to better explain the considerable variability in concentration-response rela tionships when drugs are used in large numbers of patients. 2.2 Pharmacokinetics and Pharmacodynamics The basic principles of clinical pharmacokinetics and pharmacodynamics are funda mental to the appropriate application of therapeutic drug monitoring to patient care. A drug's pharmacokinetics are governed by drug absorption, distribution, metabolism and excretion by the body. These processes, which may be depicted by mathematical relationships, result in a given serum concentration at any time following drug ad ministration. For drug monitoring purposes, the most useful pharmacokinetic para meters are clearance and half-life. Clearance is defined as the volume of blood (or plasma) totally eliminated of drug per unit time and is usually expressed as ml/min, Drug Concentration Monitoring 5 ml/min/m2 or ml/min/kg. For drugs with multiple sites of elimination (liver, kidneys), the total body clearance is simply the sum of the individual clearances of each elim inating organ: (1) where el is total systemic clearance, el is hepatic clearance, el is renal clearance B H R and eli represents all other clearance mechanisms. The other clinically useful pharma co kinetic term is half-life, which represents the time it takes for the serum concentra tion of a drug to be reduced by one-half. For drugs best described by a linear one compartment pharmacokinetic model, the half-life is proportional to the rate constant for drug elimination, K, by the equation: Tl/2 = O.693/K (2) such that a semi-logarithmic plot of the decline in serum drug concentration over time yields a straight line whose slope is - K. Half-life is useful in describing the time for attaining steady-state dosing conditions, where the rate of drug input equals the clearance, or drug output from the body. Table 1 shows how half-life can be used to calculate drug accumulation following dose initiation and drug elimination after cessation of therapy. Most clinicians use 5 half-lives as the time necessary to achieve steady-state or for estimating total drug elimination from the body. As discussed later in this chapter, clearance and half-life are utilized to calculate an individual patient's pharmacokinetic parameters, which can be used to predict future drug con centrations with a given change in dose. Another important concept in therapeutic drug monitoring is pharmacodynamics, which relates the systemic exposure to drug or concentration of drug in serum (or at the receptor site) to an effect, either therapeutic or toxic. The relationship between pharmacokinetics and pharmacodynamics as proposed by Holford and Sheiner is shown in Fig. 3 Essentially, the plasma drug concentrations determined by individ 5). ual pharmacokinetic parameters are linked to the observed therapeutic and/or toxic effects by a pharmacodynamic model. By observing the range of serum concentra tions resulting in desirable clinical response and toxic effects, a therapeutic range can be constructed. This model has been useful in describing concentration-effect rela tionships for many drugs including tocainide 6), quinidine 7) and propranolol 8). Table 1. The relationship between drug half-life and percent eliminated following drug discontinuation (% remaining) and time to reach steady state (~;.; accumulation) Half-lives (hours) % Remaining % Accumulation I 50 50 2 25 75 3 12.5 87.5 4 6.25 93.75 5 3.125 96.875