Individualized Drug Therapy for Patients

Basic Foundations, Relevant Software and Clinical Applications

Roger W Jelliffe, Michael Neely

• Publisher: Academic Press
• Year: 2016
• Print ISBN: 9780128033487
• eBook ISBN: 9780128033494
• Topic: Computer Science
• Subtopic: Digital Media
• Index: Computer Science

Individualized Drug Therapy for Patients: Basic Foundations, Relevant Software and Clinical Applications focuses on quantitative approaches that maximize the precision with which dosage regimens of potentially toxic drugs can hit a desired therapeutic goal. This book highlights the best methods that enable individualized drug therapy and provides specific examples on how to incorporate these approaches using software that has been developed for this purpose.The book discusses where individualized therapy is currently and offers insights to the future. Edited by Roger Jelliffe, MD and Michael Neely, MD, renowned authorities in individualized drug therapy, and with chapters written by international experts, this book provides clinical pharmacologists, pharmacists, and physicians with a valuable and practical resource that takes drug therapy away from a memorized ritual to a thoughtful quantitative process aimed at optimizing therapy for each individual patient.- 2018 PROSE Awards - Honorable Mention, Clinical Medicine: Association of American Publishers- Uses pharmacokinetic approaches as the tools with which therapy is individualized- Provides examples using specific software that illustrate how best to apply these approaches and to make sense of the more sophisticated mathematical foundations upon which this book is based- Incorporates clinical cases throughout to illustrate the real-world benefits of using these approaches- Focuses on quantitative approaches that maximize the precision with which dosage regimens of potentially toxic drugs can hit a desired therapeutic goal

Section III

Clinical Applications of Individualized Therapy

Outline

Chapter 12 Optimizing Single-Drug Antibacterial and Antifungal Therapy

Chapter 13 Combination Chemotherapy With Anti-Infective Agents

Chapter 14 Controlling Antiretroviral Therapy in Children and Adolescents with HIV Infection

Chapter 15 Individualizing Tuberculosis Therapy

Chapter 16 Individualizing Transplant Therapy

Chapter 17 Individualizing Dosage Regimens of Antineoplastic Agents

Chapter 18 Controlling Busulfan Therapy in Children

Chapter 19 Individualizing Antiepileptic Therapy for Patients

Chapter 20 Individualizing Drug Therapy in the Elderly

Chapter 21 The Present and Future State of Individualized Therapy

Chapter 12

Optimizing Single-Drug Antibacterial and Antifungal Therapy

M. Neely and R. Jelliffe

Abstract

Antibacterial and antifungal drugs interfere with the life cycles of infecting pathogens in various ways to help the patient’s immune system kill the organism and recover from the infection. Unfortunately, this recovery (ie, elimination of fever and other symptoms) is typically delayed from the initiation of therapy by days to weeks. Therefore, clinicians who treat infections, particularly severe, life-threatening infections, are used to the concept of measuring drug concentrations and adjusting doses to achieve concentration targets that serve as predictors of good clinical outcomes. Fundamental to this approach is the concept of a minimum inhibitory concentration (MIC). In this chapter, we consider the relationship of antibacterial and antifungal concentrations to MIC and clinical outcomes and present case vignettes to illustrate principles of therapeutic management using multiple-model Bayesian adaptive control with optimal sampling.

Keywords

Pharmacokinetics (PK); pharmacodynamics (PD); antifungal; pediatric; optimal control; dose individualization

Chapter Outline

12.1 Introduction 157

12.2 Minimum Inhibitory Concentration 158

12.3 Breakpoints 158

12.4 The Approach 159

12.4.1 Pharmacokinetic and Pharmacodynamic Relationships 160

12.5 Antifungal Agents 163

12.6 Use of Therapeutic Drug Management and Multiple Model Bayesian Adaptive Control of Dosage Regimens 163

12.7 Problems With Trough-Only Sampling 165

12.8 An Illustrative Patient 165

12.9 Issues in Fitting Data 168

12.10 The Approach to the Patient 168

12.11 Voriconazole 170

12.12 An Illustrative Patient 170

12.13 Evaluation of Dosage Guidelines 171

12.14 Another Illustrative Patient 174

12.15 Conclusion 176

References 176

12.1 Introduction

Antimicrobial drugs interfere with the life cycle of an organism in various ways. To alter the life cycle, all antimicrobials must bind to a cellular target. Binding of the drug to its target results in alteration of the normal function of the bacterium or fungus, leading to either inhibition of growth or cell death. In addition to the ability of an antimicrobial agent to reach its target site of action (ie, the receptor), the drug must also possess sufficient affinity for its receptor, and it must achieve a sufficient concentration to affect organism function. These pharmacologic characteristics are the primary determinants of antimicrobial activity.

Unfortunately, because the interaction between drug and “bug” receptors occurs on a microscopic scale, we cannot directly quantify these effects in patients. Moreover, infection eradication is the desired ultimate outcome, but this is typically delayed by days to weeks after initiation of therapy, and we do not want to wait that long to discover that we chose the wrong drug or dose. As such, we must use surrogate markers in an attempt to reflect the crucial cellular interactions and to predict our desired outcome. These surrogate markers are ideally easily measured, and they substitute for the truly desired outcome, which is eradication of infection.

12.2 Minimum Inhibitory Concentration

For antibacterials and antifungals, the most commonly used efficacy surrogate is the in vitro minimum inhibitory concentration (MIC). The MIC is a direct measure of in vitro drug potency and an indirect measure of in vivo activity. However, MIC itself does not provide sufficient information on the temporal pattern of exposure of an organism to antimicrobial agents or the antimicrobial concentration that must be achieved relative to the MIC to ensure a sufficient therapeutic response.

Consideration of the laboratory procedures involved in the determination of MICs raises additional questions about MIC alone as a primary surrogate for clinical antimicrobial activity. First, measurements of MIC are obtained in bacterial growth media that are devoid of protein, which may have implications for agents that are highly bound to plasma proteins (for example, >70% bound). Thus, antibiotic concentrations used to determine MICs represent 100% free active drug. Similar concentrations of free drug at the anatomic site(s) of infection may not be achievable clinically because of extensive protein binding, drug molecular weight, and degree of ionization at pathophysiologic pH.

12.3 Breakpoints

Breakpoints are an attempt to overcome some of these limitations by providing a clinical context in which to interpret MICs. A breakpoint is a reference MIC above which sufficient drug concentrations are unlikely to be achieved in patients (resistance breakpoint) or unlikely with standard dosing (intermediate breakpoint). Of course, a breakpoint is based on average drug kinetic behavior integrated with clinical response measured in a population. There is little in the way of individualization in the concept of a breakpoint. Second, measuring MICs usually involves maintaining a constant concentration of free drug for a standard period (generally 24 h). Such a constant concentration simulates a continuous infusion of antibiotic whereas clinically, antibiotics are usually administered intermittently, which results in peaks and troughs rather than constant concentrations. Third, MICs are measured on a standard inoculum of bacteria or fungi that may or may not reflect the actual density of bacteria present at the site of infection. Fourth, measured MICs are considered acceptable if day-to-day variability is ≤two-fold. However, two-fold above and below the “truth” means a four-fold difference is possible. Fifth, MICs from different methods may vary by at least two-fold. Finally, the laboratory procedures used to determine the MIC do not account for the antimicrobial activity of various host defenses, including immunoglobulins and leukocytes.

Despite all these limitations, the MIC is still the foundation for antimicrobial therapy against bacteria and fungi. Intuitively, it is important to select an antibiotic with demonstrated activity against the pathogen, and in vitro susceptibility testing is especially valuable in identifying antimicrobial agents that will be ineffective in eradicating the pathogen. That is, MIC is a better predictor of failure than success, because there are many factors other than a low MIC (high drug potency) that contribute to the likelihood of infection eradication. However, a very high MIC far above an established breakpoint suggests that success is unlikely with a given drug, because a safe but effective exposure will be hard to obtain. On the other hand, a pathogen can appear susceptible to a particular agent from in vitro testing (ie, low MIC), yet information is lacking on the ability of the agent to achieve the necessary concentrations for a sufficient per...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• List of Contributors
• Preface
• Acknowledgments
• Introduction: Don’t Just Dose—Choose a Specific Target Goal, Suited to the Patient’s Need, and Dose to Hit it Most Precisely
• Section I: Basic Techniques for Individualized Therapy
• Section II: The Clinical Software
• Section III: Clinical Applications of Individualized Therapy
• Index