Therapeutic Drug Monitoring Data: A Concise Guide, Fourth Edition serves as a ready resource of information on commonly monitored drugs that will help readers make decisions relating to the monitoring and interpretation of results. It is an easy-to-read source of information on intended use, pharmacokinetics, therapeutic range, and toxic concentrations, as well as bioavailability, disposition, metabolism and the excretion of commonly monitored therapeutic drugs. This fully updated fourth edition includes sections on new anticonvulsants, anti-depressant and anti-HIV drugs, new drugs for advanced cancer treatment, and thoroughly updated chapters that address new pitfalls and problems in the lab.
- Serves as a ready resource of information for commonly monitored drugs
- Presents a useful, quick guide for those making decisions related to monitoring and interpretation of results
- Provides concise, easily digestible content for clinical laboratory scientists, toxicologists and clinicians
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About the Author
Matthew D. Krasowski, MD, PhD is a clinical pathologist and the Walter L. Bierring Professor of Clinical Education at the University of Iowa Carver College of Medicine. He currently serves as the Vice Chair of Clinical Pathology and Laboratory Services in the Department of Pathology at University of Iowa Hospitals and Clinics.
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Pharmacokinetics and therapeutic drug monitoring
There are over 6000 prescription and over-the counter pharmaceutical formulations available in the United States (U.S.) The total U.S. prescription sales in the 2015 calendar year were $419.4 billion, which was 11.7% higher than sales in 2014.
When a drug enters the body, three systems come together to determine and describe its fate:
Pharmacokinetics describes the absorption, distribution, metabolism, and excretion of the drug.
Pharmacodynamics describes the action of the drug on the body.
Pharmacogenomics forms the genetic basis for the differences observed between individuals in terms of drug metabolism and response.
This chapter will provide a review of basic pharmacokinetic principles and their use in therapeutic drug monitoring (TDM). Pharmacogenomics is capable of predicting possible pharmacokinetic behavior of a drug prior to administration. In contrast, TDM can provide pharmacokinetic information after administration of a drug based on concentration of the drug in blood or other body fluid. Therefore, TDM is a phenotype approach for personalized medicine, while pharmacogenomics is a genotype approach and they complement each other. Please see Chapter 7 for more in-depth discussion on this topic.
Fortunately few drugs require routine TDM. In general, approximately 26 drugs are routinely subjected to TDM due to narrow gap between therapeutic and toxic blood levels. Immunoassays are commercially available for most of these drugs which could be easily adapted to various automated clinical chemistry analyzers for simplicity of operation as well as good turnaround time. In addition, approximately 25–30 drugs are subjected to TDM less frequently and immunoassays are available only for a few such drugs. Therefore, chromatographic techniques are used for monitoring of these drugs and such tests are only available in clinical laboratories of major medical centers and academic centers as well as reference laboratories.
TDM not only consists of measuring the concentration of a drug in a biological matrix but also involves the proper interpretation of the value using pharmacokinetic parameters, drawing appropriate conclusion regarding the drug concentration and dose adjustment. The International Association for Therapeutic Drug Monitoring and Clinical Toxicology adopted the following definition for drug monitoring; "Therapeutic drug monitoring is defined as the measurement made in the laboratory of a parameter that, with appropriate interpretation, will directly influence prescribing procedures. Commonly, the measurement is in a biological matrix of a prescribed xenobiotic, but it may also be of an endogenous compound prescribed as a replacement therapy in an individual who is physiologically or pathologically deficient in that compound". Traditionally TDM involves measuring drug concentration in a biological matrix (most commonly serum or plasma) and interpreting these concentrations in terms of relevant clinical parameters. Whole blood is the preferred matrix for TDM of immuno-suppressants (cyclosporine, tacrolimus, sirolimus and everolimus) except for mycophenolic acid. A successful TDM program requires good communication between clinicians, laboratory professionals, and pharmacists. One report clearly documented that intervention of pharmacist significantly improved appropriateness of TDM use and significantly reduced unnecessary cost. Commonly monitored and less commonly monitored drugs are listed in Table 1.1. Although not routinely monitored,TDM may be beneficial when applied to antiretrovirals. Even though TDM can be a valuable strategy in HIV management, its role remains controversial.
1.2 Compliance and TDM
Compliance (adherence) to drug therapy is an important issue for successful patient management. It is imperative that the correct drug must be prescribed and prepared. But if the patient is not taking the drug properly, i.e., they skip or add doses, then even the best analytical method would produce misleading drug concentration based on expected dosage because steady state may not be attained nor it could be maintained. Non-compliance with a prescribed drug is a commonly encountered problem especially for medications taken chronically. TDM can be a useful approach to identify non-compliant patients. Non-compliance and over-dosing/under dosing is common with digoxin therapy. In one study based on analysis of data from 10 different studies, the authors reported that in patients with heart failure and/or atrial fibrillation, the prevalence rate of non-compliance with digoxin was 38.7%; the corresponding prevalence rates of overdosing and under-dosing were 33.04% and 33.8% respectively. A high non-compliance rate of 63% with phenytoin and theophylline was reported in a study based on a study of 80 epileptic and asthmatic patients. Calcagno commented that non-compliance with antiretroviral therapy may cause treatment failure in AIDS patients. TDM of protease inhibitors including ritonavir in plasma can uncover incomplete compliance with treatment. Therefore, TDM may represent a useful tool for identifying patients in need of adherence-promoting interventions.
1.3 Basic pharmacokinetics
A drug after oral administration undergoes various processes including liberation of the drug from formulation (tablet or capsule), absorption from the gastrointestinal (GI) track, distribution in blood and tissue, binding with appropriate receptor/tissue for the intended pharmacological action metabolism and finally elimination from the body.
Before anything else can happen, drugs must be released from their solid form and made soluble (the exception are those administered intravenously). A number of drugs are found in forms that release the drug over a prolonged period of time, i.e., sustained release formulas. Such formulas allow the attainment of efficacy but at lower peak plasma concentrations and therefore with fewer adverse events. The rate at which such a drug is liberated depends upon the formulation, dosage, and ionization state, as well as the pH of the environment in which it enters.
Ionization and pH of the gastric fluid have major influence on drug liberation. Drugs are typically weak acids or bases possessing functional groups that become charged or ionized depending upon the pH in which they are placed. By knowing the pKa of a drug, one can predict the behavior of a drug in a given pH of the environment. The pKa is the pH at which the amounts of ionized and unionized forms are equal. An acidic drug will favor the ionized form when placed in an environment where the pH is higher than the pKa. Similarly, a basic drug will favor the ionized form as the pH decreases to a value less than the drug's pKa. This concept is important because ionized molecules cannot easily cross cell membranes.
After liberation, absorption describes the movement of a drug from the site of administration into the circulation. How readily absorption occurs depends on the physicochemical characteristics of the drug (solubility, pKa, ionization) and on the local physiology (pH, perfusion, GI motility, etc.). Absorption is most efficient at the pH where the drug is predominately in the unionized form. If a drug enters a compartment and becomes ionized, it is likely to be trapped there. Factors which can alter the absorption of an orally administered drug include changes in the transit time through the GI track, ionization at a point along the GI track, metabolism by intestinal enzymes, and interactions with other compounds present to form insoluble compounds.
An additional term that should be discussed at this point is bioavailability. This term is used to describe the fraction of a dose that is absorbed and therefore available to elicit a pharmacological effect. Bioavailability depends upon the previously discussed characteristics of the drug, physiology (especially that of the GI track), and other factors such as first pass metabolism, fever, perfusion, etc. It may be an issue when a patient switches from one brand of medication to another brand or from a brand-name formula to a generic.
Another factor that affects bioavailability is the presence of food in the stomach. In order to avoid food-drug interaction, certain drugs should be taken on an empty stomach (drug instructions should specify that) but other drugs may be taken with food. Alcohol should be avoided while taking certain drugs. Nevertheless, approximately 71% of American adults consume alcoholic beverages, leading to potential alcohol-drug interactions. Numerous commonly prescribed medications interact negatively with alcoholic beverages including cardiovascular agents, diuretics, central nervous system agents, narcotics, psychotherapeutic agents such as antidepressants, and others. In one study based on 26,657 adults, the authors calculated that total prevalence of alcohol interactive medication use was 41.5% among current drinkers younger than 65 years of age. Among participants aged ≤65, total prevalence of such medication use was 78.6% and adjusted prevalence among current drinkers was 77.8%.
Distribution describes the delivery of drug via the circulation to the rest of the body. How readily distribution takes place depends on the integrity of the circulatory system (how readily tissues are perfused), protein binding characteristics of the drug, and the ability of the drug to cross cellular membranes. Some drugs distribute extensively to organs and tissues while others remain confined within the vascular space.
1.3.4 Binding of drugs with serum proteins
Most drugs in the circulation bind at least some extent to serum proteins (there are also cases in which drugs are bound to erythrocytes and lipids) but the extent of protein binding may vary from being negligible (e.g., lithium) to over 99% (e.g., ketorolac). Acidic drugs are typically bound to albumin while basic drugs are predominantly bound by α1-acid glycoprotein. Only the portion of the drug that is not bound to serum proteins (unbound or free drug) can cross cell membranes and subsequently interact at the intracellular level. Protein binding varies between drugs, but under healthy conditions should be relatively consistent between individuals for a given drug. Conditions that alter the concentration of the binding proteins naturally alter the amount of free drug and the impact of such a change will be greatest for a drug with high protein binding, typically 80% or more.
One of the most important and interesting aspects of pharmacology is that of metabolism. The simplest description of metabolism is that this is the process of chemically preparing a drug for excretion by converting it into a more polar, water-soluble form. As pharmacogenetics has shown, metabolism is a relatively complex issue that contributes to the differences observed between individuals prescribed the same drug and dose. While the vast majority of metabolism takes place in the liver through the cytochrome P450 (CYP) system, other tissues and enzymes also contribute to the process. Many drugs are metabolized through multiple pathways. Usually drugs are metabolized by one or two steps. In phase I drug metabolism, a variety of enzymes (most commonly various isoforms of CYP enzymes) act to introduce reactive and polar groups into their substrates in order to transform relatively non-polar drugs to polar metabolites that are more readily excreted in urine. In subsequent phase II reactions, some drug or certain drug metabolites are conjugated with charged species such as glutathione, sulfate, glycine, or glucuronic acid in order to make such species more water-soluble. This process is also catalyzed by various enzymes mainly transferases such as UDP (Uridine 5'-diphosphate) glucuronosyl-transferases, sulfotransferases, N-acetyltransferases, glutathione S-transferases and methyltransferases (mainly thiopurine S-methyl transferase and catechol O-methyl transferase). A minority of drugs (e.g., digoxin) are not metabolized at all by liver enzymes.
The CYP isoenzymes that mediate the Phase I oxidative metabolism of many drugs include CYP1A2, CYP2C9, CYP2D6, CYP2E1 and CYP3A4. These enzymes show marked variations in different populations including genetic polymorphisms (CYP2C9, CYP2C19 and CYP2D6) and a subset of the population may be deficient in enzyme activity (poor metabolizers). Therefore, if a drug is administered to a patient who is a poor metabolizer, drug toxicity may be observed even with a standard dose of the drug. The resulting metabolites may be inactive, active, partially active, or even toxic. Metabolites may also inhibit or induce the formation of other metabolic products of the same drug or of another drug. Metabolic processing may be necessary to transform an inactive, prodrug into an active drug.
Certain orally administered drugs undergo first pass metabolism. This occurs when an orally administered drug is absorbed through the intestinal mucosa and directly transported via the portal vein to the liver where it undergoes metabolism. In some cases, a significant portion of the drug is lost before it becomes available to the circulation. In such cases it might be possible to administer the drug in a higher oral dose or to administer the drug using a non-enteral route (intravenously, transdermally or intramuscularly). Some drugs are administered as inactive, prodrugs which are metabolized to the active drug. For example, tamoxifen, an antineoplastic drug is a prodrug which is converted into its primary active metabolite endoxifen (4-hydroxy-N-desmethyl-tamoxifen) by the action of CYP2D6.(Continues…)
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Table of Contents1. Pharmacokinetics and Therapeutic Drug Monitoring
2. Before and After: The Preanalytical and Postanalytical Phases of Therapeutic Drug Monitoring
3. Clinical Utility of Monitoring Free Drug Concentrations
4. Effect of Bilirubin, Lipemia, Hemolysis, Paraproteins, and Heterophilic Antibodies on Immunoassays for Therapeutic Drug Monitoring
5. Drug-Herb and Drug-Food Interactions and Effects on Therapeutic Drug Monitoring
6. Monitoring Anticonvulsant Concentrations – General Considerations
7. Therapeutic Drug Monitoring of Cardioactive Drugs
8. Therapeutic Drug Monitoring of Antidepressants
9. Introduction to Immunosuppressive Drug Monitoring
10. Therapeutic Drug Monitoring of Antimicrobial and Antiviral Agents
11. Therapeutic Drug Monitoring of Analgesics
12. Therapeutic Drug Monitoring of Antineoplastic Drugs
13. Caffeine, Lithium, and Theophylline