1Introduction to Drug Interactions

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From: Infectious Disease: Drug Interactions in Infectious Diseases, Second Edition Edited by: S. C. Piscitelli and K. A. Rodvold © Humana Press Inc., Totowa, NJ

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Introduction to Drug Interactions

Keith Gallicano and George Drusano

INTRODUCTION

Human immunodeficiency virus (HIV), more than any other disease, is responsible for the renewed interest in drug interactions by physicians, pharmacists, nurses, scien- tists, and regulatory agencies. The importance of managing drug interactions in infectious diseases moved to the forefront as more drugs spanning the different classes of infectious disease agents became available to treat HIV and prevent or treat opportunistic infections and HIV-related malignancies. This has led to recognition of the potential for and impact of drug interactions in other infectious diseases and with a variety of anti- infective drug classes. Recent reviews (1–4), including those in this volume, and the development of computerized drug interaction databases (5) further attest to the revived interest and importance of drug interactions in the different therapeutic areas of infectious diseases.

Numerous workshops and symposia devoted specifically to drug interactions have emerged since 1995. Pharmaceutical manufacturers are conducting more pharmacokinetic drug interaction studies earlier rather than during late Phase II and Phase III of clinical drug development or during postmarket surveillance. Many of these studies are rationally designed from in vitro studies that use specific human cell lines, tissues, or tissue components. Regulatory authorities in Canada (Therapeutic Products Programme) (6), the United States (Food and Drug Administration) (7,8), and Europe (The European Agency for the Evaluation of Medicinal Products) (9) have produced guidance for con- ducting in vitro and clinical drug interaction studies. These guides emphasize the importance of appropriate study design and data analysis techniques, which are highlighted in Chapter 15 of this volume. Further regulatory perspective is presented in Chapter 4.

Drug product labels and monographs now frequently include detailed information on drug interactions. This widespread interest in drug interactions has resulted in more scientific and clinical data available to the consumer and prescriber. Consequently, the management of drug interactions has become more challenging.

Drug interactions represent one of eight categories of drug-related problems that have been identified as events or circumstances of drug therapy that may interfere with opti- mal clinical outcome (10). Identification, resolution, and prevention of drug-related prob-

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lems are important determinants for patient management and are the responsibility of those providing pharmaceutical care. The continued development of new, high-potency drugs increases the potential for drug interactions. However, the incidence of clinically important interactions remains difficult to quantify because both drug-related (Table 1) and patient-related (Table 2) factors influence the likelihood of a clinically relevant interaction occurring. Consideration must also be given to the level of documentation of the interaction, the frequency of use of the coadministered agents, and the mechanism and time-course of the interaction.

A drug interaction occurs when the pharmacokinetics or pharmacodynamics of a drug in the body are altered by the presence of one or more interacting substances. The

Table 2

Patient-Related Factors Affecting Drug Interactions

• Body weight, composition, and size

• Quantity and activity of specific drug-metabolizing enzymes (genetic polymorphism)

• Inherent inter- and intraindividual variability in pharmacokinetics and pharmacological response

• Age

• Gender

• Race

• Tobacco use

• Alcohol use (acute or chronic)

• Diet

• Underlying disease states and their severity (acute, chronic, unstable)

• Malfunction and disease of organs of drug elimination (e.g., liver, kidney)

• Polypharmacy (particularly with enzyme inhibitors or inducers) Table 1

Drug-Related Factors Affecting Drug Interactions

• Narrow therapeutic range

• Low bioavailability

• Drug formulation (presence of interacting excipients)

• Drug stereochemical and physiochemical properties

• Drug potency

• Steep dose–response curve

• Duration of therapy (acute vs chronic administration)

• Drug dosage (a higher dose yields a more significant interaction)

• Drug concentration in blood and tissue

• Timing and sequence of administration of interacting drugs (staggered vs simultaneous administration)

• Route of administration

• Baseline blood concentration of interacting drug and its therapeutic index

• Extent of drug metabolism (fraction of systemic clearance from metabolism)

• Rate of drug metabolism (hepatic extraction ratio and hepatic clearance)

• Degree of protein binding of interacting drugs

• Volume of distribution of affected drug

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most commonly encountered or perceived interactions are those between two drugs.

However, multiple drug interactions are possible with the polypharmaceutical drug regimens often encountered in the prophylaxis and treatment of infectious diseases.

Other than drug–drug interactions, drugs may interact with food (11); drink (12); nutri- ents (e.g., vitamins, minerals); alternative medicines (herbal products, homeopathic remedies) (13,14); drug formulations (e.g., excipients) (15); cytokines; or environmen- tal chemical agents (e.g., cigarette smoke) (16). Drug–food and drug–cytokine interac- tions are discussed in Chapters 12 and 13, respectively. Various disease states may also alter the magnitude and duration of interaction.

The term drug interaction is sometimes used to describe in vitro and ex vivo interac- tions that occur outside the body. These pharmaceutical or physicochemical interactions result from the physical incompatibility of drugs (e.g., admixtures in intravenous lines), from contact with pharmaceutical packaging or devices, or in loss of drug during laboratory analysis (e.g., binding to storage containers). This volume focuses on drug interactions that occur within the body.

PHARMACOKINETIC DRUG INTERACTIONS

Pharmacokinetic interactions alter the absorption, transport, distribution, metabolism, or excretion of a drug. Corresponding or independent changes in pharmacologi- cal response or therapeutic outcome may or may not occur (6,12,17,18). The rate and extent of absorption can be affected by physicochemical factors such as complexation and nonspecific adsorption of the drug and by physiological factors such as gastrointestinal motility, gastrointestinal pH, presence of gastrointestinal disease, gastric emptying time, intestinal blood flow, intestinal metabolism, and inhibition/induction of transport proteins (e.g., P-glycoprotein). In infectious diseases, changes in extent are more clinically important than changes in rate of absorption. As safety and effec- tiveness are concerns in pharmacokinetic interaction studies, the use of exposure rather than rate and extent of absorption concepts is encouraged, because the term exposure expresses more clinical relevance and focuses on the shape of the drug concentration–

time profile (19).

Altered distribution in drug interactions is explained mainly by displacement of drug from plasma proteins or receptor-binding sites. The most common binding proteins are the high-affinity, low-capacity protein α₁-acid glycoprotein and the low-affinity, high- capacity protein albumin. Protein-binding displacement interactions after oral and intravenous dosing of low hepatically and nonhepatically extracted drugs are generally clinically unimportant because unbound drug concentrations at steady state in plasma do not change or are only transiently changed by displacement (20–22). Average un- bound plasma concentrations at steady state of high hepatically extracted drugs administered orally are also not expected to be affected by displacement, provided that changes in bioavailability and unbound clearance are proportional. Moreover, drugs that are bound to both α₁-acid glycoprotein and albumin may show no overall change in fraction of unbound drug in plasma because displacement from α1-acid glycoprotein can be buffered by binding to albumin (e.g., saquinavir; [23]). Protein-displacement interactions may cause adverse events if the displaced drug is highly bound (>95%) to plasma proteins at therapeutic concentrations and has a small volume of distribution and a narrow therapeutic range.

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Most clinically relevant interactions result from changes in drug elimination caused by inhibition or induction of metabolic enzymes present in the liver and extrahepatic tissues (17,24). These processes can cause changes in intrinsic clearance of elimination pathways, which result in alterations in unbound plasma concentrations at steady state for orally administered drugs. The clinical consequences of inhibition or induction can be difficult to predict when active or toxic metabolites are present. Inhibition results in accumulation of the parent drug, whereas induction decreases concentrations of the parent drug. However, concentrations of active metabolites can increase or decrease depending on whether their formation and elimination are directly or indirectly affected by inhibition or induction and thus influence whether a metabolite predisposes patients to drug toxicity or lack of drug effectiveness. Furthermore, metabolites may persist longer than parent drug in plasma after an inhibitor is discontinued. The extent of pharmacokinetic consequences depends on the contribution to overall drug elimination and the relative importance of the affected pathways. Pharmacokinetic mechanisms are discussed in further detail in Chapters 2 and 3.

The outcome of a pharmacokinetic drug interaction may be no measurable pharmacological or toxicological effects or enhancement or diminution of these effects. Harm may result from interactions that cause elevated drug exposure, leading to an increase in adverse effects or reduced drug exposure, leading to a decrease in the desired effect or the development of drug-resistant organisms. However, benefit may be obtained from interactions that increase drug exposure, improve therapeutic outcome, and minimize side effects. The use of ritonavir to enhance blood concentrations of other protease inhibitors in antiretroviral treatment of HIV is an example of a beneficial pharmacokinetic interaction that provides enhanced viral suppression (4).

PHARMACODYNAMIC DRUG INTERACTIONS

Pharmacodynamic interactions are an alteration in the pharmacological response of a drug. They may be caused by direct competition at certain sites of action or by indirectly involving altered physiological mechanisms but do not always modify a drug’s concentration in tissue fluids. Different terminology is used to describe outcomes depending on whether two drugs are active or inactive (25). If the response from the combination is greater than predicted, then the outcome is termed synergism (both drugs active), potentiation (one drug active), or coalism (neither drug active). If the response is equal to that predicted, then the outcome is termed additivity/independence (both drugs active) or inertism (one or both drugs inactive). Antagonism refers to a less-than- predicted response if one or both drugs are active. Idiosyncratic interactions produce effects that are not expected based on the known effects of either agent when given alone.

Pharmacodynamic interactions can be beneficial in that an improved therapeutic response may occur or be detrimental in that toxicity may be heightened. Also, therapeutic activity and toxic effects may occur simultaneously in opposite directions, resulting in a balance between positive and negative responses. Beneficial pharmacodynamic drug interactions abound in infectious disease therapy because of the many of drug com- binations used to treat infections. An example of such an interaction is the effective synergistic combination of ampicillin and gentamicin or streptomycin in the treatment of enterococcal endocarditis (26).

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PHARMACOEPIDEMIOLOGY

The reports of overall frequency of drug–drug interactions vary widely in the litera- ture (27). Incidence rates reported in the 1970s and 1980s ranged between 2.2 and 70.3% for ambulatory, hospitalized, or nursing-home patients (28–34). Overall, the incidence of potentially harmful drug interactions is generally low, but certain populations, such as the elderly, extensive or poor metabolizers, those with hepatic or renal dysfunction, and those who are likely to take multiple medications, particularly for off- label use, are more at risk. Data collected over 1995–1997 suggest that potential interactions are as high as 75% in the population with HIV, with an actual 25% incidence of clinically significant interactions (35).

Some studies have attempted to quantify the incidence of symptoms resulting from these potential interactions. A range of 0 to 1% has been reported in hospitalized patients (36), but the incidence is likely increasing (35). Although the number of potential inter- actions may be high and the number of clinically significant interactions in many reports appears low, there are still data that indicate drug interactions can lead to harmful conse- quences (37–40). An inability to quantify the actual incidence accurately should not minimize the importance of this drug-related problem.

The variance in incidence in the early literature can be attributed to a number of factors (27–29,41). Study methodologies differed with respect to design (retrospective or prospective), population studied, interactions/categories that were assessed, defini- tions of clinical significance, denominators used to calculate incidence, and methods used to determine the incidence of the significant interactions (36). Underreporting of drug interactions also likely occurred.

Literature reports of drug interactions began in the 1970s, when there were fewer drugs on the market. Knowledge of mechanisms of interactions, particularly in drug metabolism, has since grown, leading to recognition of more potential interactions.

Improvements in analytical methods to measure drug levels in biological fluids has led to more refined and robust techniques with better selectivity, sensitivity, and efficiency for characterizing drug interactions. This has led to inclusion of pharmacokinetics (e.g., therapeutic drug monitoring) with clinical decision making for a number of agents. The means to evaluate drug interactions, either mechanistically or clinically, are now readily accessible to the clinician.

PHARMACOECONOMICS

The literature suggests that up to 2.8% of hospitalizations result from drug interac- tions (36). An association also has been found between the risk of hospitalization and interactions of various medications, including anti-infective agents, thus supporting the premise that drug interactions compromise health and incur costs (42). Individual case reports can demonstrate the measurable financial impact of drug interactions.

However, quality of life and cost to the patient and society are less apparent but equally or more important (43). Although data are scarce regarding cost increases secondary to drug interactions, the impact of such events remains a concern (44).

CLINICAL VS STATISTICAL SIGNIFICANCE

The term clinical significance describes the degree to which a drug interaction changes the underlying disease or the condition of the patient (45). The magnitude of

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the change in effects may be statistically significant but not clinically relevant. A measurable effect such as a change in blood drug concentrations or laboratory parameters must be interpreted regarding whether the effect produces a change in clinical outcome. An interaction is considered clinically relevant when the therapeutic activity or toxicity of a drug is changed to such an extent that a dosage adjustment of the medica- tion or medical intervention may be required (9). Next, the desired outcome must be assessed in relation to benefit and risk before changes in management are made.

An important statistical and clinical consideration is the evaluation of changes in both

“mean” and individual pharmacokinetic and pharmacodynamic variables. Drug interaction reports may conclude that a mean change is statistically and clinically insignificant, but certain individuals may be affected by the drug interaction. Evaluation of individual changes in study participants is therefore important to determine if a particular subset of individuals responds differently to the treatment. Conversely, some individuals are not affected by drug interactions even though significant mean changes may occur.

The aim of many interaction studies is to demonstrate that there is no clinically relevant interaction. The currently accepted bioequivalence approach (i.e., the inclusion of the 90% confidence limits for the ratio/difference of the means or medians within some prespecified equivalence range) seems appropriate (46). The equivalence interval represents the range of clinically acceptable variation in mean or median pharmacokinetic changes and is the only link between clinical and blood concentration significance. For agents with wide therapeutic windows, an equivalence range of

±20% or higher appears reasonable, depending on the drug. However, a smaller equivalence range may be required for agents with a narrow therapeutic window. A detailed presentation on biostatistical concepts in drug interaction studies is provided in Chapter 15.

CLINICAL SIGNIFICANCE GRADING

The clinical significance grading of a detrimental drug interaction can be difficult.

The level of documentation must be assessed to determine the degree of confidence that the interaction exists. The predictability of drug interactions from documentation can be divided into five levels: established (well documented), probable, suspected, possible, or unlikely. The data may be from in vitro studies, animal studies, anecdotal case reports, or randomized controlled trials in the target population or healthy volunteers.

The severity of the interaction must also be graded and can be classified into three levels: minor, moderate, or major. An interaction of minor severity is one that may occur but is not considered significant as potential harm to the patient is likely slight.

An example is the minor decrease in ciprofloxacin absorption with antacids when doses are taken more than 2 hours apart (47). An interaction of moderate severity is one for which potential harm to the patient may be possible, and some type of intervention/monitoring is often warranted. An example of a moderate interaction is the combination of vancomycin and gentamicin, for which monitoring for nephrotoxicity is important (48). An interaction of major severity is one that has a high probability of harm to the patient, including outcomes that are life threatening. An example is the development of arrhythmias caused by the coadministration of erythromycin and terfenadine (49).

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The Drug Interaction Facts classification scheme combines the three severity levels and five documentation levels into 15 interaction categories, with five levels of clinical significance assigned to those 15 categories (50). A scale of the clinical significance of drug–drug interactions that reflects the professional judgments of practicing pharma- cists has been proposed by Roberts et al. (45).

EVALUATION OF DRUG INTERACTION LITERATURE

Each report of a drug interaction must be assessed for a variety of criteria (17). Manage- ment decisions should be in response to clinically important outcomes resulting from coadministration of drugs. Consideration must be given to the time-course of the interaction (or lack thereof if a negative report is under assessment) to be sure that the occurrence of the most prominent effect is captured. The timing and order of administration of drugs must be evaluated in drug interaction reports because the sequence of administration can determine if an interaction will manifest. Interactions that affect drug absorption can often be mitigated by staggering the dosages and giving the object drug (i.e., drug with the effect that is altered) first. Examples are drug–food (Chapter 12) and quinolone–antacid (Chapter 8) interactions. Dose also affects interactions. A smaller-than-usual dose reduces the chance of observing an interaction, whereas a larger-than-usual dose increases the possibility of detecting an interaction.

Drug interactions reported for one member of a drug class may not reflect those of other members of that class (51). Drugs within a class usually have different pharmaco- kinetic properties, which lead to differing interaction patterns for individual drugs. Stud- ies in healthy volunteers instead of diseased subjects must be viewed with caution.

Patients may be at higher risk of adverse outcomes associated with a predisposition to drug interactions because of their disease. Also, study populations may be too restrictive and not representative of the target population. As mentioned in the Clinical vs Statisti- cal Significance section, another consideration is the reporting of mean pharmacokinetic changes that do not reflect the range of observed changes in certain individuals.

CLINICAL MANAGEMENT

After assessing the level of documentation in the literature and the significance grading of the interaction, consideration must be given to the onset and offset of the event, the mechanism, the change in outcome, management suggestions, and any discussion in the available literature concerning the interaction. When a patient has been identified to be at risk of experiencing a clinically relevant drug interaction, steps must be taken to prevent or minimize this potential event (17). If possible, the combination should be avoided or one or more of the agents stopped. The medication(s) may be replaced by noninteracting medication(s) that are therapeutically equivalent, doses may be staggered, dose strength or interval may be modified, or the route of administration may be changed.

An important consideration is not to overreact to potential interactions. Actions such as discontinuation of an important agent in the management of the patient, an unneces- sary increase or decrease in dose, needless increased visits for monitoring, or extrane- ous orders for drug concentration measurements or laboratory work are not desirable.

A five-class categorization system for management has been recommended and is pre- sented in Table 3 (52).

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CURRENT TRENDS: PREDICTION

OF IN VIVO INTERACTIONS FROM IN VITRO DATA

Although human studies provide the most definitive data on the likelihood and magnitude of a drug interaction, there are important limitations to performing such studies.

There is always potential risk to the subject, even if it is small or unlikely. Regulatory requirements for control and monitoring of these studies are becoming increasingly costly and time consuming. Consequently, the number and spectrum of studies that can be performed are limited. A search for alternatives has led to the use of human liver components (e.g., microsomes, hepatocytes) or other tissues to represent or predict the interaction in vivo (53). Chapters 2 and 3 provide an overview of in vitro methods to predict drug interactions.

There are now human liver banks that have microsomes and purified or recombinant human cytochrome P450 enzymes available for extensive in vitro study of metabolic pathways of new drugs (54). During early development of a new drug, these in vitro systems can predict if the drug will display variations in clearance from genetic polymorphism, and if the drug will be susceptible to clinically significant interactions. They also allow the determination of mechanisms of previously observed, unexplained interactions. Moreover, multiple drug interactions are easier to investigate in vitro than in vivo. Some concerns of in vitro/in vivo scaling include differences in the concentrations used in vitro compared to those obtained in vivo at the metabolizing enzyme (53,54), the isolation of the enzyme when studied in vitro, and the lack of specific markers available for in vivo studies to confirm in vitro findings (54). Nevertheless, in vitro screens offer a useful early warning system for the rational selection of in vivo studies provided there is careful analysis of all pharmacokinetic information available.

CONCLUSION

With the increasing appreciation of known and potentially important drug interactions covering the broad spectrum of infectious diseases, the need for clarification of

Table 3

Classification Scheme for Management of Drug Interactions

Class 1 Avoid administration of the drug combination. The risk of adverse patient outcome precludes the concomitant administration of the drugs.

Class 2 Combination should be avoided unless it is determined that the benefit of coadministration of the drugs outweighs the risk to the patient. The use of an alternative to one of the interacting drugs is recommended when appropriate. Patients should be monitored carefully if the drugs are coadministered.

Class 3 Several potential management options are available: use of an alternative agent, change in drug regimen (dose, interval) or route of administration to minimize the interaction, or monitor patient if drugs are coadministered.

Class 4 Potential for harm is low and no specific action is required other than to be aware of the possibility of the drug interaction.

Class 5 Available evidence suggests no interaction.

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the clinical importance of these interactions has become imperative. An awareness of the role of pharmacokinetics, pharmacodynamics, and factors that alter these processes and insight into differentiating clinical and statistically significant effects are important variables in the clinician’s process of decision making.

This volume is intended to provide an in-depth review of drug interactions related to a number of topics in infectious diseases. An emphasis on the clinical approach with specific examples and cases will guide the reader in developing skills for identifying drug interactions and problem drugs as well as strategies for circumventing of drug interactions.

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