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Era of Drug Interactions and PKPD Relationships

The importance of the relationship of changes in pharmacokinetics to drug safety and efficacy is a continuing topic of much discussion. One related area is drug interactions, which sometimes are extremely important. The interaction of fluorouracil and sorivudine, which caused a number of deaths in Japan 36 in the 1990s, served as an important reminder of the potential consequences of drug-drug interactions. Sorivudine was withdrawn in Japan after 15 patients who were prescribed both sorivudine and fluorouracil died. They had developed aplastic anemia, after taking sorivudine with fluorouracil. Knowing the situation that had occurred in Japan, sorivudine was not approved in the United States because of this potentially fatal drug interaction and the fact that alternative drugs to sorivudine were available, without the serious drug interaction potential. In response to the significance of drug interactions, Guidances for the study of potential drug interactions, both in vitro 38 and in...

Drug Interactions And Adverse Drug Reactions

Patients on polytherapy are more likely to have type A reactions. The likelihood of developing an adverse interaction increases with the number of drugs prescribed (D'Arcy, 1986). To date, this has largely been a problem in the elderly where polypharmacy is prevalent (Williamson and Chopin, 1980), but is becoming increasingly frequent in younger patients with chronic diseases such as AIDS, where patients may be on 6-10 different drugs (Bayard et al., 1992). An Australian study showed that 4.4 of all adverse drug reactions resulting in hospital admission were due to drug interactions (Stanton et al., 1994). Drug interactions due to effects on metabolic pathways may either be due to enzyme induction or enzyme inhibition (Brodie and Feely, 1991). Enzyme induction usually leads to increased metabolism of the drug and thus increases drug clearance. This will lead to reduced drug efficacy rather than drug toxicity (unless the adverse reaction is due to a metabolite rather than to the parent...

Drug Metabolism Drug Interaction Studies in the Drug Development Process Studies In Vitro Guidance 1998

The guidance covers the following topics observations and conclusions techniques and approaches for in vitro studies for drug metabolism and drug-drug interactions (DDI) correlations between studies in vitro and in vivo timing of metabolism studies labeling and related applications and considerations. This subject is discussed in detail in Chapter 6 of this book.

In Vivo Drug Metabolism Drug Interaction Studies Study Design Data Analysis and Recommendations for Dosing and Labeling

This guidance provides recommendations to sponsors of NDAs and biologies license applications (BLAs) for therapeutic biologies (hereafter drugs) who intend to perform in vivo drug metabolism and metabolic drug-drug interaction studies. The guidance reflects the Agency's current view that the metabolism of an investigational new drug should be defined during drug development and that its interactions with other drugs should be explored as part of an adequate assessment of its safety and effectiveness. For metabolic drug-drug interactions, the approaches considered in the guidance are offered with the understanding that whether a particular study should be performed will vary, depending on the drug in development and its intended clinical use. Furthermore, not every drug-drug interaction is metabolism-based, but may arise from changes in PK caused by absorption, tissue, and or plasma binding, distribution and excretion interactions. Drug interactions related to transporters or...

Drug Drug Interaction Studies

As per the guideline, such interactions are of particular importance to geriatric patients, who are more likely to be using concomitant medications than younger patients, but of course are not limited to this age group. Therefore it is a general principle, not specific to these guidelines, that in cases where the therapeutic range (i.e., a range of toxic to therapeutic doses) of the drug or likely concomitant drugs is narrow, and the likelihood of the concomitant therapy is great, that specific drug-drug interaction studies be considered. The studies needed must be determined case-by-case, but the following are ordinarily recommended

Methods To Assess Drugdrug Interaction Potential

In vitro studies are useful for assessing the potential of metabolism-based drug-drug interaction 2-4 , a major concern for the effective and safe use of therapeutic agents and a critical factor contributing to the recent withdrawal of various drugs from the United States market 5-6 . Since cytochrome P450 plays a key role in the metabolism of numerous important drugs in clinical use, cytochrome P450-mediated drug-drug interactions have attracted most attention, although the importance of transporter-based drug-drug interactions has also been recognized in the last few years. Central to the issue of metabolism-based drug-drug interactions is the identification of the cytochrome P450(s) responsible for the metabolism of the interacting drugs. Major activity alterations of the involving cytochrome P450 species, due to either inhibition or induction, can result in potential, significant pharmacokinetic changes of interacting drugs in humans. As described in the following sections,...

Contraindications and Drug Interactions

The long half-life of leflunomide must be taken into account to prevent drug interactions. Hepatotoxicity is possible if leflunomide is given in conjunction with a he-patotoxic agent such as methotrexate or certain NSAIDs. Leflunomide inhibits CYP2C9, the enzyme responsible for the metabolism of numerous drugs. Rifampin induces the P450 enzyme responsible for converting leflunomide

Pharmacokinetics metabolism and drug interactions

Olanzapine has a half-life of 24 to 30 h, which indicates that single daily administration is adequate. (6) The metabolic pathways of olanzapine involves CYP2D6, CYP1A2 and flavin-containing mono-oxygenases, as well as M-glucuronidation. It has a low potential for drug-drug interactions and requires extremely high concentrations not likely to be achieved under clinical conditions to inhibit cytochrome P-450 systems. Plasma levels of approximately 9.3 ng ml have been reported to predict better clinical response to olanzapine in inpatients with an acute exacerbation. (75) Amisulpride has a half-life of 10 to 15 h. It is well tolerated. There are no known drug interactions.

Adverse Effects Contraindications and Drug Interactions

Zanamivir is contraindicated in individuals with severe or decompensated chronic obstructive lung disease or asthma because it has not been shown to be effective in these individuals and can cause serious adverse pulmonary reactions. Individuals with mild to moderate asthma may have a decline in lung function when taking zanamivir. The safety and efficacy of this medication have not been determined in individuals with severe renal insufficiency. No clinically significant drug interactions have been reported. Zanamivir does not decrease the effectiveness of the influenza vaccine.

Drugdrug Interaction Mechanisms

Pharmacokinetic drug-drug interactions are commonly classified according to whether they occur during the absorption, the distribution, the metabolism, or the elimination phase (ADME). An alternative mechanistic classification scheme groups drug-drug interactions into i. drug-drug interactions based on the reaction with one or more macromolecules

Drug Drug Interactions with Involvement of Macromolecules

Drug-drug interactions with the involvement of macromolecules are based on either the blockade of binding sites of one drug by a competing drug, or generally, the change in binding behavior of a drug to a macromolecule in the presence of an interacting molecule, or a change in the amount of macromolecules present (e.g., an increase of drug metabolizing enzymes in the presence of enzyme-inducing drugs). Macromolecules that are important contributors of a drug-drug interaction can be drug-metabolizing enzymes, which catalyze phase I or phase II metabolic reactions, resulting in the formation and elimination of pharmacologically active and or inactive metabolites. Furthermore, a drug-drug interaction can take place as a result of an interaction of drugs with one or more, transporter proteins, which may be critical for the passage of drugs across biological membranes. This process is sometimes also being referred to as phase III of drug metabolism. In this particular case, the excretion...

Drugdrug Interactions based on Pharmacodynamic Pharmacokinetic and Pharmacodynamic Mechanisms

Pharmacodynamic-pharmacokinetic drug-drug interactions originate from situations, where a pharmacological effect of a particular drug can modify the pharmacokinetics of a second drug. For example, a compound which affects the gastrointestinal motility may influence the rate and extent of absorption of another co-administered drug by altering gastric emptying times and passage times across the small intestine. Thus the absorption of paracetamol can be delayed with concurrent administration of propantheline, a muscarinic receptor antagonist and with opiate-type analgesics. Metoclopramide and other prokinetic agents however, increase motility and transit of material in the gastrointestinal tract. The question as to whether the extent of drug absorption of a particular compound is modified by a prokinetic agent is frequently dependent on the intestinal permeability of the drug. For compounds with high permeability, the extent of drug absorption remains unchanged, since the residence times...

FDA Guidance on in vivo Metabolic Drug Interactions Studies

In November of 1999, the FDA issued a guidance on the study design, data analysis, and recommendations for dosing and labeling of in vivo metabolic drug interaction studies 95 . The basic concepts that are behind the recommendations in this guidance are as follows 4. The clinical importance of a drug interaction sometimes depends on the genetic polymorphism (whether a patient is considered a slow or fast metabolizer) of the individual. Moreover, other covariates such as age, race, and gender can be of prime importance in the clinical outcome of the interaction.

Drug Interactions

Antineoplastic drugs may participate in several types of drug interactions. Methotrexate, for example, is highly bound to serum albumin and can be displaced by sali-cylates, sulfonamides, phenothiazines, phenytoin, and other organic acids. The induction of hepatic drug-metabolizing enzymes by phenobarbital may alter the metabolism of cyclophosphamide to both active and inactive metabolites. Mercaptopurine metabolism is blocked by allopurinol, an occurrence that may result in lethal toxicity if the dosage of mercaptopurine is not reduced to one-fourth of the usual dosage. Methotrexate is secreted actively by the renal tubules, and its renal clearance may be delayed by salicylates.

European Guidance on the Investigation of Drug Interactions

The European Agency for the Evaluation of Medicinal Products issued in December 1997 a note for guidance on the investigation of drug interactions 98 . This guidance took effect in June 1998. Unlike the FDA guidance which only dealt with the in vivo metabolic aspects of drug interactions, the European guidance covered both pharmacodynamic and pharmacokinetic drug interactions (absorption, distribution, and elimination both at the renal excretion and hepatic biliary levels as well as changes in blood flow).

Canadian Guidance on Drug Drug Interaction Studies

According to this guidance all documented and anticipated drug interactions should be included in the Drug Interactions subsection of the Precautions section with appropriate cross references to other sections of the label. Drug interactions should be presented as contraindications if they have the capacity to be life-threatening, cause permanent damage, or elicit other reactions that would prohibit concomitant administration. Interactions having the potential to cause serious or severe consequences that are reversible or not life-threatening should normally be included in the Warning section together with recommendations for appropriate risk management measures. Drug interactions of unknown clinical significance or resulting in adverse effects that are merely bothersome can generally be adequately dealt with in the Drug Interactions subsection of the Precautions section. In addition when describing the results of in vivo clinical drug interaction studies, the monograph should...

Role Of Population Pharmacokinetics In The Study Of Drug Interactions

Collecting sparse sampling during the larger phase III clinical trials can help identify both the intrinsic and extrinsic factors that might affect exposure to a drug. Thus using such a screening approach might be valuable in detecting unsuspected drug-drug interactions especially in patients exhibiting a higher incidence of side effects. Both the U.S. FDA guidance and the Canadian guidance state that a well-executed population analysis can provide further evidence of the absence of a drug interaction when in vitro data suggest the lack of one. However, on the other hand both guidances agree that the sparse sampling approach to detect a drug interaction is not yet well established and that it is unlikely that one will be able to rule out an interaction that is strongly suggested by information that is obtained from in vitro or in vivo studies specifically designed to detect an interaction. This is due to the presence of confounding variables that are not controlled in the study that...

Vitamindrug Interactions

Drug interactions and the adverse effects that can result are a special concern. Although vitamins are not always thought of as being drugs, these nutrients can interact with drugs and result in a variety of effects. Vitamin-drug interactions can produce either a decrease or an increase in the effectiveness of the drug conversely, the intake of drugs can affect the disposition of vitamins in the body. Many drugs, such as some laxatives and cholestyramine, can produce vitamin malabsorption or fecal nutritional loss, resulting in drug-induced nutrient depletion and hypovitaminosis. Both fat-soluble and water-soluble vitamins can be affected by drug intake.

Contraindications Cautions and Drug Interactions

Dietary intake of vitamin K and prior or concomitant therapy with a large number of pharmacologically unrelated drugs can potentiate or inhibit the actions of oral anticoagulants. Laxatives and mineral oil may reduce the absorption of warfarin. The patient's pro-thrombin time and international normalized ratio (INR) should be monitored when a drug is added or removed from therapy. Selected drug interactions involving oral anticoagulants are summarized in Table 22.1. TABLE 22.1 Drug Interactions Involving Oral Anticoagulants TABLE 22.1 Drug Interactions Involving Oral Anticoagulants

Vancomycin and Drug Drug Interactions

Also avoid giving vancomycin if the patient has taken any aminoglycosides because they increase the potential for ototoxicity (ear) and nephrotoxicity (kidney). If the patient receives vancomycin and aminoglycosides, then you must closely monitor vancomycin serum levels to determine that it remains within the safe range. Drug-drug interaction may occur if administering Vancomycin with

Food and Drug Administration Rockville Maryland USA

Adverse drug reactions (ADRs) have had a major impact on morbidity, mortality, and health economics. In studies going back to 1974, up to the present time, approximately 15-20 of hospitalized children and 25-30 of hospitalized adults have experienced drug-related adverse events 3, 4 . The overall incidence of drug-induced adverse events in nonhospitalized patients is thought to be around 7 5 . The economic cost of drug-related morbidity and mortality to society has been estimated to be almost 200 billion dollars 6 . While there are many reasons, some of them unknown, for the relatively high incidence of ADRs (e.g., medication errors, drug interactions), it is thought that the majority of the risks associated with drug therapy are known and most drug-related adverse events are preventable 7 .

Role Of Clinical Pharmacology

Often, in parallel with phase III clinical trials, a group of clinical pharmacology studies, such as those in special populations, are conducted in human volunteers to develop a knowledge database of factors influencing drug exposure. These data are crucial for an understanding of when, and how much, to adjust dosage regimens. Because these studies typically focus on changes in systemic exposure, as a surrogate marker for either efficacy or toxicity, the availability and the intelligent use of exposure (e.g., dose, PK measurements)-response (e.g., biomarkers, surrogate clinical endpoints, clinical outcomes, PD) relationships to interpret the results of these studies become critical to information for various sections of the product label. These studies can be broadly classified into two broad categories (1) those dealing with patient-intrinsic factors that include gender, age, race, diseases states (primarily renal and or hepatic impairment), and genetic (e.g., activity of cytochrome...

M The United States Pharmacopoeia and The National Formulary

United States Pharmacopoeia Dispensing Information. The United States Pharmacopoeia Convention, Inc publishes the United States Pharmacopoeia Dispensing Information annual publication. This reference is designed to be used by individuals who dispense drugs and by persons who administer drugs after the drugs have been prescribed. The following information about a drug is discussed in the text category of use, precautions to use, (that is, drug interactions and medical warnings), drug preparation immediately prior to administration, side effects with an indication of their significance, guidelines for patient consultation on safe and effective use of the drug, dosing information, and requirements for packaging and storage. One section, Advice for the Patient, provides guidelines for patient use of the drug. These guidelines are written in lay terms. Bimonthly updates keep the information in the United States Pharmacopeial Dispensing Information current.

The Art And Science Of Diagnosis

Quired before diagnostic examination or clinical treatment is undertaken. Some patients require antibiotic prophylaxis before clinical examination because of systemic conditions like heart valve replacement, a history of rheumatic fever, or advanced AIDS. Patients who daily take anticoagulant medications may need to have the dose reduced or dosing suspended if the clinician is to conduct the thorough periodontal examination, which is integral to a complete endodontic workup. When patients report being infected with communicable diseases such as AIDS, hepatitis B, or tuberculosis, dentist and staff need to be especially attentive to the use of protective barriers. In case endodontic therapy is required, the clinician must know what drugs the patient is taking so that adverse drug interactions can be avoided. In such cases, consultation with (he patient's physician is recommended. Patients who present with mental or emotional disorders are not uncommon. Some patients are aware of their...

Systemic Administration

Some drugs can only be administered systemically. Because of the extensive blood supply to the lids, orbit, and posterior segment, drugs given via local injection can dissipate rapidly. In these cases, venous or oral administration can be highly effective and is often the route of choice. Drugs given in these ways have the potential to affect the body's entire system. Side effects and drug interactions increase markedly when drugs are administered systemically.

Discovery Assays by Stage DABS

The primary task of DMPK during the discovery support phase is to project the plasma exposure of potential therapeutic agents in humans by conducting appropriate studies in preclinical species or with human and animal in vitro systems. The ultimate mission for the DMPK group is to (1) eliminate drug attrition in clinical development due to exposure-based failures, (2) eliminate metabolism based toxicities, and (3) minimize the potential for drug-drug interactions. In 2002, a new discovery paradigm Discovery Assays by Stage (DABS) was initiated at Millennium Pharmaceuticals, Inc. The discovery process is divided into four stages (1) High Throughput Screen (HTS), (2) Hit to Lead (HTL), (3) Lead Optimization (LO), and (4) Development Candidate (DC) selection. The main emphasis of the HTS stage, for both medicinal chemistry and pharmacology, is to identify pharmacophore series chemical scaffolds (i.e. Hits). The involvement of DMPK at this stage is predictive ADME (i.e. pADME). Metabolism...

Drug Development In The United States

The modern uses of clinical pharmacology data in the United States may be thought of as having several phases, beginning with early efforts in the 1970s, which related to the increased availability of sensitive and specific analytical methods around that time. This was followed by application of these capabilities to various areas such as the study of specific subpopulations. Further implementation has emphasized the link of pharmacokinetic data to clinical safety and efficacy data. Most recent emphasis has included better understanding of drug interactions and optimal dose adjustment for various sub-populations. Communication of information and recommended approaches has been facilitated by the preparation of FDA Guidances as well as ICH Guidelines.

The relevance of studying Cytochrome P450s CYPs in the natural product industry

CYPs are involved in the metabolism of almost all drugs in the market today and have been shown to be crucial in the metabolism of a variety of natural products. They are linked to numerous drug-drug interactions 12 of particular interest has been the issue of drug-natural product interactions which has received much attention both in the scientific and non-scientific communities, given the global trend of increasing consumption of natural products. Table 1 illustrates a few examples, the involvement of specific CYPs, their toxicological and pharmacological impact and the mechanisms responsible for such interactions. Table 1. Examples of a few reported natural product-drug interactions involving CYPs Table 1. Examples of a few reported natural product-drug interactions involving CYPs The numerous reports of natural-product drug interactions 14,16-18 strongly suggest the value of undertaking such experiments involving the taking of natural products with prescription medicines, to...

CFR 30050Combination Drugs

Related to 21 CFR 300.50 from a clinical pharmacology and biopharmaceutics perspective, specifically for the scenario where the new combination product is to be administered as an alternative to giving two or more currently marketed, single ingredient products, one is referred to 21 CFR 320.25 (g) as identified above. Here it indicates that an in vivo bioavailability study is needed to determine if the rate and extent of absorption of each active drug ingredient or therapeutic moiety of the combination product is equivalent to the rate and extent of absorption of each active drug ingredient or therapeutic moiety administered concurrently in separate single-ingredient preparations. Information to address drug-drug interaction implications for the two or more drugs in a combination product is also usually needed.

Interactions In Relation To Multiple Drug Prescribing

Multiple drug prescribing which leads to the occurrence of drug-drug interactions. Drug interactions represent a change in either the magnitude or duration of action of one drug caused by the presence of a second. This may enhance or reduce the efficacy of one or both of the drugs or a new effect may appear which is not seen with either of the drugs alone. Interactions may be pharmacokinetic or pharmacodynamic. The most important adverse interactions occur with drugs that have easily recognisable toxicity and a low therapeutic index (i.e. the dose or plasma concentration of drug which is effective lies close to that which causes toxicity) (Lin and Lu, 1998).

Guideline for the Study of Drugs Likely to be used in the Elderly 1989

Even though written 12 years ago with the primary intent to advice sponsors on how to undertake clinical investigation of drugs likely to be used in the elderly, this guideline is a milestone in terms of identifying, explaining, and recommending clinical pharmacology studies in terms of drug-drug interactions, drug-disease interactions, special populations (elderly, renally impaired and hepatically impaired), and pharmacodynamic studies (in the elderly). Further, this guideline also established the concept of Pharmacokinetic Screen which has subsequently matured into the science of Population Pharmacokinetics. In view of the authors, this is a must-read classical document. Not surprisingly, this is also one of the first topics that were finalized at the ICH and in view of the authors, the E7 document, namely Clinical Trials in Special Populations Geriatrics is an excellent update of this '89 document. The E7 document is covered in detail later on in the chapter.

Stimulus Antagonism

An effective strategy for determining drug mechanisms involved in the stimulus effects of psychoactive agents is to study drugs which antagonize their effects. The rationale of this procedure is that the training agent will only be blocked by antagonists that interfere with the training drug's mechanism of action. Three approaches could be utilized. With the first approach it can be determined whether the stimulus effect of 1.0 mg kg of S(+)-amphetamine can be attenuated when various doses of a suspected antagonist, such as the dopamine D2 receptor antagonist haloperidol, are combined with the training stimulus. A dose-response antagonism of percent S(+)-amphetamine appropriate responding will occur in the case of haloperidol blocking the amphetamine stimulus. With the second approach the dose-response of S(+)-amphetamine is determined both in the presence and absence of a constant dose of haloperidol a shift of the amphetamine dose-response curve to the right could occur. A parallel...

Pharmacokinetic Studies

Often related to impairment of excretory (renal or hepatic) function or to drug-drug interactions. It is important to determine whether or not the pharmacokinetic behavior of the drug in elderly subjects or patients is different from that in younger adults and to characterize the effects of influences, such as abnormal renal or hepatic function, that are more common in the elderly even though they can occur in any age group. Information regarding age-related differences in the pharmacokinetics of the drug can come, at the sponsor's option, either from a Pharmacokinetic Screen or from formal pharmacokinetic studies, in the elderly and in patients with excretory functional impairment.

Specific neurotransmitter antagonists

Acamprosate is excreted unchanged in the kidney. It has few unwanted effects diarrhoea and abdominal discomfort are the only ones reported in more than 10 per cent of patients (up to 20 per cent) and these are mild and transient. It does not exacerbate psychomotor impairment caused by alcohol. There are no known drug interactions.

E8 General Considerations for Clinical Trials Guideline 1997

A very informative section in this guideline is Table 1 that provides an approach to classifying clinical studies according to objectives. The table breaks down the types of studies into four categories, namely Human Pharmacology, Therapeutic Exploratory, Therapeutic Confirmatory, and Therapeutic Use and lists the objectives of such studies along with examples. The first two categories of studies identify clinical pharmacology studies. The Human Pharmacology category comprises studies that assess tolerance, define describe PK and PD, explore drug metabolism and drug interactions, and enzyme activity. Examples of such studies are dose-tolerance studies, single and multiple dose PK and or PD studies, and drug interaction studies. Similarly, the Therapeutic Exploratory category consists of studies that explore use for the targeted indication, estimate dosage for subsequent studies, provide basis for confirmatory study design, endpoints, and methodologies. Examples of such studies are the...

Pharmacokinetic Pharmacodynamic and Dose Response Considerations

Evaluation of the pharmacokinetics and pharmacodynamics, and their comparability, in the three major racial groups most relevant to the ICH regions (Asian, Black, and Caucasian) is critical to the registration of medicines in the ICH regions. Basic pharmacokinetic evaluation should characterize absorption, distribution, metabolism, excretion (ADME), and where appropriate, food-drug and drug-drug interactions. Adequate pharmacokinetic comparison between populations of different regions allows rational consideration of what kinds of further pharmacodynamic and clinical studies (bridging studies) are needed for the new region. In contrast to the pharmacokinetics of a medication, where differences between populations may be attributed primarily to intrinsic ethnic factors and are readily identified, the pharmacodynamic response (clinical effectiveness, safety, and dose-response) may be influenced by both intrinsic and extrinsic ethnic factors and this may be difficult to identify except...

Studies Pertinent to Pharmacokinetics Using Human Biomaterials

The guideline defines human biomaterials as proteins, cells, tissues, and related materials derived from human sources, which are used in vitro or ex vivo to assess PK properties of drug substances. The types of studies identified are plasma protein binding studies, and hepatic metabolism and drug interaction studies. Examples include cultured human colonic cells that are used to assess permeability through biological membranes and transport processes, and human albumin that is used to assess plasma protein binding. Of particular importance is the use of human biomaterials such as hepatocytes and or hepatic microsomes to study metabolic pathways and to assess drug-drug interactions with these pathways.

Human Pharmacokinetic Studies

On occasion, PK studies may include measurement of drug distribution into other body tissues, body organs, or fluids (e.g., synovial fluid or cerebrospinal fluid). These studies should characterize the drug's PK and provide information about the absorption, distribution, metabolism, and excretion of a drug and any active metabolites in healthy subjects and or patients. Studies of mass balance and changes in PK related to dose (e.g., determination of dose proportionality) or time (e.g., due to enzyme induction or formation of antibodies) are of particular interest. Additional studies can also assess differences in systemic exposure as a result of changes in PK due to intrinsic (e.g., age, gender, racial, weight, height, disease, genetic polymorphism, and organ dysfunction) and extrinsic (e.g., drug-drug interactions, diet, smoking, and alcohol use) factors. In addition to standard multiple-sample PK studies, population PK analyses based on sparse sampling during clinical studies can...

Balancing Renal Clearance and Absorption

As a clearance route the renal route has attractive features for the design of drugs. For instance clearance rates, certainly for neutral compounds, are low. Moreover, the clearance process by filtration is not saturable and tubular secretion is only saturated at high doses with acidic and basic compounds. In a similar vein drug interactions

In vitroIn vivo Correlation

Although significant progress has been made in recent years in the evaluation of drug-drug interaction potential based on in vitro data, a complete understanding of the relationship between in vitro findings and in vivo human results of metabolism-based drug-drug interaction studies is still emerging. In some cases, excellent correlation of in vitro and in vivo results has been demonstrated while in others, the in vitro and in vivo correlation has been poor 15 . Because of the complexities of various factors impacting both in vitro and in vivo drug-drug interactions, accurate predictions of the extent of in vivo drug interactions from in vitro metabolic studies will require continued efforts in obtaining additional high quality correlation data to permit rational evaluation of new drugs. At the present time, the feasibility of predicting in vivo drug interactions based on in vitro metabolic data is still under rigorous debate. Some investigators believe that a quantitative prediction...

Cytochrome P450 Identification

Unequivocal identification of one or more specific cytochrome P450 enzymes responsible for the metabolism of new therapeutic agents is the cornerstone of in vitro metabolism studies. This information is also critical for the follow-up cytochrome P450 inhibition and induction studies in the overall evaluation of in vitro drug-drug interactions. For all these studies, the experimental conditions should be that the measured initial reaction rates (in terms of product formation) are linear with respect to enzyme concentration and incubation time. It is preferable to use low enzyme concentration (e.g., below 0.5mg human liver microsomal protein per mL) and short incubation time (less than 20 min) to minimize protein binding and depletion of substrate and inhibitor (no more than 20 consumption, preferably less than 10 ). If the analytical sensitivity is not an issue, lower enzyme concentration and shorter incubation time are highly desirable. In case of a slow substrate turnover, higher...

Cytochrome P450 Inhibition

If an NME and clinically co-administered drugs are metabolized by the same cytochrome P450 isoform, inhibition of this cytochrome P450 can lead to the accumulation of either of the drugs and thereby cause potential serious drug-drug interactions. This potential can be evaluated using an in vitro system of human liver microsomes in the presence of both the drugs. The importance in the proper use of concentrations of either of the drugs is as described in the preceding section. The Ki value for either of the drugs can be determined and the potential of drug-drug interaction of co administered drugs can be evaluated.

Cytochrome P450 Induction

Cytochrome P450 induction represents another mechanism for metabolismbased drug-drug interactions, although it is much less common than inhibition-mediated interaction events. Drug treatment can result in the induction of cytochrome P450 responsible for its own metabolism (i.e., auto-induction) or other cytochrome P450s responsible for the metabolism of co-administered drugs. The major effect of cytochrome P450 induction is the alteration of drug efficacy and safety over time due to increased clearance of therapeutic agents resulting in decreased parent drug concentrations and increased metabolite levels. In addition to primary human hepatocytes, other in vitro methods such as receptor ligand assay and reporter gene assay have also been used to evaluate the intrinsic induction potential of drug candidates 13, 32, 34 . A positive result of the in vitro induction study can help design clinical trials to determine if induction is likely to occur at clinical doses and if the extent of...

Exclude the impact of drugs

Many prescription drugs and several illicit drugs cause delirium ( Tabje.3 and Tab e.4). Of particular interest are those used commonly in intensive care settings (Tabje. . .4). A thorough review of the medications given, i.e. study of the nurse's records rather than the doctor's order book, is essential. The clinician must also be aware of drug-drug interactions that can lead to significant elevations of one or more drug levels even when used at deceivingly low dosages.

Digitalis And The Related Glycosides

Digitalis and related glycosides have very narrow therapeutic indices (the treatment dose is very close to the toxic dose) and many drug-drug interactions. The dose must also be adjusted in renal failure, which is common in CHF patients. For these reasons digitalis is reserved for acute symptomatic heart failure or in those patients with CHF and atrial fibrillation.

Benefit of Using Markers in the Drug Development Process

Rational Labeling Decisions Appropriate PK PD modeling with an acceptable biomarker helps assessing and interpreting the PK results of equivalence studies, i.e., food-effect, chronic renal and hepatic disease-effect, and drug-drug interaction studies, by allowing to define a target range of no clinically significant PK difference ( What-If Scenarios).

Psychopharmacological treatments

In the medically ill patient, both pharmacokinetic and pharmacodynamic changes may require dosage adjustments. Pharmacokinetics changes are produced by age, hepatic or renal disease, and drug interactions, as well as by smoking and the use of alcohol and illicit drugs. Many medically ill patients receive polypharmacy (five or more drugs per day), increasing the risk of decreased compliance and undesirable reactions to one of the drugs and of interactions between them.

Dosages and administration

Except for nortriptyline and the use of plasma concentrations to obtain a minimal effective level, it is generally the patient's clinical response that dictates dosage adjustments. One difficulty is that some patients with plasma concentrations outside the therapeutic range do respond and many patients with concentrations within the therapeutic range do not. Thus, the dosage needs to be adjusted depending on the individual patients response. Clearly plasma concentration monitoring can be helpful in many situations such as evaluating plasma levels when higher than standard doses are used, assessing toxicity, use in elderly patients or patients with comorbid conditions to evaluate possible drug interactions, or where compliance is questioned. Blood for drug levels is usually obtained for plasma levels during elimination phase which is usually in the morning 12 h after the last dose.

Effects of withdrawal

Before initiating therapy with carbamazepine, a medical history and physical examination should be performed, with emphasis on neurological, haematological, and hepatic abnormalities. It is also important to note any medications the patient is taking. The patient should be educated about the signs and symptoms of blood dyscrasias, hepatic failure, and severe dermatological reactions, and told to report these to the physician immediately. Patients, especially women taking oral contraceptives, should be educated about potential drug interactions.

Chapter References

Ketter, T.A., Post, R.M., and Worthington, K. (1991). Principles of clinically important drug interactions with carbamazepine. Part I. Journal of Clinical Psychopharmacology, 11, 198-203. 24. Ketter, T.A., Post, R.M., and Worthington, K. (1991). Principles of clinically important drug interactions with carbamazepine. Part II. Journal of Clinical Psychopharmacology, 11, 306-13. 25. Spina, E., Pisani, F., and Perucca, E. (1996). Clinically significant pharmacokinetic drug interactions with carbamazepine. An update. Clinical Pharmacokinetics, 31, 198-214.

Recommendations For Treatment Of Active Tuberculosis

Alternative regimens include isoniazid, rifampin, pyrazinamide, and either streptomycin or ethambutol for 2 weeks followed biweekly with the same regimen for 6 weeks, and subsequently with biweekly administration of isoniazid and rifampin for 16 weeks. In HIV-infected patients the treatment should be prolonged 9 to 12 months or sometimes even longer if the response is slow. Treatment of tuberculosis is more challenging in an HIV-infected population taking highly active anti-retroviral therapy because of drug interactions.

Nonnucleoside Reverse Transcriptase Inhibitors

All NNRTIs are active against HIV-1 reverse tran-scriptase only and do not require phosphorylation for activation. These agents share certain adverse effects (e.g., rash) and are subject to numerous drug interactions due to their metabolism by and induction of hepatic cytochrome P450 enzymes. NNRTIs may modify plasma levels of protease inhibitors, which are also metabolized by cytochrome P450 enzymes (Table 51.4). The list of drug interactions provided in this text is not all-inclusive it is necessary to check for all drug interactions when prescribing NNRTIs. These agents should be used with caution in patients with hepatic disease.

Interactions as a Result of Alterations in Plasma Protein Binding

Drug (restrictively cleared drug) may however be readily compensated by an increase in its clearance, and an additional buffering effect by an increase in its volume of distribution. Thus, although total drug plasma concentrations may be diminished in an interaction situation, the unbound concentrations of the drug may remain constant and no dosage adjustment needs to be made. An example is the displacement of phenytoin by valproic acid. Coadministration of valproic acid to phenytoin has been reported to decrease total steady-state plasma phenytoin concentrations in a dose-dependent manner 77 . In accordance with the theory, unbound concentrations of phenytoin remained constant in that study. On the other hand, the theory of plasma protein binding displacement interactions being the common cause of clinically significant interactions has been questioned 78 . In the case of valproic acid and phenytoin, additional mechanisms are likely to be the major ones responsible for the...

Physicochemical Interactions and Interactions based on Changes in Local pH and Ionization State of Molecules

A few drugs have structures that readily form chelate complexes with divalent or trivalent cations such as aluminium, magnesium, iron, or calcium. The complexed drugs are not absorbed across the intestine and hence their plasma concentrations may be subtherapeutic. Examples include quinolone antibiotics (e.g., ciprofloxacin) and tetracyclines which are markedly less absorbed when administered together with magnesiumaluminium antacids. Other cations, such as calcium, iron, and probably zinc, appear to interact in a similar manner. Cholestyramine is a basic anion-exchange resin used in the treatment of hypercholesterolemia. The hydrophilic but water insoluble powder is not absorbed in the GI tract, however, it can adsorb bile acids and a number of drugs (e.g., digitalis glycosides, coumarin, diuretics, quinidine, thyroxine, propranolol, and some antibiotics). As a safety precaution it has been recommended to discontinue resin administration for short-term courses of antibiotics,...

Study Design Considerations

One of the major considerations in designing a drug-drug interaction study is whether to dose the substrate (S) or the interacting drug (I) as single dose or chronically (multiple dose). On the other hand, the vast majority of absorption-based drug interaction studies with drugs such as antacids or drugs that affect gastric motility use a single single-dose study design since with this design one can determine whether the bioavailability of the S is affected.

Statistical Design Considerations

The most common statistical design for pharmacokinetic drug interactions is the crossover design accounting for half of all the studies submitted to the Agency from 1987 to 1997. More recently an increased reliance on a fixed sequence design (where a subject receives a drug for a According to the FDA guidance, the results of the drug-drug interaction studies should be reported as 90 confidence intervals about the geometric mean ratio of the observed PK measure with and without the interacting drug. Confidence intervals will provide an estimate of the distribution of the observed systemic exposure with and without the interacting drug and thus conveying a probability of the magnitude of the interaction. On the other hand, tests of significance are not appropriate for such studies due to the fact that clinically insignificant exposure differences can achieve statistical significance without having to recommend dosing adjustments or contraindications. Moreover, the FDA guidance...

Route of Administration

In general, it is recommended that both the substrate and interacting drug be administered in the same way these drugs are used (or going to be used clinically). However, if multiple routes of administration are possible, it might be necessary in some cases to investigate the possibility of drug interactions with the different routes of administration. This is particularly true for drugs that undergo gut wall metabolism whereby the amount of metabolism will differ between the oral and intravenous routes. Therefore it is thought that the differences in exposure that result from a drug interaction will be different depending on the route of administration (viagra interaction with erythromycin), which will consequently result in different dosing adjustment recommendations, then in such cases one is better off obtaining the true magnitude of interaction for the different routes of administration.

Genetic Polymorphisms And Response To Drugs

It is now commonly accepted that individual drug response is determined by both genetic and nongenetic factors. Polymorphisms may influence drug response in three ways, through (i) pharmacokinetic interactions (e.g., caused by the polymorphisms in the CYP450 system), (ii) pharmacodynamic gene-drug interactions (e.g., that involve gene

Human Immunodeficiency Virus HIV Infection

The complexity of treating HIV leads to many situations where exposure-response information is useful. Most patients take three or more antiretroviral drugs per day, in addition to drugs that treat or prevent opportunistic infections and treat complications of the antiretroviral agents, so there is the potential for many drug interactions. Many of the drugs are administered two or three times per day some drugs have stringent food restrictions. Exposure-response information helps determine appropriate dose and regimen adjustments when drugs interact with each other and when food alters exposure. Due to the large pill burden, drug companies want to use exposure-response information to support changes in formulations and dosing regimens. For example, a drug company may want to change a dosing regimen from three times per day to two times per day. When making such a change for a drug with dose-proportional pharmacokinetics, the twice daily regimen will provide similar total exposure to...

Interaction With Protease Inhibitors

Concerns were also raised in 1999 of a probable interaction between sildenafil and protease inhibitors leading to a potentiation of the effects of sildenafil and an increased likelihood of adverse effects.742 3 In Europe, Pfizer and European Union regulators agreed to a sildenafil labelling change that concomitant treatment with ritonavir is not advised, and planned to expand the drug interaction precaution to include other protease inhibitors.751 2 Similarly, in the United States, the FDA and Pfizer discussed updating the labelling of sildenafil to include a warning about possible interactions with protease inhibitors.751 2

Genetic and Environmental factors

Pharmacogenomics may help to explain much of the variation in response to medications, but it will not explain all of the difference. Drug interactions, age, nutrition, renal and liver function, and a variety of environmental factors influence the essential pharmocodynamics and pharmacokinetics of drug response (Evans and Relling, 1999 Omenn, 2001). Thus, to understand the role of genetic factors, it will also be necessary to study the effects of environmental factors, both individually and in combination. Only with greater knowledge about the role of both genetic and environmental factors will it be possible to develop drug response profiles for individual patients as well as patient-specific prevention strategies.

Adverse Reactions Contraindications and Interactions

It is recommended that echinacea not be taken by anyone for more than 8 continuous weeks, and most clinical use is under 2 weeks' duration. Echinacea has not yet been shown to be safe in pregnant or breastfeeding women and small children. No specific herb-drug interactions are reported, but for theoretical reasons those taking immunosuppressant drugs should avoid echinacea.

Treatment of depression

Tricyclic Antidepressants List

Tricyclic antidepressants are effective but require monitoring of cardiac function and drug levels in patients who are prone to toxicity and side-effects. Constipation and dry mouth are undesirable in cancer patients, especially those on opioids. Response time is also longer, which is often a problem. The side-effects of sedation and weight gain can be used to advantage. The tricyclic antidepressants are also well proven to be good adjunct analgesic agents, especially for neuropathic pain. They may be administered intramuscularly or by suppository when the patient cannot tolerate medication by mouth. Moreover, they are more affordable than other antidepressants. The commonly used antidepressants and their starting dose are outlined in Ta.ble6. Several antineoplastic agents utilize the hepatic cytochrome P-450 system, and the 3A4 isoenzyme appears to be particularly significant because it is also used by several antidepressants. For example, nefazodone and fluvoxamine inhibit the 3A4...

Disadvantages Of The Use Of Antianxiety Agents

The antianxiety agents can interact with central nervous system depressants to produce a further degree of depression to the central nervous system. Thus, patients who are on antianxiety therapy should be cautioned against drinking alcohol or taking other central nervous system depressants.

OnChip Protein Synthesis for Making Microarrays

Target Protein Array

The recent development of functional protein microarrays has stirred excitement in the proteomics community (1-7). The power of this approach is that, by spotting many proteins on a single array surface, many biochemical activities can be studied simultaneously. These activities include identifying interacting proteins, examining the selectivity of drug binding, finding substrates for active enzymes, and looking for unintended drug interactions. Typically, the array is probed with a labeled query molecule to identify interactions with proteins on

Metabolic Idiosyncrasy

For example, fasting leads to glycogen depletion and decreased glucur-onidation, depletion of glutathione and induction of CYP2E1 leading to an increased risk of paracetamol-induced liver injury (Price et al., 1987 Whitcomb and Block, 1994). Acquired factors enhancing the rate of biotransformation of a drug to its reactive metabolites through the induction of cytochrome P450 isoenzymes play an important role in increasing the direct toxicity. Alcohol is a potent inducer of CYP2E1 and to a lesser extent CYP3A4. Subjects who consume alcohol regularly may therefore have increased bioactivation of paracetamol (which is metabolised by CYP2E1 and 3A4), resulting in hepatotoxicity at conventional therapeutic doses (Zimmerman and Maddrey, 1995). In individuals with heavy alcohol intake this is compounded by reduced glutathione synthesis and low glutathione stores due to inhibition of glutathione synthatase and ethanol-related oxidative stress, respectively. Isoniazid...

Pharmacological Properties

Nimesulide is extensively metabolised in the liver following multiple pathways, including cytochrome P450 (CYP) 2C9 isoenzymes. Therefore, there is the potential for a drug interaction with concomitant administration of drugs which are metabolised by CYP2C9 (see under section 4.5). The main metabolite is the para-hydroxy derivative which is also pharmacologically active. The lag time before the appearance of this metabolite in the circulation is short (about 0.8 h) but its formation constant is not high and is considerably lower than the absorption constant of nimesulide. Hydroxynimesulide is the only metabolite found in plasma and it is almost completely conjugated. T1 2 is between 3.2 and 6 h.

First Generation Sulfonylureas

The first-generation sulfonylureas are not frequently used in the modern management of diabetes mellitus because of their relatively low specificity of action, delay in time of onset, occasional long duration of action, and a variety of side effects. They also tend to have more adverse drug interactions than the second-generation sulfonylureas. They are occasionally used in patients who have achieved previous adequate control with these agents.

Pharmacokinetic Interactions

Drug interactions may result in impaired drug absorption from the gastrointestinal tract. The rate at which a drug is absorbed may be decreased by drugs such as anticholinergics, which inhibit gastric motility conversely, drugs such as meto-clopramide (which increase gastric motility) may enhance the absorption rate. Certain drugs form chelates and complexes with other drugs, altering their solubility and absorption. For example, agents that bind to digoxin in the gut (such as antacids and cholestyramine) reduce the extent of its absorption by 20 -35 (Brown and Juhl, 1976). However, despite these potential interactions few drug-drug interactions affect drug absorption to a clinically significant extent (May et al., 1987 Mclnnes and Brodie, 1988). Drugs that undergo extensive first-pass metabolism may be affected by other drugs, which alter liver blood flow or compete for metabolism. For example, the non-selective monoamine oxidase inhibitors (MAOIs), such as phenelzine, reduce the...

On Adult Presentations

Drug-induced sleepiness is the most commonly reported side effect of central nervous system active pharmacological agents the 1990 Drug Interactions and Side Effects Index of the Physicians' Desk Reference lists drowsiness as a side effect of 584 prescription or OTC preparations (103).

Pharmacogenetic Interactions in Hormone Replacement Therapy

Both OCP and HRT enhance procoagulant and diminish anticoagulant activities in the plasma. When estrogen progesterone therapy is combined with inherited prothrombo-tic risk factors, the risk of VTE is further increased, confirming a pharmacogenetic interaction for this adverse drug reaction. Case-control studies of young women with and without a history of spontaneous DVT confirm a genetic-drug interaction (47,48). The risk of DVT was 3.8 and 6 times greater with OCP use, 7.9 and 9 times greater for carriers of FVL, and 6 times greater for carriers of PG 20210 (48). The relative risks for OCP and FVL were 20 and 34.7 and for OCP and PG20210, 16.3 (48), respectively, indicating a multiplicative interaction between drug and heritable risk factors. Both FVL and PG 20210 mutations are associated with an increased risk for cerebral vein thrombosis, and the risk is markedly increased with OCP use (49).

Codeine and Other Phenanthrene Derivatives

Adverse effects and drug interactions with codeine are similar to those reported for morphine, although they are less intense. Overdose in children results in the same effects as overdose of morphine, such as respiratory depression, miosis, and coma these symptoms are treated with naloxone administration.

Other Agents Of The Same Pharmacological Class

Specific chemical class usually associated with one therapeutic area but have later been developed or used clinically in an entirely different therapeutic area. Terfenadine is another typical example. It was discovered through a central nervous system programme aimed at synthesising new neuroleptic agents but because of its potent secondary pharmacological effects at the -antihistamine receptor, it was developed as the first non-sedating -antihistamine. It was a highly successful and popular drug until withdrawn due to reports of torsade de pointes resulting from drug interactions. Like all neuroleptics, it attracted considerable regulatory attention because of its effect on the QT interval. Sildenafil, originally intended for development as an antianginal drug, was developed instead for male erectile dysfunction and it is not surprising that at high concentrations, it has been shown to prolong cardiac repolarisation by blocking the rapid component of the delayed rectifier potassium...

Biotransformationbased Pharmacokinetic Interactions

A number of prominent drug products have been withdrawn in recent years because of severe drug-drug interactions and despite preclinical safety assessment. Mibefradil, a novel calcium antagonist, for example, was approved in Switzerland in 1996 and was also launched in the U.S. in 1997 as well as in several other European countries. Shortly following its launch as an antihypertensive and antianginal agent, reports about serious pharmacokinetic and pharmacodynamic interactions with other drugs frequently administered to patients with cardiovascular diseases were noted. These interacting drugs are to a great extent metabolized by Cytochrome P45o (CYP45o)-dependent microsomal enzymes, including widely prescribed drugs like quinidine, digoxin, cyclosporin A, terfenadine, and metoprolol. In addition, reports on severe rhabdomyolysis in patients on mibefradil who were simultaneously receiving lovastatin or simvastatin were issued. Mibefradil was reported to mainly inhibit CYP2D6 and 3A4...

Concluding Remarks And Future Strategies

Accumulating data suggests that OS might be involved in the pathogenesis of EAE and MS, and that antioxidant administration may be useful in the prevention and treatment of EAE. However, very few clinical studies have been performed to determine whether antioxidant intake might truly protect or slow down the progression of MS. To obtain efficacy in delaying MS progression, the candidate antioxidant must be given as early as possible, before oligodendrocyte and irreversible neuronal loss. It also should be tailored to the precise OS physiology, e.g. the type of ROS involved, the place of generation, and the severity of the damage. The chosen antioxidant should also be able to penetrate the BBB after systemic administration in order to attain a critical therapeutic level within the CNS. In addition, it should have a favorable safety profile with minimal drug-drug interaction in order to reduce adverse events. Thus, antioxidant cocktails or those combined with the conventional therapies,...

Regulatory Considerations

Evaluation of an NMEs drug-drug interaction potential is an integral part of the regulatory review prior to its market approval 1, 7 . The clinical pharmacology and biopharmaceutic review of an NDA focuses on key questions relevant to the review and integrates information across various Among drug-drug interaction questions, the following may be addressed via in vitro studies Is there an in vitro basis to suspect in vivo drug-drug interaction Depending on the answers to the above questions, additional studies may be conducted to fully assess the interaction potential of an NME with other drugs, herbal products, and or food juices. Figure 3 illustrates one algorithm in the evaluation of CYP enzyme-based drug-drug interactions of an NME starting with in vitro evaluations of the metabolic profile and the CYP enzyme-modulating effects of the NME using human enzymes. Based on the outcomes of these in vitro evaluations, which are reviewed along with additional in vivo clearance information,...


Inhibitory potency of drug candidates provide important information regarding their drug interaction potential. However, it must be recognized that clinical implications in terms of seriousness and scope of drug interactions resulting from inhibition of different CYP enzymes is considerably varied. For example, a potent inhibitor of CYP3A4, an enzyme that accounts for (i) metabolism of over 50 of all the pharmaceutical agents (Rendic and Di Carlo, 1997) and (ii) over 30 of all CYP enzymes present in human liver ((Shimada et al., 1994), should be considered unsuitable for further development because it is likely to cause drug interactions with a wide range of co-administered drugs. In contrast, inhibitors of CYP enzymes such as 1A1, 2A6, and 2B6 may affect only a few co-administered drugs because each of these CYP enzymes account for metabolism of


Physicians should exercise caution when prescribing drugs for pediatric and geriatric patients. This is virtually axiomatic in premature infants, whose severely restricted ability to metabolize drugs is well documented. Caution also must be exerted in prescribing for the elderly population, since these individuals may be taking 10 to 15 different drugs daily. Problems associated with drug interaction and declining physiological function are very real. It is simply inadequate to administer drugs to very young and very old patients strictly on a body mass basis. Dose adjustments often must be made empirically, depending upon the changing pharmacokinetic characteristics of the drug in question, the nature of the disease, and the physiological status of the major organs and tissues involved in drug absorption, distribution, metabolism, and excretion.

Specific Texts

Hansten wrote this text. It is written for the health-care provider who is concerned about drug interactions and or the effects upon clinical laboratory tests by specific agents. Section one of the book is divided into chapters based upon drug interactions of particular therapeutic categories. Section two deals with the impact of certain medications upon specific clinical laboratory test results. k. Facts and Comparisons. Facts and Comparisons, Inc wrote this reference. It is designed to be used by most medical personnel in general and by pharmacy personnel in particular. Facts and Comparisons are organized into twelve main chapters by drug use. Drugs and or drug products are listed together in such a way as to provide rapid comparisons between drugs or products that are similar in use or content. Individual drug monographs provide comprehensive information on drug actions, contraindications, warnings and precautions, drug interactions, adverse...

Year 2000 and Onward

Effective labeling has become an important topic, as large amounts of information become available for newly approved drugs. Drug interactions studied for a new drug have implications for the other drugs involved in the interactions and keeping labeling up to date for all drugs is a difficult task. As difficult is the task of healthcare providers being aware of all patient situations where dose adjustment may be appropriate, related to age, gender, race, renal or hepatic function, or drug interactions. FDA has proposed a new labeling format 42 in the effort to present important dosing and other safety information more clearly and obviously.


A dosage that yields a serum drug level ranging from 8 to 12 ug mL is recommended. Evening dosing may control decreased nighttime airflows and improve morning respiratory symptoms. Adverse drug interactions occur with ciprofloxacin, erythromycin, cimetidine, and zileuton.

Epilepsy Treatment

The majority of patients respond to drug therapy (anticonvulsants). In intractable cases surgery may be necessary. Drug treatment should be simple, preferably using one anticonvulsant (monotherapy). Poly therapy is to be avoided especially as drug interactions occur between major anticonvulsants.


So what does all this have to do with drug safety Aside from its potential impact on risk, comorbidities and their treatments may modify the risk of adverse events either directly or by increasing the probability of a drug interaction or exacerbation of one illness due to the treatment for another. Comorbidities may suggest product exposures that may not be captured by pharmacy claims data because they are over-the-counter (OTC) products, nutraceuticals, vitamins or substances like alcohol, tobacco or street drugs. However, detection of comorbidities, like the index diseases themselves, is dependent on the source of information. In studies using claims data, there are the obvious issues relating to coding, ascertainment, eligibility of patients for insurance coverage for certain services in clinical data, as in claims data, detection is dependent on the patient presenting with symptoms, the physician making the diagnosis, and the coding reflecting the encounter. This is very similar...

Figure 62

Decrease cocaine-maintained responding.38,39 This type of drug interaction has been attributed to a satiation of cocaine-maintained responding by pretreatment with a drug having dopaminergic effects. The latter approach to cocaine medication development has been referred to as substitute agonist pharmacotherapy.40 Hence, response-independent delivery of a dopamine reuptake inhibitor may have decreased cocaine self-administration by substituting for the reinforcing effects of response-produced cocaine. This interpretation is supported by studies showing that GBR 12909 will substitute for cocaine as a reinforcer in squirrel monkeys.41-43 Human drug use often involves a ritualized sequence of behaviors that occurs in a specific environment. The environmental stimuli associated with drug use are believed to play a major role in the maintenance of drug-seeking behavior.27 Second-order schedules of drug self-administration have been used in nonhuman primates to maintain extended sequences...


Complete draft sequences are now available for the genomes of many eubacteria, several archaebacteria, several unicellular eukaryotes, several plants and animals. As these sequences have accumulated it has become increasingly apparent that new methods are needed to exploit the information that they contain. Three types of proteomics have been applied in biology (Graves and Haystead 2002). Protein expression proteomics concerns the quantitative study of protein expression between samples that differ by some variables. This approach has allowed the determination of specific proteins in signal transduction or in disease processes. Structural proteomics aims to identify all proteins of a protein complex (e.g. in subcellular organelles) assessing their location and characterising all protein-protein interactions. Functionalproteomics,abroad termformany specifically directed proteomic approaches, allows the study and characterisation of a selected group of proteins and can provide important...


It has become increasingly evident that drug transporters, such as P-glycoprotein, play an important role in the absorption, distribution, and excretion of many drugs 36-38, 40 . Many substrates, inhibitors, and inducers of CYP3A4 are also substrates, inhibitors, and inducers of P-gp 40-45 . Drug-Drug interactions involving transporters, particularly P-glycoprotein, have become the new focuses in drug discovery and development. When drugs compete for the same binding sites on the P-glycoprotein molecule, drug-drug interactions can occur. At the present time, the in vitro methodologies have not been standardized for the identification of substrates and inhibitors for P-glycoprotein and other transporters. Prediction of the in vivo drug-drug interactions from in vitro studies is still problematic. It is expected that more selective probe substrates and inhibitors will be available for P-glycoprotein and other transporters (e.g., OATP, MRP, BCRP) in the future, and that our ability to...


Drug interactions and precautions for the use of methadone are similar to those of morphine. In addition, rifampicin and hydantoins markedly increase the metabolism of methadone and can precipitate withdrawal from methadone. Conversely, the tricyclic anti-depressants and certain benzodiazepines can inhibit metabolism of methadone, thereby increasing accumulation of the drug, prolonging its half-life, and intensifying its side effects. Continuous dosing with methadone may lead to drug accumulation and to an increased incidence of side effects methadone is generally not used for PCA. In pregnant heroin-addicted women, substitution of methadone for heroin has been shown to be associated with fewer low-birth-weight newborns and fewer learning and cognition problems later in the life of the child.


Nalbuphine (Nubain) is a mixed agonist-antagonist that is similar in structure to both the antagonist naloxone and the agonist oxymorphone. It is administered par-enterally and is equipotent to morphine and 5 times as potent as pentazocine. Although the pharmacological effects (analgesia, respiratory depression, sedation, and so on) are similar to those produced by pentazocine, nal-buphine produces fewer psychotomimetic effects. It differs from pentazocine in that it has far greater antagonist than agonist effect. Thus, its use is likely to precipitate severe withdrawal in opioid-dependent patients. It is used much as pentazocine is, that is, for moderate to severe pain, postsurgical anesthesia, and obstetrical analgesia. Nalbuphine's abuse potential is less than that of codeine and propoxyphene, although tolerance and dependence have been shown following chronic administration. High doses are perceived by addicts as being like those of the barbiturates. Drug interactions and...


Absorption of the active moiety is a stipulation for systemically acting drugs that are administered by an extravascular route 1 . Bioavailability is defined as the rate and extent of absorption of the intact drug or active moiety. Studies that concern the evaluation of dose-linearity, potential food-drug interactions, and the pharmacokinetics after repeated administration are discussed in subsequent sections of this chapter. Alternative approaches, i.e., pharmacodynamic studies, to those described in this chapter might be necessary for locally acting drugs, where systemic exposure is not intended and cannot be assessed. However, if the bioavailability (or bioequivalence) of a drug can be determined by a pharmacokinetic study, a pharmacodynamic approach is not recommended.

Multidrug Resistance

One of the salient features of P-gp is its broad substrate recognition pattern. Over the past decade the substrate list expanded from the original description of P-gp as conferring resistance to the vinca alkaloids and anthracyclines, to the current very large list of compounds, which includes structurally unrelated anticancer agents, antihuman immunodeficiency virus (HIV) agents, and fluorophores. A classification of the drug interaction with P-gp has been done on four categories agonists, partial agonist, antagonists, and nonsubstrates 32 . An agonist would be both an ATPase activator and a transport substrate. Some typical examples are the classical substrates of P-gp, that is, the anthracyclines and the vinca alkaloids. A partial agonist would be a molecule that stimulates the P-gp ATPase activity but which does not show any significant transport substrate features. To this group belong verapamil and progesterone, both of which activate P-gp at the catalytic level, but inhibit at...


The second-generation Hj-receptor antagonists are also rapidly absorbed, with peak plasma concentrations being reached within 1 to 3 hours. Their duration of action generally varies between 4 and 24 hours (Table 38.2). Loratadine (Claritin) and its active metabolite, desloratadine (Clarinex), undergoes extensive first-pass metabolism and is converted by CYP3A4 isozymes to an active metabolite. A number of drug interactions result from the ability of various compounds to induce, inhibit, or compete for metabolism by this cytochrome P450 system. In contrast, cetirizine (Zyrtec) and fexofenadine (Allegra) undergo little hepatic metabolism and are eliminated mainly as unchanged compounds in the urine and feces, respectively.

The Safety Mandate

Legal responsibilities of pharmacists have changed dramatically in recent years. A lengthy body of case law now recognizes a firm responsibility of pharmacists to detect and rectify obvious errors in a physician's prescription (Hornish, 2000). When a pharmacist observes that a physician has prescribed a medication that may lead to a significant drug-drug interaction, an overdose, or an allergic reaction, the pharmacist has a legal duty to contact the physician. The attention paid to medical error in the widely publicized Institute of Medicine Report entitled To Err is Human (Kohn et al., 2000) has emphasized the importance of this prescription-screening function. Pharmacists cannot guarantee that all prescribing has been done without error, but they are responsible for ensuring that an obvious mistake by a physician is brought to the physician's attention. The pharmacist functions as a safety net in drug therapy, ensuring that patients receive what their physician intends and not what...


MAOIs have been used for many years to treat phobic states, and evidence of the efficacy for some, particularly phenelzine, is quite impressive. Unfortunately, the well-known range of unwanted effects, including hypotension, oedema, and dietary and drug interactions, preclude their widespread use. The selective reversible MAOI antidepressant, moclobemide, has been evaluated in social-anxiety disorder with some success. A similar compound, brofaromine, appeared even more successful in anxiety disorders, but its development has been discontinued. (4

Interactions Lithium

Owing to its renal excretion, lithium has renally mediated rather than hepatically mediated drug-drug interactions. Lithium excretion is decreased by medications such as thiazides, non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, and, to a lesser extent, frusemide (furosemide), and by physiological states such as dehydration, advanced age, and renal disease (T. ble ,3.).(66) Owing to lithium's poor therapeutic index, these interactions can result in clinical lithium toxicity, unless a dosage adjustment is made. In contrast, lithium clearance is less consistently affected by amiloride, acetylsalicylic acid, and sulindac, and increased with other medcations with diuretic effects such as acetazolamide, mannitol, aminophylline, caffeine, and theophylline, as well as during pregnancy. Increases in lithium clearance may yield clinical inefficacy if plasma lithium concentrations fall below the therapeutic range. Table 3 Summary of the most important drug...


In general, valproate can be combined safely with other psychotropic medications and antiepileptic drugs. However, given that valproate is highly protein-bound and can inhibit hepatic enzymes, some drug- drug interactions have been identified. (3) Aspirin, which is highly protein-bound, has been found to significantly elevate the free fraction of valproate, resulting in increased effects of valproate on the central nervous system. Valproate can displace diazepam, phenytoin, carbamazepine, and warfarin from protein-binding sites, resulting in increased activity of these drugs. Co-administration of valproate with lamotrigine significantly increases the half-life of the latter and can increase the risk of lamotrigine-induced rashes. When administered with carbamazepine, three potential interactions may occur valproate can increase the concentration of carbamazepine's metabolite, carbamazepine-10,11-epoxide, by inhibiting its further metabolism carbamazepine may lower the valproate level...

Dose Adjustments

An important factor in deciding the dose adjustment is the knowledge of exposure-response relationship 1 . Delineation of no-effect boundaries, based on dose- and or concentration-response studies would be beneficial. Once the influence of intrinsic and extrinsic factors on drug exposure has been characterized and exposure-response has been established, appropriate dose adjustments can be recommended. Guidance on special populations (hepatic, renal) and extrinsic factors (food effect, drug interactions) recommend that in the absence of exposure-response data, the employment of a standard 90 confidence interval of 80-125 for AUC and Cmax can be used. If differences for populations of interest are within these boundaries then dose adjustments are not needed. These guidances also acknowledge that FDA recognizes that documentation that a PK parameter remains within an 80-125 no effect boundary would be very difficult given the small numbers of subjects usually entered into these studies....

Side Effects

The systemic effects and drug interactions of all antibiotics are too exhaustive to list. The potential for allergic, toxic, and other adverse reactions exists with all antimicrobial agents. Such responses are related to the specific drug chemistry, dosage, route of administration, age of the patient, and the patient's liver and kidney function. Specifics of individual ophthalmic drugs will be covered where applicable within the text. However, there are a few general conclusions that can be made about most antimicrobial therapies.

BPhenytoin Dilantin

Drug interactions can occur between phenytoin and alcohol, barbiturates, folic acid, coumarin-type anticoagulants, disulfirams, the sulfonamides, and sympathomimetic agents. Phenytoin should be used cautiously with patients who are alcoholics or who have blood dyscrasias.


Rifabutin appears as effective as rifampin in the treatment of drug-susceptible tuberculosis and is used in the treatment of latent tuberculosis infection either alone or in combination with pyrazinamide. Clinical use of rifabutin has increased in recent years, especially in the treatment of HIV infection. It is a less potent inducer of cytochrome 450 enzymes pathways than ri-fampin and results in less drug interaction with the protease inhibitors and nonnucleoside reverse tran-scriptase inhibitors. Rifabutin is therefore commonly substituted for rifampin in the treatment of tuberculosis in HIV-infected patients. Another important use of ri-fabutin in the HIV-infected population is prevention and treatment of disseminated MAC. The adverse effects that most frequently result in discontinuation of rifabutin include GI intolerance, rash, and neutropenia. Rifabutin levels will be increased with concurrent administration of fluconazole and clar-ithromycin, resulting in anterior uveitis,...


We use the interleukin 2 (IL-2) inhibitor tacrolimus in place of cyclosporine for primary immunosuppressive therapy in heart transplant recipients. Compared with cyclosporine (also an IL-2 inhibitor), tacrolimus-treated heart transplant recipients have a lower incidence of hypertension and an improved quality of life. However, in a series of liver transplant patients treated with either tacrolimus or cyclosporine, the tacrolimus-treated group displayed a twofold increase in neuro- and nephrotoxicity. Since toxicity and efficacy are dependent on blood levels, and given the wide array of drug interactions seen with both cyclosporine and tacrolimus, adding or withdrawing medications from the transplant patient's regimen requires caution and knowledge of drug interaction. Medications that may alter each other's blood levels are listed in Table 4 and Table 5. Table 5 Based on clinical experience these medications may alter tacrolimus levels (no formal drug interaction studies with...