Chapter 005. Principles of Clinical Pharmacology (Part 6)

Principles of Dose Selection The desired goal of therapy with any drug is to maximize the likelihood of a beneficial effect while minimizing the risk of adverse effects. Previous experience with the drug, in controlled clinical trials or in postmarketing use, defines the relationships between dose (or plasma concentration) and these dual effects and provides a starting point for initiation of drug therapy.Figure 5-1 illustrates the relationships among dose, plasma concentrations, efficacy, and adverse effects and carries with it several important implications:1. The target drug effect should be defined when drug treatment is started. With some drugs, the desired...
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Chapter 005. Principles of Clinical Pharmacology (Part 6) Chapter 005. Principles of Clinical Pharmacology (Part 6) Principles of Dose Selection The desired goal of therapy with any drug is to maximize the likelihood ofa beneficial effect while minimizing the risk of adverse effects. Previousexperience with the drug, in controlled clinical trials or in postmarketing use,defines the relationships between dose (or plasma concentration) and these dualeffects and provides a starting point for initiation of drug therapy. Figure 5-1 illustrates the relationships among dose, plasma concentrations,efficacy, and adverse effects and carries with it several important implications: 1. The target drug effect should be defined when drug treatment is started.With some drugs, the desired effect may be difficult to measure objectively, or theonset of efficacy can be delayed for weeks or months; drugs used in the treatmentof cancer and psychiatric disease are examples. Sometimes a drug is used to treat asymptom, such as pain or palpitations, and here it is the patient who will reportwhether the selected dose is effective. In yet other settings, such as anticoagulationor hypertension, the desired response is more readily measurable. 2. The nature of anticipated toxicity often dictates the starting dose. If sideeffects are minor, it may be acceptable to start at a dose highly likely to achieveefficacy and downtitrate if side effects occur. However, this approach is rarely ifever justified if the anticipated toxicity is serious or life-threatening; in thiscircumstance, it is more appropriate to initiate therapy with the lowest dose thatmay produce a desired effect. 3. The above considerations do not apply if these relationships betweendose and effects cannot be defined. This is especially relevant to some adversedrug effects (discussed in further detail below) whose development is not readilyrelated to drug dose. 4. If a drug dose does not achieve its desired effect, a dosage increase isjustified only if toxicity is absent and the likelihood of serious toxicity is small. Forexample, a small percentage of patients with strong seizure foci require plasmalevels of phenytoin >20 g/mL to control seizures. Dosages to achieve this effectmay be appropriate, if tolerated. Conversely, clinical experience with flecainidesuggests that levels >1000 ng/mL, or dosages >400 mg/d, may be associated withan increased risk of sudden death; thus dosage increases beyond these limits areordinarily not appropriate, even if the higher dosage appears tolerated. Other mechanisms that can lead to failure of drug effect should also beconsidered; drug interactions and noncompliance are common examples. This isone situation in which measurement of plasma drug concentrations, if available,can be especially useful. Noncompliance is an especially frequent problem in thelong-term treatment of diseases such as hypertension and epilepsy, occurring in25% of patients in therapeutic environments in which no special effort is made toinvolve patients in the responsibility for their own health. Multidrug regimens withmultiple doses per day are especially prone to noncompliance. Monitoring response to therapy, by physiologic measures or by plasmaconcentration measurements, requires an understanding of the relationshipsbetween plasma concentration and anticipated effects. For example, measurementof QT interval is used during treatment with sotalol or dofetilide to avoid markedQT prolongation that can herald serious arrhythmias. In this setting, evaluating theelectrocardiogram at the time of anticipated peak plasma concentration and effect(e.g., 1–2 h postdose at steady state) is most appropriate. Maintained highaminoglycoside levels carry a risk of nephrotoxicity, so dosages should beadjusted on the basis of plasma concentrations measured at trough (predose). Onthe other hand, ensuring aminoglycoside efficacy is accomplished by adjustingdosage so that peak drug concentrations are above a minimal antibacterialconcentration. For dose adjustment of other drugs (e.g., anticonvulsants),concentration should be measured at its lowest during the dosing interval, justprior to a dose at steady state (Fig. 5-4), to ensure a maintained therapeutic effect. Concentration of Drugs in Plasma as a Guide to Therapy Factors such as interactions with other drugs, disease-induced alterations inelimination and distribution, and genetic variation in drug disposition combine toyield a wide range of plasma levels in patients given the same dose. Hence, if apredictable relationship can be established between plasma drug concentration andbeneficial or adverse drug effect, measurement of plasma levels can provide avaluable tool to guide selection of an optimal dose. This is particularly true whenthere is a narrow range between the plasma levels yielding therapeutic and adverseeffects, as with digoxin, theophylline, some antiarrhythmics, aminoglycosides,cyclosporine, and anticonvulsants. On the other hand, if drug access to importantsites of action outside plasma is highly variable, monitoring plasma concentrationmay not provide an accurate guide to therapy (Fig. 5-5A ). Effects of Disease on Drug Concentration and Response