Appendix II: Design and Optimization of Dosage Regimens: Pharmacokinetic Data

Design and Optimization of Dosage Regimens: Pharmacokinetic Data: Introduction This appendix provides a summary of basic pharmacokinetic information pertaining to drugs that are in common clinical use and are delivered to the systemic circulation following parenteral or nonparenteral administration. Drugs designed exclusively for topical administration and those that are not significantly absorbed into the bloodstream (e.g., ophthalmic and some dermal applications) are not included. Approximately 750 drugs were considered. Less than half of these could be included in Tables A–II–1, A–II–2, A–II–3, A–II–4, A–II–5, A–II–6, A–II–7, A–II–8, A–II–9, A– II–10, A–II–11, and A–II–12 due to space limitations. Thus, some drugs that appeared in the ninth edition of this book were deleted to make space for the large number of new products that have reached the market since 1995. Pharmacokinetic data for many drugs not included in this appendix can be found in earlier editions of this book. A major objective of this appendix is to present pharmacokinetic data in a format that informs the clinician of the extent of interindividual differences in drug disposition and allows rational design of an appropriate drug-dosage regimen. Tables A–II–1, A–II–2, A–II–3, A–II–4, A–II–5, A–II–6, A– II–7, A–II–8, A–II–9, A–II–10, A–II–11, and A–II–12 contain quantitative information about the absorption, distribution, and elimination of drugs and the effects of disease states on these processes, as well as information about the correlation of efficacy and toxicity with drug concentrations in blood/plasma. The general principles that underlie the design of appropriate maintenance dose and dosing interval (and, where appropriate, the loading dose) for the average patient are described in Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination. The concept of individualization of dosage regimens for a particular patient is presented here. To use the data that are presented, one must understand clearance concepts and their application for drug-dosage regimens. One also must know average values of clearance as well as some measures of the extent and kinetics of drug absorption and distribution. The text below defines the eight basic parameters that are listed in the tabular material for each drug as well as key factors that influence these values both in normal subjects and in patients with particular diseases. It obviously would be most useful if there were a consensus about a standard value for a given pharmacokinetic parameter; rather than a wide range of reported estimates. Unfortunately, a generally agreed set of pharmacokinetic values has been reached for only a limited number of drugs. In Tables A–II–1, A–II–2, A–II–3, A–II–4, A–II–5, A–II–6, A–II–7, A–II–8, A–II–9, A–II–10, A– II–11, and A–II–12, a single set of values for each parameter and its variability in a relevant population has been selected from the literature, based on the scientific judgment of the authors. Most of the data are in the form of a study population mean value ± 1 standard deviation. However, some data are presented as mean and range of values (in parentheses) observed for the study population, with a dash separating the lowest and highest value reported. In some cases, only a range of values (separated by a dash) is reported. In other cases, only a single mean value for the study population was available in the literature and is reported as such. For some drugs, data were reported as a geometric mean with 95% confidence interval, and this is specifically indicated by a footnote. Finally, if there were sufficient data available, we also included in parentheses, below the primary study data, a range of mean values obtained from different studies of similar design.

Unless otherwise indicated in footnotes, data reported in the table are those determined in healthy adults. The direction of change for these values in particular disease states is noted below the average value. One or more references are provided for each of the established drugs, typically a recent paper or review on its clinical pharmacokinetics, which can then serve as a source for a broader range of papers for the interested reader. For the most recently approved drugs, multiple references are provided, including a review article where possible. Tabulated Pharmacokinetic Parameters Each of the eight parameters presented in Tables A–II–1, A–II–2, A–II–3, A–II–4, A–II–5, A–II–6, A–II–7, A–II–8, A–II–9, A–II–10, A–II–11, and A–II–12 has been discussed in detail in Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination. The following discussion focuses on the format in which the values are presented as well as on factors (physiological or pathological) that influence the parameters. Bioavailability The extent of bioavailability is expressed as a percentage of the administered dose. This value represents the percentage of the administered dose that is available to the systemic circulation—the fraction of the oral dose that reaches the arterial blood in an active or prodrug form. Fractional availability (F), which appears elsewhere in this appendix, denotes the same parameter; this value varies from 0 to 1. Measures of both the extent and rate (see Tmax ) of availability are presented in the table. An understanding of the extent of availability is essential to the design of a dosage regimen to achieve a specific target blood concentration (seeChapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination). Values for multiple routes of administration are provided, when appropriate and available, from the literature. In most cases, the tabulated value represents an absolute oral bioavailability that has been determined against an intravenous reference dose. For those drugs where intravenous administration is not possible, an approximate estimate of oral bioavailability based on secondary information (e.g., urinary excretion) is presented, or the column is left blank [denoted by a long dash (—)]. It is important to keep in mind that poor patient compliance may be mistaken for a reduced extent of bioavailability. A true decrease in bioavailability may result from a poorly formulated dosage form that fails to disintegrate or dissolve in the gastrointestinal fluids, interactions between drugs in the gastrointestinal tract, metabolism of the drug in the lumen of the gastrointestinal tract, first-pass intestinal metabolism or active efflux into the lumen, and first-pass hepatic metabolism or biliary excretion (seeChapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination). In the case of drugs with extensive first-pass metabolism, hepatic disease may cause an increase in oral availability because hepatic metabolic capacity decreases and/or because vascular shunts develop around the liver. Urinary Excretion of Unchanged Drug The second parameter in Tables A–II–1, A–II–2, A–II–3, A–II–4, A–II–5, A–II–6, A–II–7, A–II–8, A–II–9, A–II–10, A–II–11, and A–II–12 is the amount of drug eventually excreted unchanged in the urine, expressed as a percentage of the administered dose. Values represent the percentage expected in a healthy young adult (creatinine clearance equal to or greater than 100 ml/min). When possible, the value listed is that determined after bolus intravenous administration of the drug, for which bioavailability is assumed to be 100%. If the drug is given orally, this parameter may be underestimated due to incomplete absorption of the dose; such values are indicated in a footnote. The parameter obtained after intravenous dosing is of greater utility, since it will reflect the relative

contribution of renal elimination to the total body clearance irrespective of bioavailability. Renal disease is the primary factor that causes changes in this parameter. This is especially true when alternate pathways of elimination are available; thus, as renal function decreases, a greater fraction of the dose is available for elimination by other routes. Because renal function generally decreases as a function of age, the percentage of drug excreted unchanged also then decreases with age when alternate pathways of elimination are available. In addition, for a number of acidic and basic drugs with values of pK a in the range of the usual pH of urine, changes in the latter will affect the rate or extent of urinary excretion (seeChapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination). Binding to Plasma Proteins The tabulated value is the percentage of drug in the plasma that is bound to plasma proteins at concentrations of the drug that are achieved clinically. In almost all cases, the values are from measurements performed in vitro (rather than from measurements of binding to proteins in plasma obtained from patients to whom the drug had been administered). When a single mean value is presented, there is no apparent change in this percentage over the range of plasma drug concentrations normally found in patients taking the drug. In cases in which saturation of binding is approached at usual plasma drug concentrations, values are provided at concentrations that correspond to the lower and upper limits of the usual range. For some drugs, there is disagreement in the literature about the extent of binding, and the range of reported values is given. Plasma protein binding is affected primarily by disease states (such as hepatic disease or inflammatory diseases) that alter the concentration of albumin, 1-acid glycoprotein, or other proteins in plasma that bind drugs. Some metabolic states and conditions, such as uremia, also change the binding affinity of albumin for some drugs. Such changes in protein binding as a function of disease can dramatically affect the volume of distribution, clearance, and elimination half-life of a drug. Clearance Total systemic clearance of drug from plasma or blood [seeEquations (1–4) and (1–5), Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination] is given in Tables A–II–1, A–II–2, A–II–3, A–II–4, A–II–5, A–II–6, A–II–7, A–II–8, A–II–9, A–II–10, A–II– 11, and A–II–12. Clearance varies as a function of body size and, therefore, is presented most frequently in the table in units of ml · min–1 · kg–1 of body weight. Although normalization to measures of body size other than weight sometimes may be appropriate, weight is so convenient that its use often offsets any small loss in accuracy of clearance estimate, especially in adults. Exceptions to this rule are the anticancer drugs, for which dosage normalization to body surface area is conventionally used. When unit conversion was necessary, we used individual or mean body weight or body surface area (when appropriate) from the cited study or, if this was not available, we assumed a body mass of 70 kg or a body surface area of 1.73 m2 for healthy adults. In some cases, separate values for renal and nonrenal clearance also are provided. For some drugs, particularly those that are excreted predominantly unchanged in the urine, equations are given that relate total or renal clearance to creatinine clearance (also expressed as ml · min–1 · kg–1). For drugs that exhibit saturation kinetics, Km and Vmax are given and represent, respectively, the plasma concentration at which half of the maximal rate of elimination is reached (in units of mass/volume) and the maximal rate of elimination (in units of mass · time–1 · kg–1 of body weight). Concentration

of the drug in plasma (C p) must, of course, be in the same units as K m. As discussed in Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination, intrinsic clearance from blood is the maximal possible clearance by the organ responsible for elimination when blood flow (delivery) of drug is not limiting. When expressed in terms of unbound drug, intrinsic clearance reflects clearance from intracellular water. Intrinsic clearance is tabulated for a few drugs. It is also mathematically related to the biochemical intrinsic clearance [Vmax/(K m + C)] determined in vitro. For example, Vmax and Km parameters can be determined for any number of drug biotransformation pathways in liver homogenates, or microsomes or with purified enzyme. The total intrinsic clearance for the eliminating organ is the sum of the individual Vmax/(K m + C) terms for each pathway, scaled appropriately for the total mass of subcellular fraction or enzyme in the entire organ. For a drug that exhibits saturable metabolism or transport, intrinsic clearance is defined in terms of the concentration of drug in blood. When saturable metabolism or transport is not encountered in vivo (i.e., Cp << Km ), the intrinsic clearance (Vmax /K m) and total body clearance are constant. If one wishes to relate changes in elimination of drug to pathological changes either in the organ itself or to blood flow to the organ, it is necessary to express clearance with respect to concentrations of drug in blood rather than those in plasma. This requires measurement of concentrations in whole blood or knowledge of the distribution of drug between plasma and red blood cells (seeChapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination). Such information currently is limited, but is provided in a footnote when available. In almost all cases, plasma clearances are presented in Tables A–II–1, A–II–2, A–II–3, A–II–4, A–II– 5, A–II–6, A–II–7, A–II–8, A–II–9, A–II–10, A–II–11, and A–II–12, because these are most useful for relating drug dosage to plasma drug concentrations that have been determined previously to be effective or toxic. The few exceptions where clearance from blood is presented are indicated by footnote. Clearance can be determined only when the fractional availability (F) of the drug is known. Therefore, to be accurate, clearances must be determined after intravenous dosage. When such data are not available, the ratio of CL/F is given; values of this kind are indicated in a footnote. When a drug, or its active isomer for race- mic compounds, is primarily a substrate for a particu- lar cytochrome P450 (CYP) isoform or secretory transporter (as discussed in Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination), this information is provided in a footnote. This information is becoming increasingly important to understand and predict metabolically based drug-drug interactions. [For a more extensive coverage of this topic, see Metabolic Drug Interactions. (Levy, R.H., Thummel, K.E., Trager, W.F., Hansten, P.D., and Eichelbaum, M., eds.) Lippincott Williams & Wilkins, Philadelphia, 2000.] Volume of Distribution The total body volume of distribution at steady state (Vss) is given in Tables A–II–1, A–II–2, A–II– 3, A–II–4, A–II–5, A–II–6, A–II–7, A–II–8, A–II–9, A–II–10, A–II–11, and A–II–12 and is expressed in units of liters/kg, or in units of liters/m2 for some anticancer drugs. Again, when unit conversion was necessary, we used individual or mean body weights or body surface area (when appropriate) from the cited study or, if such data were not available, we assumed a body mass of 70 2 kg or a body surface area of 1.73 m for healthy adults. When estimates of Vss were not available, values for Varea were provided (seeChapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination). Varea represents the distribution volume during the terminal elimination phase and is computed readily by

dividing clearance by the terminal rate constant for elimination. Unlike Vss, this volume term varies when the rate constant for drug elimination changes, even though there is no change in the distribution space. Because we may wish to know whether a particular disease state influences either the clearance or the tissue distribution of the drug, it is preferable to define volume in terms of Vss, a parameter that is theoretically independent of changes in the rate of elimination. As in the case for clearance, Vss usually is defined in the table in terms of concentration in plasma rather than blood. Further, if data were not obtained after intravenous administration of the drug, a footnote will make clear that the apparent volume estimate, Vss/F, is offset by the bioavailability. Half-Life Half-life (t1/2 ) is the time required for the plasma concentration to decline by one-half when elimination is first-order. It also governs the rate of approach to steady state and the degree of drug accumulation during multiple dosing or continuous infusion, as described in Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination. For example, at a fixed dosing interval, the patient will be at 50% of steady state after one half-life, 75% of steady state after two half-lives, 93.75% of steady state after four drug half-lives, etc. Determination of half-life is straightforward when drug elimination follows a monoexponential pattern (i.e., onecompartment model). However, for a number of drugs, plasma concentration follows a multiexponential pattern of decline over time. The mean value listed in Tables A–II–1, A–II–2, A– II–3, A–II–4, A–II–5, A–II–6, A–II–7, A–II–8, A–II–9, A–II–10, A–II–11, and A–II–12 corresponds to an effective rate of elimination that covers the clearance of a major fraction of the absorbed dose from the body. In many cases, this half-life refers to the rate of elimination in the terminal exponential phase. For a number of drugs, however, a more prolonged half-life may be observed at very low plasma concentrations when extremely sensitive assay techniques are used. If this component accounts for 10% or less of the total area under the plasma concentration-time curve (AUC), predictions of drug accumulation in plasma during continuous or repetitive dosing will be in error by no more than 10% if this longer half-life is ignored, no matter how large its value. The clinician should know the half-life that will best predict accumulation in the patient. That will be the appropriate half-life to use for estimating the rate constant to incorporate into Equations (1–18) and (1–19) (seeChapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination) to predict time to steady state. It is this multiple dosing or accumulation half-life that is given in the table. Half-life is usually independent of body size because it is a function of the ratio of two parameters, clearance and volume of distribution, each of which is proportional to body size. Time to Peak Concentration Since clearance concepts are used most often in the design of multiple dosage regimens, the extent rather than the rate of availability is more critical to estimate the average steady-state concentration of drug in the body. However, in some circumstances, the degree of fluctuation between peak and trough concentrations, and as a result the drug efficacy and side effects profile, can be greatly influenced by modulation of drug absorption rate, such as the use of sustained- or extended-release formulations. Controlled-release formulations often permit a reduction in dosing frequency from 3 or 4 times daily to once or twice daily. There also are drugs that are given as a single dose for the relief of breakthrough pain or to induce sleep, for which the rate of drug absorption is a critical determinant of drug efficacy. Thus, information about the expected average time to achieve maximal plasma or blood concentration and the degree of interindividual variability in that parameter have been included in Tables A–II–1, A–II–2, A–II–3, A–II–4, A–II–5, A–II–6, A–II–7,

A–II–8, A–II–9, A–II–10, A–II–11, and A–II–12. The time required to achieve a maximal concentration (T max) is dependent, in part, on the rate of drug absorption into blood from the site of administration. From mass balance principles, Tmax occurs when the rate of absorption equals the rate of elimination from the reference compartment. Prior to this time, absorption rate exceeds elimination rate and the plasma concentration of drug increases. After the peak is reached, elimination rate exceeds the absorption rate and, at some point, defines the terminal elimination phase of the concentration-time profile. If drug is introduced at a constant and continuous rate, blood concentrations will rise until a steady-state level is achieved, where the two rates are equivalent. This applies to a constant rate intravenous infusion, but it also could apply to continuous delivery at any other site in the body. The rate of drug absorption will depend on the formulation and physicochemical properties of the drug, as well as on the anatomical barrier and blood flow to the delivery site. For an oral dose, some absorption may occur very rapidly within the buccal cavity, esophagus, and stomach, or absorption may be delayed until the drug reaches the small intestine or until the local pH in the intestine permits disintegration of the dosage formulation. In the most extreme case, the rate of absorption can be sufficiently controlled by the drug formulation to permit sustained or extended delivery as drug traverses the entire length of the gastrointestinal tract. In some instances, the terminal elimination of drug from the body following a peak concentration reflects the slower rate of absorption and not elimination ("flip-flop" effect). When more than one type of drug formulation is available commercially, we have provided absorption kinetic information for the two extremes, an immediate-release and a sustained-release formulation. Not surprisingly, the presence of food in the gastrointestinal tract can alter both the rate and extent of drug availability. We have indicated with footnotes when the consumption of food in proximity to the ingestion of an oral dose might have a significant effect on the bioavailability of the drug, such that specific recommendations are made by the manufacturer. Peak Concentration There is no general agreement about the best way to describe the relationship between the concentration of drug in plasma and its effect. Many different kinds of data are present in the literature, and use of a single effect parameter or effective concentration is difficult. This is particularly true for antimicrobial agents, since the effective concentration depends on the identity of the microorganism causing the infection. It also is important to recognize that concentrationeffect relationships are most easily obtained at steady state or during the terminal log-linear phase of the concentration-time curve, when the drug concentration(s) at the site(s) of action is expected to parallel that in plasma. Thus, when attempting to correlate a blood or plasma level to effect, the temporal aspect of distribution of drug to its site of action must be taken into account. Despite these limitations, it is possible to define effective or toxic concentrations for some of the drugs currently in clinical use, as reported in previous editions of this book. However, in reviewing the list of drugs approved within the last five years, it is rare to find a declaration of an effective concentration, even in the manufacturers' package labeling. Thus, it is necessary to infer effective concentrations from concentration-time profiles following effective dosage regimens. Although a mean steady-state blood or plasma concentration and the associated interindividual variability might be the most appropriate parameter to report, from first principles, these data often are unavailable even in the primary literature. One can estimate the mean steady-state concentration during a dose interval ( ss) by dividing the mean AUC by the duration of the dose interval. However, this approach does not apply to single-dose administration, nor does it permit the presentation of

expected population variability. Further, in some instances, drug efficacy may be more closely linked with peak concentration than with the average or trough concentration, and it is sometimes the case that differences in peak concentration for special populations (e.g., elderly) are associated with increased incidence of drug toxicity. For a number of clinical and practical reasons, the most commonly reported parameter, C max (peak concentration), is reported in Tables A–II–1, A–II–2, A–II–3, A–II–4, A–II–5, A–II–6, A–II–7, A– II–8, A–II–9, A–II–10, A–II–11, and A–II–12, rather than effective or toxic concentrations. This provides a more consistent body of information about drug exposure from which one can infer, if appropriate, efficacious or toxic blood levels. We acknowledge that the value reported is the highest that would be encountered in a given dose interval. However, Cmax can be related to the mean concentration and the trough concentration through appropriate mathematical equations (seeChapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination). Because peak levels will vary with dose, we have attempted to present concentrations observed with a customary dose regimen that is recognized to be effective in the majority of patients. When a higher or lower dose rate is used, the expected peak level can be adjusted by assuming dose proportionality, unless nonlinear kinetics are indicated. In some instances, there are only limited data pertaining to multiple dosing, so single-dose peak concentrations are presented. When specific information is available about an effective therapeutic range of concentrations or about concentrations at which toxicity occurs, it has been incorporated into a footnote. For every drug, the reader also is referred to a specific chapter or chapters in which more detailed information sometimes can be obtained. It is important to recognize that significant differences in C max will occur when comparing similar daily-dose regimens for an immediate-release and sustained-release product. Indeed, the sustainedrelease product sometimes is administered to reduce peak-trough fluctuations during the dosing interval and to minimize swings between potentially toxic or ineffective drug concentrations. Again, we have reported C max for immediate-release and extended-release formulations, when available. In addition to parent drug concentrations, we have tried to include information on any active metabolite that circulates at a concentration that may contribute to the overall pharmacological effect, particularly those active metabolites that accumulate with multiple dosing. Although total drug or metabolite concentrations are reported, it is important to recognize that the concentration of unbound drug determines the degree of pharmacological effect. Accordingly, changes in protein binding due to disease may be expected to cause changes in the unbound concentration associated with desired or unwanted effects. However, this is not always the case, since an increase in free fraction will increase the apparent clearance of an orally administered drug and of a low extraction drug dosed intravenously. Under such a scenario, the mean unbound plasma concentration at steady state will not change with reduced or elevated plasma protein binding, despite a significant change in mean total drug concentration. Alterations of Parameters in the Individual Patient Dose adjustments for an individual patient should be made according to the manufacturer's recommendation in the package labeling when available. This information is generally available when disease, age, or ethnicity has a significant impact on drug disposition, and particularly for drugs that have been introduced within the last ten years. In some cases though, a significant difference in drug disposition from the "average" adult can be expected, but it may not require dose adjustment because of a sufficiently broad therapeutic range. In other cases, dose adjustment may be necessary, but no specific information is available. Under these circumstances, an estimate of the appropriate dosing regimen can be obtained based on pharmacokinetic principles described in

Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination. Unless otherwise specified, the values in Tables A–II–1, A–II–2, A–II–3, A–II–4, A–II–5, A–II–6, A–II–7, A–II–8, A–II–9, A–II–10, A–II–11, and A–II–12 represent mean values for populations of normal adults; it may be necessary to modify them for calculation of dosage regimens for individual patients. The fraction available (F) and clearance also must be estimated to compute a maintenance dose necessary to achieve a desired average steady-state concentration. To calculate the loading dose, knowledge of the volume of distribution is needed. The estimated half-life is used to identify a dosing interval that provides an acceptable peak-trough fluctuation. The values reported in the table and the adjustments apply only to adults, unless specifically designated otherwise. Although the values at times may be applied to children who weigh more than about 30 kg (after proper adjustment for size; see below), it is best to consult a textbook of pediatrics or other source for definitive advice. For each drug, changes in the parameters caused by certain disease states are noted within the eight segments of the table. In most cases, a qualitative direction of changes is noted, such as " Hep," which indicates a significant decrease in the parameter in a patient with hepatitis. A reasonable, quantitative translation is to multiply the value of the parameter by 0.5 for each applicable condition that is noted to decrease the parameter and to multiply it by 2 for each condition that is noted to increase the parameter. Such an adjustment can be only approximate; yet, since reliable data are limited, no better approach may be possible. The relevant literature should be consulted for more definitive, quantitative information. Protein Binding Most acidic drugs that are extensively bound to plasma proteins are bound to albumin. Basic lipophilic drugs, such as propranolol, often bind to other plasma proteins (e.g., 1-acid glycoprotein and lipoproteins). The degree of drug binding to proteins will differ in pathophysiological states that cause changes in plasma-protein concentrations. Unfortunately, among binding proteins only albumin is commonly measured. For drugs that are bound to albumin (alb), a patient's fraction of unbound drug ( pt) can be approximated from the following relationship:

where albnl and nl refer to values of the concentration of albumin in plasma and the fraction of unbound drug in normal individuals, respectively. Use of this equation assumes that the molar concentration of drug is far less than that of albumin, that only one type of drug binding site is present on albumin, and that there are no cooperative binding interactions. Therefore, it is an approximation that is useful in the absence of actual measurement of the patient's plasma free fraction. Clearance For drugs that are partly or predominantly eliminated by renal excretion, plasma clearance changes in accordance with the renal function of an individual patient. This necessitates dosage adjustment that is dependent on the fraction of normal renal function remaining and the fraction of drug normally excreted unchanged in the urine. The latter quantity appears in the table; the former can be estimated as the ratio of the patient's creatinine clearance (CLcr) to a "rounded" normal value (100 ml/min per 70 kg body weight). If urinary creatinine clearance has not been measured, it may be

estimated from the concentration of creatinine in serum (Ccr). In men:

For women, the estimate of CLcr by the above equation should be multiplied by 0.85 to reflect their smaller muscle mass. The fraction of normal renal function is estimated from the following:

This provides a rough estimate, but more accurate ones are seldom necessary, since the adjustment of clearance is an approximation given the considerable degree of interindividual variation in nonrenal clearance. The following equation for adjustment of clearance uses the quantities discussed: rfpt = 1 – [fenl · (1 – rfxpt)] (A–4) where fenl is the fraction of systemic drug excreted unchanged in normal individuals (seeTables A– II–1, A–II–2, A–II–3, A–II–4, A–II–5, A–II–6, A–II–7, A–II–8, A–II–9, A–II–10, A–II–11, and A– II–12). The renal factor (rf pt) is the value that, when multiplied by normal total clearance (CLnl) from the table, gives the total clearance of the drug adjusted for the impairment in renal function. Example The clearance of vancomycin in a patient with reduced renal function (creatinine clearance = 25 ml/min per 70 kg) may be estimated as follows:

Importantly, such a dosage adjustment should be regarded only as an initial step in optimizing the dosage regimen; depending on the patient's response to the drug, further individualization may be necessary. In the case of reduced clearance with significant hepatic cirrhosis, as denoted by Cirr, a reasonable quantitative translation is to multiply the clearance by 0.5 and decrease the dosing rate by 50%. Again, such an adjustment can be only approximate, and the relevant literature or manufacturer's package labeling should be consulted for more definitive quantitative guidance. Conventionally, clearance is adjusted for the size of the patient to reflect a difference in the mass of the eliminating organ. For orally administered drugs, the applicability of such an adjustment may be limited by the available dosage strengths of commercial formulations. In some cases, the type of formulation permits physical splitting of the tablet (commercial tablet splitters are available) to increase the number of available dosages. However, this practice should be followed only with the

recommendation of the drug manufacturer, since it can compromise the systemic bioavailability of some products. With the exception of certain oncolytic agents, the data presented in the table are normalized to weight. Thus, interindividual variability in the weight-normalized clearance reflects a variation in the intrinsic metabolic or transport clearance, and not the size of the organ. Further, these differences can be attributed to variable expression/ function of metabolic enzymes or transporters. However, it is important to recognize that liver mass and total enzyme/ transporter content may not increase or decrease in proportion to weight in obese or malnourished individuals. Alternative approaches such as normalization for body surface area or the use of specific nomograms may be more appropriate. For example, many of the drugs used to treat cancer are dosed according to body surface area. In the tabulation, if the literature reported dose per body surface area, we chose to present the data in the same unit. If the cited clearance data were not normalized, but the preponderance of the literature utilized body surface area, we followed the practice of using individual values of body surface area or a standard of 1.73 m2 for a healthy adult. Volume of Distribution Volume of distribution should be adjusted for the modifying factors indicated in Tables A–II–1, A– II–2, A–II–3, A–II–4, A–II–5, A–II–6, A–II–7, A–II–8, A–II–9, A–II–10, A–II–11, and A–II–12, as well as for body size. Again, the data in the table are most often normalized to weight. Unlike clearance, volume of distribution in any individual is most often proportional to weight itself. Whether or not this applies to a specific drug, however, depends on the actual sites of distribution of drug; no absolute rule applies. Whether or not to adjust volume of distribution for changes in binding to plasma proteins cannot be decided in general, since the decision depends critically on whether or not the factors that alter binding to plasma proteins also alter binding to tissues. In such cases, the qualitative changes in volume of distribution are indicated in the table. Again, each adjustment to volume of distribution should be made independently of any other, and the final estimate should reflect all adjustments simultaneously. Half-Life Half-life may be estimated from the adjusted values of clearance and volume of distribution for the patient (pt):

Because half-life has been the parameter most often measured and reported in the literature, qualitative changes for this parameter are almost always given in the table. Individualization of Dosage By using the parameters for the individual patient, calculated as described above, initial dosing regimens may be chosen. The maintenance dose may be calculated with Equation (1–16) in Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination and the estimated values for CL and F for the individual patient. The target concentration may have to be adjusted for changes in protein binding in the patient, as described above. The loading dose may be

calculated using Equation (1–20) in Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination and the estimated parameters for Vss and F. A particular dosing interval may be chosen; the maximal and minimal steady-state concentrations can be calculated by using Equations (1–18) and (1–19) in Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination, and these can be compared with the known efficacious and toxic concentrations for the drug. As with the target concentration, these values may need to be adjusted for changes in the extent of protein binding. Use of Equations (1–18) and (1–19) also requires estimates of values for F, Vss, and k (k = 0.693/t1/2) for the individual patient. Note that these adjustments of the pharmacokinetic parameters for an individual patient are suggested for the rational choice of initial dosing regimen. As indicated in Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination, measurement of drug concentrations in the patient then can be used as a guide to further adjust the dosage regimen. However, optimization of a dosage regimen for an individual patient will depend ultimately on the clinical response produced by the drug. Acknowledgement The authors wish to acknowledge the contribution of Drs. Leslie Z. Benet, Svein Øie, and Janice B. Schwartz, authors of this appendix in the ninth edition of Goodman & Gilman's The Pharmacological Basis of Therapeutics, some of whose text and tabulated data have been retained in this edition.