General Principles of Pharmacokinetics and Pharmacodynamics

Drug effect is produced only when an exposure (amount and duration) occurs that is sufficient to produce a drug-receptor interaction capable of modulating the cellular milieu and inducing a physiologic response. Thus, exposure-response relationships for a given drug represent an interface between pharmacokinetics and pharmacodynamics that can be simply conceptualized by consideration of two profiles: plasma concentration vs. effect (Fig. 57-1) and plasma concentration vs. time (Fig. 57-2).

Figure 57-1 Plasma concentration vs. effect curve. The percent effect is measured as a function of increasing drug concentration in the plasma. The dosage at which no effect is seen in the population is E₀. The dosage required to produce a specified effect in 50% of the population is EC₅₀. The concentration associated with the maximal effect is E_max.

(From Abdel-Rahman SM, Kearns GL: The pharmacokinetic-pharmacodynamic interface: determinants of anti-infective drug action and efficacy in pediatrics. In Feigin RD, Cherry JD, Demmler-Harrison GJ, et al, editors: Textbook of pediatric infectious disease, ed 6, Philadelphia, 2009, Saunders/Elsevier, pp 3156–3178.)

Figure 57-2 Semilogarithmic plot of the plasma concentration vs. time curve for a hypothetical drug following extravascular administration. The area under the plasma level–time curve (AUC) is a concentration- and time-dependent measure of systemic drug exposure. After administration, the drug is absorbed and reaches the maximal concentration (C_max) at its peak time (T_max). Following completion of drug absorption and distribution, plasma drug concentrations decline in an apparent monoexponential fashion, whereby the slope of the apparent elimination phase represents the apparent elimination rate constant (ke).

(From Abdel-Rahman SM, Kearns GL: The pharmacokinetic-pharmacodynamic interface: determinants of anti-infective drug action and efficacy in pediatrics. In Feigin RD, Cherry JD, Demmler-Harrison GJ, et al, editors: Textbook of pediatric infectious disease, ed 6, Philadelphia, 2009, Saunders/Elsevier, pp 3156–3178, reproduced with permission.)

The relationship between drug concentration and effect for most drugs is not linear (see Fig. 57-1). At a drug concentration of 0, the effect from the drug is generally 0 or not perceptible (E₀). Following administration of drug and/or escalation of dosage, the concentration increases as does the effect, first in an apparently linear fashion (at low drug concentrations) and then with a nonlinear increase in effect to an asymptotic point in the relationship where a maximal effect (E_max) is attained that does not perceptibly change with further increases in drug concentration. The point in the concentration-effect relationship where the observed effect represents 50% of the E_max is defined as EC₅₀, a common pharmacodynamics term used to compare concentration-effect relationships between patients (or research subjects) and between drugs that may be in a given drug class. In practice, E_max can be derived either from visual interpolation of the concentration-effect profile or via mathematical curve fitting of the relationship.

Because it is rarely possible to measure drug concentrations at or near the receptor, it is necessary to use a surrogate measurement to assess exposure-response relationships. In most instances, this surrogate is represented by the plasma drug concentration vs. time curve. For drugs whose pharmacokinetic properties are best described by first-order (as opposed to zero- or mixed-order) processes, a semilogarithmic plot of plasma drug concentration vs. time data for an agent given by an extravascular route of administration (e.g., intramuscular, subcutaneous, intracisternal, oral, transmucosal, transdermal, rectal) produces a pattern depicted in Figure 57-2. The ascending portion of this curve represents a time during which the liberation of a drug from its formulation, dissolution of the drug in a biologic fluid (e.g., gastric or intestinal fluid, interstitial fluid; a prerequisite for absorption) and absorption of a drug are rate-limiting relative to its elimination. After the time (T_max) where maximal plasma concentrations (C_max) are observed, the plasma concentration decreases as metabolism and elimination become rate limiting, the terminal portion of this segment of the plasma concentration vs. time curve being representative of drug elimination from the body. Finally, the area under the plasma concentration vs. time curve (AUC), a concentration- and time-dependent parameter reflecting the degree of systemic exposure from a given drug dosage, can be determined by integrating the plasma concentration data over time.

By being able to characterize the pharmacokinetics of a specific drug in a specific condition, the clinician can adjust the “normal” dosing regimens for patients who, by virtue of development and/or disease, do not demonstrate “normal” dose-concentration-response relationships, thereby individualizing the dosage to produce the degree of systemic exposure associated with desired pharmacologic effects. For drugs whose therapeutic plasma concentration range and/or “target” systemic exposure (i.e., AUC) is known, a priori knowledge of pharmacokinetic parameters for a given population or patient within a population can help in selecting a drug-dosing regimen. When linked with information regarding the pharmacodynamic behavior of a drug and the status of the patient (e.g., age, organ function, disease state, concomitant medications), the application of pharmacokinetics allows the practitioner to exercise some real degree of adaptive control over therapeutic decision making by enabling him or her to select a drug and dosing regimen with the greatest likelihood of efficacy and safety.

Definitions of Terms

A glossary of pharmacokinetic terms helps equip the reader with a working knowledge of pharmacokinetics as a tool that can enhance therapeutic success.

Absolute bioavailability (F) is the fraction of a drug dose administered by an extravascular route that is absorbed into the systemic circulation. It is determined within a given individual by comparing the AUC following administration of an oral dose of a drug with the AUC resulting from an intravenous dose (e.g., F = (AUC_po × dose_iv) ÷ (AUC_iv × dose_po), with corrections made for possible differences in the terminal elimination rate constant between the dosing periods used for evaluation.

Absorption of drugs describes the process of drug uptake from a site of extravascular administration (oral, intramuscular, subcutaneous, intraperitoneal, intraosseous, intratracheal, intravaginal, intraurethral, sublingual, buccal, rectal, or dermal) into the systemic circulation. A critical prerequisite for drug absorption is that it be in true solution. Thus, in the case of administration of solid dosage forms (e.g., preparations for oral use), the active drug must first be liberated from the formulation wherein it is contained. Drug absorption is most accurately conceptualized by considering rate (e.g., absorption half life, time to peak concentration) and extent (e.g., bioavailability), either of which can be influenced by biopharmaceutical (e.g., drug formulation), physicochemical (e.g., pH, solubility, hydrophilicity and lipophilicity, protein binding, complexation characteristics with food or drugs), and physiologic factors (e.g., barrier integrity, motility, volume and pH of body fluids at absorptive site, protein binding capacity, or degradation or biotransformation potential).

Area under the curve (AUC) is, conceptually, a measure of both the extent of drug absorbed and its persistence in the body. Thus, it is both concentration- and time-dependent. Mathematically, AUC represents the integral of blood drug levels over time from 0 to either a predetermined postdose time point (AUC_0→tx) or extrapolated to infinity (AUC_0→∞), which is calculated by using the apparent terminal elimination rate constant (similarly calculated from the observed plasma concentration vs. time plot; see Fig. 57-2).

Bioequivalence of a drug product is achieved if its extent and rate of absorption are not significantly different (within 80-125%) from those of a reference standard drug product when administered at the same molar dose. The determination of bioequivalence does not entail a relative comparison of drug action and efficacy but rather is simply an assessment of whether one drug formulation (e.g., a generic drug) produces a rate and extent of absorption that is comparable to that of the reference formulation. It assumes that effect and toxicity profiles of the two drugs are virtually identical if the systemic exposures (as determined from AUC) are comparable.

Clearance of a drug is conceptually represented by the volume of blood from which a certain amount of unmetabolized drug is removed (cleared) per unit time by any and all pathways capable of drug removal (e.g., renal, hepatic, biliary, pulmonary, breast milk, sweat). In pharmacokinetics, clearance (Cl) is generally represented as either total body (or plasma) clearance, renal clearance (Cl_ren) or nonrenal clearance (Cl_nr). Clearance is easily determined from knowledge of the drug dosage and AUC and can be calculated as follows:

where AUC can either represent the AUC_0→∞ for single dose administration or the AUC from time zero to the end of the dosing interval at steady state (i.e., AUCss_0→τ). Calculation of Cl_ren requires a complete, quantitative collection of urine (usually over 24 hr) to determine the amount of drug excreted unchanged (Ae). Cl_nr is generally determined as the difference between Cl and Cl_ren. For drug administration by any extravascular route, the calculation of Cl yields an “apparent” value (e.g., Cl/F) which must be corrected for bioavailability.

A compartment in pharmacokinetics represents a hypothetical space that is helpful in quantitating the relationship between drug dosage and the amount of drug in the body at a given time. A simple 1-compartment open model treats all body fluids and tissues as 1 space with definable rates of drug ingress and egress and thus it greatly oversimplifies physiology. More complex models (2- and 3-compartment open models; physiologic models) separate fluid, organ, and/or tissue spaces into discrete spaces and therefore can be more precise in describing relationships between drug concentration and effect. Because of their mathematical complexity, the use of multicompartment models is largely limited to research settings. In all instances, compartmental models oversimplify the true processes of ADME. However, they have been repeatedly demonstrated to be useful as a means to reliably predict the relationship between drug dosage and concentration in plasma and tissue.

Disposition refers collectively to the processes of drug absorption, distribution, metabolism and elimination, all of which occur simultaneously following drug administration, as opposed to being discrete pharmacologic events.

Elimination half-life (T_1/2) of a drug represents the time for postabsorption blood or plasma concentrations to be reduced by 50%. The apparent elimination rate constant (ke) can be reliably estimated from two drug concentrations obtained on the elimination phase of the concentration vs. time curve (see Fig. 57-2). The T_1/2 is then determined as the natural logarithm of 2 divided by the elimination rate constant (T_1/2 = 0.693/ke). T_1/2 reflects the elimination of parent drug by all of the routes involved in its clearance. Although T_1/2 is often considered a surrogate indicator of drug clearance, this should be done cautiously because it depends upon the clearance and the apparent volume of distribution (Vd), as illustrated by the following equation:

Practically speaking, T_1/2 is an important pharmacokinetic parameter, because it can be used to determine the time required for a dosing regimen to produce steady-state plasma concentrations (e.g., 5 × T_1/2 elimination) and the time required for most of a drug to be completely eliminated from the body (e.g., 10 × T_1/2).

First-pass effect describes a phenomenon whereby a drug may be metabolized and/or chemically degraded following extravascular administration before it reaches the systemic circulation. It is generally a consideration for drugs given by the oral or rectal routes. Examples include biotransformation of selected drugs in the enterocyte, the transport or drugs from the enterocyte back into the lumen of the gastrointestinal (GI) tract, and the hydrolysis of active drug in the lumen of the GI tract. Drugs subject to first-pass effect generally have a reduced rate and/or extent of relative bioavailability when compared to that achieved with parenteral administration.

Protein binding results when a drug combines with plasma or with extracellular or tissue proteins to form a reversible drug-protein complex. Binding of drug and protein is usually nonspecific and depends on the drug’s affinity for the protein molecule (i.e., binding site), the number of protein binding sites, and the drug and protein concentrations. With few exceptions, drugs that are bound to proteins are pharmacologically inactive and cannot be readily metabolized or excreted. There are pharmacokinetic consequences of drug-protein binding that can influence the disposition profile. Drugs with extensive tissue binding have a Vd that is far in excess of the total body water space. Generally, these drugs have long elimination half-lives (e.g., phenothiazines, digoxin). Conditions where intravascular proteins escape to extravascular sites (e.g., nephrotic syndrome, severe burns, ascites) can increase the Vd and T_1/2 of drugs that are extensively (>70%) bound to albumin. Also, for drugs that have extensive binding to circulating plasma proteins, the concentration-effect profiles can differ as a consequence of altered unbound (free) drug concentrations in patients with normal vs. abnormal plasma protein concentrations (e.g., phenytoin neurotoxicity in a patient who has an apparently therapeutic total plasma drug concentration and hypoalbuminemia).

Relative bioavailability reflects the extent of drug absorbed from one dosage form given by an extravascular route of administration in comparison with a dosage of a “standard” drug formulation administered by the same route. Generally, it reflects the relative extent of systemic availability (F) and is calculated by a comparison of the AUC of the test article relative to the standard formulation (e.g., F = (AUC_test × dose_standard) ÷ (AUC_standard × dose_test).

Steady state reflects a level of drug accumulation in blood and tissue upon multiple dosing when the rate of input (the amount of drug placed into the systemic circulation) and output (drug clearance) are at equilibrium. When drugs are given at fixed doses and dosing intervals, the steady-state concentrations in blood or plasma fluctuate between a maximum (C_max) and minimum (C_min) within a given dosing interval. The interdose values of C_max and C_min should be identical provided that dose size, method of administration, dosing interval, and drug pharmacokinetics do not change between doses. For drugs that follow first-order pharmacokinetics, steady-state plasma concentrations are attained in a period corresponding to 4-5 times the T_1/2 after institution of treatment and/or a change in a given dosing regimen. In general, the pharmacokinetics of a drug at steady state provides the most accurate means to assess the drug’s effect(s).

Therapeutic range represents a range of plasma drug concentrations where the drug has desirable therapeutic effects in the majority of subjects receiving a drug at an age-appropriate “normal” (recommended) dosage. Consequent to interindividual differences in pharmacodynamics, some patients with plasma drug concentrations within a recommended therapeutic range exhibit either no discernable drug effect or concentration-related adverse drug effects. The therapeutic index (also known as therapeutic ratio) is a comparison of the amount of a drug that causes the desired therapeutic effect to the amount that causes death: Therapeutic index = LD₅₀/ED₅₀, where LD₅₀ and ED₅₀ represent the lethal and effective dosages, respectively, for 50% of the normal population receiving a drug.

Volume of distribution (apparent volume of distribution) represents a hypothetical volume of body fluid that would be required to dissolve the total amount of drug at the same concentration as that found in the blood and is illustrated by the equation

where Cp₀ represents the highest attainable plasma concentration following administration of a single dose. As a proportionality constant, Vd is a determinant of plasma drug concentrations attained following administration of a given drug dose. For drugs that do not distribute extensively or associate with great affinity to proteins and tissue, the Vd may dimensionally correspond to a physiologic or anatomic body space: Vd < 0.1 L/kg ≅ intravascular space, 0.1-0.3 L/kg ≅ extracellular space, 0.6-0.7 L/kg ≅ total body water space. Disease and development can influence the Vd, and thus the achievable concentration, for a given drug. Following extravascular drug administration, the apparent Vd is affected by the extent of drug absorbed (Vd/F). In instances in which a drug has incomplete absorption, plasma concentration can underestimate the true value of the Vd.

A working knowledge of these pharmacokinetic definitions makes it possible to understand the relationship among drug dose, concentration, and effect.

The Impact of Ontogeny on Drug Disposition

Development represents a continuum of biologic events that enable adaptation, somatic growth, neurobehavioral maturation, and eventually reproduction. The impact of development on the pharmacokinetics of a given drug is determined, to a great degree, by age-related changes in body composition and the acquisition of function in organs and organ systems that are important in determining drug metabolism and excretion. Although it is often convenient to classify pediatric patients on the basis of postnatal age for providing drug therapy (e.g., neonate ≤1 mo of age; infant = 1-24 m of age; child = 2-12 yr of age; adolescent = 12-18 yr of age), it is important to recognize that the changes in physiology are not linearly related to age and might not correspond to these age-defined breakpoints. The most dramatic changes in drug disposition occur during the first 18 mo of life, when the acquisition of organ function is most dynamic. Additionally, the pharmacokinetics of a given drug may be altered in pediatric patients consequent to intrinsic (e.g., gender, genotype, ethnicity, inherited diseases) or extrinsic (e.g., acquired disease states, xenobiotic exposure, diet) factors that can occur during the first 2 decades of life.

Selection of an appropriate drug dosage for a neonate, infant, child, or adolescent requires an understanding of the basic pharmacokinetic properties of a given compound and how the process of development affects each facet of drug disposition. Accordingly, it is most useful to conceptualize pediatric pharmacokinetics by examining the impact of development on the physiologic variables that govern drug ADME.

Dramatic pharmacokinetic, pharmacodynamic, and psychosocial changes occur as preterm infants mature toward term, as infants mature through the first few years of life, and as children reach puberty and adolescence (Fig. 57-3). To meet the needs of these different pediatric groups, different formulations are needed for drug delivery that can influence drug absorption and disposition, and different psychosocial issues influence compliance, timing of drug administration, and reactions to drug use. These additional factors must be considered in conjunction with known pharmacokinetic and pharmacodynamic influences of age when developing an optimal patient-specific drug therapy strategy.

Figure 57-3 Developmental changes in physiologic factors that influence drug disposition in infants, children, and adolescents. Physiologic changes in multiple organ systems during development are responsible for age-related differences in drug disposition. A, the activity of many cytochrome P450 (CYP) isoforms and a single glucuronsyltransferase (UGT) isoform is markedly diminished during the first 2 mo of life. In addition, the acquisition of adult activity over time is enzyme- and isoform-specific. B, Age-dependent changes in body composition, which influence the apparent volume of distribution of drugs. Infants in the first 6 mo of life have markedly expanded total body water and extracellular water, expressed as a percentage of total body weight, as compared with older infants and adults. C, Age-dependent changes in both the structure and function of the gastrointestinal tract. As with hepatic drug-metabolizing enzymes (A), the activity of CYP1A1 in the intestine is low during early life. D, The effect of postnatal development on the processes of active tubular secretion, represented by the clearance of p-aminohippuric acid and the glomerular filtration rate, both of which approximate adult activity by 6 to 12 mo of age. E, Age dependence in the thickness, extent of perfusion, and extent of hydration of the skin and the relative size of the skin surface area (reflected by the ratio of body surface area to body weight). Although skin thickness is similar in infants and adults, the extent of perfusion and hydration diminishes from infancy to adulthood.

(From Kearns GL, Abdel-Rahman SM, Alander SW, et al: Developmental pharmacology—drug disposition, action, therapy in infants and children, N Engl J Med 349:1157–1167, 2003.