Principles of Drug Therapy

Lee Goldman MD , in Goldman-Cecil Medicine , 2020

Problems with Interpreting Drug Concentration

The time of blood collection, perhaps more than any other factor, contributes to the misinterpretation of drug levels. As can be seen inFigure 26-2 , if sampling is performed too early, while the drug is still in the distribution phase, the drug level may be high and not reflect drug concentration at the site of action. It is therefore important to sample after the distribution phase.

For many drugs administered intermittently, a trough level, obtained immediately before the next dose is administered, is most useful for making decisions about dose adjustments (seeTable 26-1). For drugs administered by infusion or intermittently at short intervals (seeFig. 26-4), the best time to draw blood is during steady state.

Protein binding is another major factor that contributes to the misinterpretation of drug levels. Free drug (not bound to protein and able to equilibrate with tissues and to interact with the site of action) is the critical drug concentration when therapeutic decisions are being made. Many drugs are tightly bound to plasma protein, however.Table 26-1 shows that many commonly used drugs, such as aspirin, carbamazepine, phenytoin, and glimepiride, have protein binding of more than 75%. Because many of the commonly used drug assays determine total drug concentration (which includes protein-bound drug and free drug), assessment of the "true" free drug concentration may be inaccurate, particularly if the fraction of drug bound to protein varies. In addition, the drug's binding may be decreased by disease or by other drugs, leading to increased unbound drug levels that alter the interpretation of the measured drug concentrations. Kidney and liver disease can change the binding of certain drugs (e.g., phenytoin) to protein because of a decrease in protein (e.g., decreased albumin, as in nephrotic syndrome or liver disease) or as a result of competition for protein binding by endogenously produced substances (e.g., uremia in kidney disease, hyperbilirubinemia in liver disease). Similarly, other drugs being administered may compete for binding to protein. A major problem secondary to these changes in protein binding is that free drug is not typically measured in many of the common drug assays used by clinical laboratories. Lastly, changes in drug binding to protein can affect the pharmacokinetics of the drug, the main effect being on the VD, which increases as protein binding decreases.

The usefulness of a drug assay is also limited by physiologic changes that may alter the response at a particular drug concentration. An example of this pharmacodynamic change is the response produced by a certain level of digoxin in the presence of altered electrolyte concentrations (e.g., potassium, calcium, and/or magnesium). Tolerance, a reduced response to a given concentration of drug with continued use, is another pharmacodynamic change that may alter how a drug concentration is interpreted. Tolerance is commonly observed with the continued use of narcotics (e.g., in terminal cancer patients); initially, adequate pain control is noted at a given drug concentration, but after long-term administration, the same drug concentration is no longer associated with pain relief. Positive (placebo) or negative (nocebo) effects may also be associated with many drugs and may mimic their known benefits or toxicities. 1c

Clinical Utility of Free Drug Monitoring

Florin Marcel Musteata , in Therapeutic Drug Monitoring, 2012

Conclusions

Free drug concentrations correlate to therapeutic effects better than total drug concentrations, for both small and large molecules. Unfortunately, current technical difficulties in accurately measuring free concentrations prevent full clinical application, and further research in this field is needed. Nevertheless, in clinical laboratories ultrafiltration followed by measurement of the drug in the protein-free ultrafiltrate using a commercially available immunoassay or a chromatographic method is routinely used for free drug monitoring of phenytoin, valproic acid, carbamazepine and mycophenolic acid. Such routine monitoring of free drug concentrations certainly has demonstrated clinical usefulness. As bioanalytical methods become more sensitive, accurate and precise we will certainly witness an increase in monitoring of free drug concentrations, which represent the "active" fraction of the drug.

As an alternative, when free drug concentrations are too complicated to monitor or the procedure is too costly, the total drug concentration can be normalized by using equation 4.6, or specific equations such as those proposed for phenytoin [1, 8] or testosterone [54]. However, direct measurement of free drug is certainly superior to indirect estimation of free drug using a mathematical equation.

An important trend in the next decade will be the development of new analytical methods based on in vivo microextraction and biosensors. These new approaches will naturally determine free drug concentrations, and will also allow investigation of pharmacokinetics in target tissues, further expanding the utility of free drug monitoring.

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Pharmacokinetics in Neonatal Medicine

Richard J. Martin MBBS, FRACP , in Fanaroff and Martin's Neonatal-Perinatal Medicine , 2020

Pharmacokinetic Models Describe Concentration of Drug Over Time

Pharmacokinetic models describe the mathematical relationship between the dose of a medication administered to a patient and the drug concentration over time after a given dose ( Figs. 45.4 and45.5). These drug concentration-versus-time curves describe the disposition of drug through the body and are the basis for the mathematical models (kinetics of decay) that predict individual drug concentrations over time in specific patients. Drug concentrations are typically only available from the blood and serve as a surrogate for drug concentration at sites of action to correlate with pharmacologic response.

First-Order or Zero-Order Kinetics

The drug-concentration-over-time graphs inFig. 45.4 depict the rate of elimination of a drug from the body on a linear and semi-logarithmic plot. Most drugs follow first-order kinetics, and mathematical equations inTable 45.1 are appropriate for drugs that are eliminated using properties of first-order kinetics. 19,20 For drugs that follow first-order kinetics, a constant percentage of drug is metabolized over time. Since the rate of elimination (Kel ) is proportional to the amount of drug in the body, then a large amount of drug is removed per unit time initially with a small amount drug when concentrations are low. When drugs follow first-order kinetics, the concentration time curve shows an exponential decrease in the plasma drug concentration over time, and a linear decrease in drug concentration on logarithmic scale (see Fig. 45.5). The half-life of drug elimination is independent of drug dosage. Most drugs used in neonates follow first-order kinetic properties, including ampicillin, gentamicin, and phenobarbital.

Rarely, drugs may follow what is called zero-order kinetics or nonlinear, saturable kinetics. In drugs that follow zero-order kinetics, a constant amount of drug is metabolized or eliminated per unit of time regardless of concentration. The drug concentration follows a linear decrease of serum concentration over time (seeFig. 45.4). The elimination rate constant (Kel) is highly variable, with a smaller percentage of the drug eliminated at the beginning and a higher percentage of the residual drug eliminated toward the end, as demonstrated on log-transformed scale. The half-life of drugs whose elimination follows zero-order kinetics is dependent on drug dosage; larger doses yield a longer half-life. One example is ethanol. After ingesting alcohol, the liver's alcohol dehydrogenase quickly becomes saturated such that only a fixed amount can be metabolized over a given amount of time. There is a maximum yet constant amount that the body can eliminate at any given time. Small increases in dose can yield large increases in levels, because the amount of drug removed is constant and not proportional to the dose. Phenytoin is another zero-order kinetic drug, owing to saturable kinetics of the metabolizing enzymes. 9 Some drugs that typically follow first-order kinetics can follow zero-order kinetics when given at a very high dosage if enzymatic metabolism becomes saturated until the drug concentrations decrease to the point that enzymatic reactions are no longer saturated and then first-order kinetics can resume.

Protein and Peptide Delivery through Respiratory Pathway

Hemal Tandel , ... Ambikanandan Misra , in Challenges in Delivery of Therapeutic Genomics and Proteomics, 2011

9.5.3.2.2.5 Drug Concentration, Dose, and Administered Volume

Drug concentration, dose, and volume of administration are three interrelated parameters that impact the performance of the nasal delivery system. Nasal absorption of 1-tyrosyl- l-tyrosine was shown to increase with drug concentration in nasal perfusion experiments [91,97]. The effect of drug dose on nasal absorption has been reported by numerous studies based on molecules like calcitonin [98], GnRH agonist [99], desmopressin [100,101], and secretin [102–104]. All studies conclude that by increasing the drug dose, greater transnasal absorption was achieved. The optimal formulation volume for nasal administration is 25–200   μl per nostril. More than this volume can lead to anterior leakage or postnasal dripping of the formulation.

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Skin Barrier and Transdermal Drug Delivery

Jean L. Bolognia MD , in Dermatology , 2018

Drug Concentration

The driving force for percutaneous absorption is the concentration ofsoluble drug in the vehicle. Many older topical drug products were marketed with the expectation that higher concentrations were more potent. Although true for some products such as tretinoin gels and creams (0.01–0.1%), in which the drug is completely solubilized at all concentrations, for others it is not the case. Hydrocortisone 1% and 2.5% in a cream formulation have been shown to be of equal potency, as have triamcinolone acetonide 0.025%, 0.1% and 0.5% creams 49 . One of the major advances in formulating glucocorticoids, as first shown with fluocinonide, came when it was discovered that the addition of propylene glycol to the vehicle could completely solubilize the drug. This led to corticosteroid products with greater potency, as demonstrated in the vasoconstrictor assay.

Newer products are now tested during the development process to ensure that increased drug concentration results in increased bioavailability. However, excess non-dissolved drug can sometimes be advantageous, especially in transdermal patches worn for prolonged periods of time (e.g. up to a week). In this situation, as dissolved drug is absorbed into the body, non-dissolved drug can then become dissolved in order to maintain an equilibrium, thereby maintaining a constant dissolved drug concentration over time and providing a constant rate of delivery 50 .

Antiseizure Drug Therapy in Children

Jeannine M. Conway , ... Angela K. Birnbaum , in Swaiman's Pediatric Neurology (Sixth Edition), 2017

What to Measure

Total drug concentrations generally are measured; however, it also is possible to determine levels of free or unbound drug, as well as of metabolites of the administered drug. Free drug concentrations correlate best with clinical effect and toxicity. In most cases, the ratio of free to bound drug is relatively constant for a particular patient; therefore, total drug concentrations usually are adequate. In certain instances, however, particularly with critically ill patients under intensive care, determination of free drug levels, especially for phenytoin and valproic acid, is essential. In such patients, many drugs are typically administered, increasing the likelihood that antiseizure drugs will be displaced from protein-binding sites. The percentage of unbound valproic acid increases with higher drug concentrations and with comedication, or when valproic acid is rapidly administered. When the bound fraction is doubled, the valproic acid free fraction may be eight times higher.

Occasionally, measurement of antiseizure drug metabolites is useful. With several antiseizure drugs, metabolites are clinically active and contribute to both response and toxicity. Phenobarbital is an active metabolite present during primidone therapy. Carbamazepine-10,11-epoxide is a derivative of carbamazepine and contributes to toxicity. Clinical monitoring of oxcarbazepine and eslicarbazepine acetate treatment is evaluated by measuring their primary metabolites.

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PK Interpretation of Drug Distribution: General Concepts and Application to Special Populations

Shinya Ito , in Reference Module in Biomedical Sciences, 2021

2.1.1 Concentration-time profile

Drug concentration-time profiles in body fluid are quantitatively analyzed and interpreted using PK concepts, which guide drug development at a population level and pharmacological management of individual patients. In other words, PK analyses of concentration—time curves provide information necessary to define the dose-concentration-effect relationship, establishing appropriate dosing schedules.

The body fluid for drug concentration measurement is usually plasma, serum or blood (In this chapter, drug concentrations are assumed to be measured in plasma, unless stated otherwise). Although the time course and mode of drug administration influences the concentration-time curves, a common pattern emerges after sufficient time has elapsed from the last dose. For example, after intravenous bolus injection of a drug at a therapeutic dose, plasma drug concentration starts decreasing from the initial peak, following a pattern of a curve that can be best described by a single exponential decay function with the base e in a form of e −  a  ∙ x , or a combination of them.

This observed pattern of decay is a process common to many phenomena in nature, where a quantity of a substance is shrinking at a declining rate proportional to its present quantity as seen in radioactivity decay. A general form of such a function as a plasma drug concentration—time curve is given by:

(1) C = ∑ i = 1 n A i ∙ e − λ i ∙ t

A variable C is a plasma drug concentration at time t, and −  λ i is a constant that defines a log-linear slope of each exponential function as −  λ/Ln10 or −  λ/2.303 , and has a unit of reciprocal time (e.g., min−   1). A i corresponds to the Y-intercept of each exponential term. A mono-exponential decay (n  =   1 in Eq. 1) is the simplest form:

(2) C = A ∙ e − λ ∙ t

In Eq. (1) and Eq. (2) (as a special case of Eq. 1) describing drug concentration—time profiles, the coefficient and the exponent are defined as mathematical parameters in relation to the curve. As seen below, however, a more physiologic interpretation is also possible.

Assume a mono-exponential decay curve (Eq. 2) for simplicity. The derivative of a mono-exponential decay function (Eq. 2) provides the velocity or the rate of concentration change as follows:

(3) dC dt = − λ ∙ C

The minus sign before λ indicates that the change direction is quantity reduction as time elapses. In Eq. (3), the proportionality constant λ determines the reduction rate of the concentration (i.e., dC/dt), which is proportional to C at a given time. It is evident from Eq. (3) that the rate or the velocity of concentration decay steadily slows down as time passes because C is declining. Note that Eqs. (1)–(3) are based on the assumption that the system volume remains unchanged. They can be rewritten as amount-based formulae. For example, Eq. (3) can be expressed as follows because C  = X  ∙   (volume)−   1 :

(4) dX dt = − k ∙ X

where X is the amount of drug in the system at time t, and k is called an elimination rate constant, indicating its defining role for the rate of drug elimination dX/dt. Although an elimination rate constant k in Eq. (4) and a concentration decay rate λ in Eq. (3) are symbolized differently, they are equivalent.

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ADME-Tox Approaches

J.V. Turner , S. Agatonovic-Kustrin , in Comprehensive Medicinal Chemistry II, 2007

5.29.2.5 Impact of Interindividual Variability

Drug concentration is amongst the most important determinants of clinical response to a drug. Variability in pharmacokinetic profiles makes drug concentrations unpredictable: the greater the variability, the greater the magnitude of this problem.

Bioavailability of a drug may vary within the same person over time as well as between different people in a population. The cause of large interpatient pharmacokinetic variability is multifactorial and includes differences in drug absorption, metabolism, or distribution, and complex drug–drug or drug–food interactions. 53 Population subgroups such as infants, pregnant women, and other groups with underlying traits or disease states are also likely to exhibit variable bioavailability and absorption, distribution, metabolism, and excretion (ADME) characteristics. 54 Population variability in clinical data is a reality and should be incorporated into the modeling process.

Although predictive models may be constructed with good accuracy based on a given data set, the quality of such models ultimately reflects the quality of the data: poor-quality bioavailability data with wide uncertainty will result in poor models regardless of apparent accuracy. Care must also be taken when extrapolating outside the limits of model training data.

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Design and Fabrication of Brain-Targeted Drug Delivery

Vandana Soni , ... Rakesh K. Tekade , in Basic Fundamentals of Drug Delivery, 2019

14.6.3.1.9 Drug Concentration and Dosing Volume

The drug concentration and dosing volume can have an effect on the nasal delivery of drug to the brain. The drug concentration has a direct effect on the nasal drug absorption, that is, increase in the concentration of drug causes better absorption at the site of administration. This is more important for the drugs primarily having a passive diffusion mechanism of absorption of the drug. But, higher concentrations of the drug when administered in large volume can have opposite effect on the absorption of the drug; which may be as a result of local adverse effects. In some cases, it may cause nasal mucosa damage. The delivery of the dosing volume and their drug concentration is restricted by the size and shape of the nasal cavity. A volume of 25–200  µL/nostril and an upper limit of 25   mg/dose are recommended (Kushwaha et al., 2011).

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Influence of transporters in treating cancers in the CNS

Gautham Gampa , ... William F. Elmquist , in Drug Efflux Pumps in Cancer Resistance Pathways: From Molecular Recognition and Characterization to Possible Inhibition Strategies in Chemotherapy, 2020

Targeted bioavailability

The drug concentrations in the blood or plasma are routinely measured as surrogates for concentrations at the site of action, due to ease of accessibility. While the drug concentration in systemic circulation may somewhat reflect the concentration at the site of action when the target is in a peripheral, more accessible, tissue, their use as a surrogate for brain drug concentrations can be misleading. This is important particularly in the context of brain compared to other organs due to presence of the BBB that can severely restrict drug distribution to the brain [13, 14]. To differentiate the bioavailability estimated using drug concentrations at the site of action, brain in this discussion, from the traditional bioavailability determined using the systemic concentrations, we would like to use the term 'targeted bioavailability' [48] (Fig. 2). Various factors can influence a compound's targeted bioavailability in the brain such as BBB permeability, drug transport by transport proteins, drug metabolism, protein binding, protein expression, receptor affinity, gene regulation and dosage regimen [48]. The findings from various studies testing different anti-cancer agents indicate that the concentrations of a drug in the brain can be remarkably different from systemic concentrations [13, 14, 49]. The relevance of the concentration–effect relationship should be judiciously assessed when using systemic concentrations, as the variability in pharmacodynamic measurements (i.e., drug response, and toxicity) may not be reflected by the variability observed in the pharmacokinetic measurements [48]. Therefore, the measurement of target site concentrations, when possible, is more appropriate to evaluate a pharmacokinetic–pharmacodynamic (PK–PD) relationship.

Fig. 2

Fig. 2. A schematic representation of some of the barriers that an orally administered compound must pass before reaching the site of action. The barriers that a compound must pass to reach the systemic circulation are traditionally thought to contribute to the final bioavailability of a compound, whereas the barriers that must be overcome after the drug leaves the bloodstream to reach the site of action are related to drug targeting. The overall consideration of barriers from the site of administration to the site of action, which is usually extravascular, can be thought of as related to targeted bioavailability.

 Adapted from Elmquist WF. Targeted bioavailability, a fresh look at pharmacokinetic and pharmacodynamic issues in drug delivery. In: Wang B, Siahaan TJ, Soltero R, editor. Drug delivery: principles and applications. Wiley Online Library; 2005. p. 73–82, with permission.

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