Developmental pharmacology

Introduction

Developmental changes profoundly affect the clinical response to medicines. Dr. Abraham Jacobi, a founder of American pediatrics, recognized more than a century ago that children are not “miniature men and women, with reduced doses and the same class of disease in smaller bodies,” that pediatrics “has its own independent range and horizon,” and that age-appropriate pharmacotherapy was important ( ). More recently, as the immaturity of renal and metabolic systems has been recognized, the pharmacologic uniqueness of babies and infants has been specifically recognized ( ). Physical growth, development, organ maturation, physiologic changes, and coexisting disease that occur throughout the spectrum of development—from preterm newborn to adolescence and adulthood—profoundly influence drug pharmacokinetics and pharmacodynamics and ultimately the panoply of both desirable and undesirable clinical responses. This chapter presents the basic pharmacologic principles relevant to understanding basic pediatric pharmacology in general and pediatric anesthetic pharmacology in particular.

Medications that are commonly used in children are not regularly tested in children, and drug labeling often consists exclusively of adult data. Of the 140 new molecular entities of potential use in pediatrics, only 38% were labeled for use in children when they were initially approved ( ). Much use of drugs in pediatrics, particularly in newborns and infants, is off-label use ( ). About 33% of drugs prescribed in office-based pediatric practice, 66% of those prescribed in hospitals, and 90% of drugs used in pediatric intensive care units are used for indications other than those for which they have been approved ( ). When data were submitted to the U.S. Food and Drug Administration (FDA) to support labeling changes intended to guide pediatric drug use, on average, only 2.2 pediatric studies were represented ( ). A considerable amount of pediatric drug use is based on “extrapolation” (or worse) from guidelines for dosing and use in adults. A half century ago, Dr. Harry Shirkey defined the pediatric population as “therapeutic orphans” to emphasize the lack of and need for drug development studies in children ( ). Development of new drugs for the pediatric population is complex and faces many challenges. These include ethical concerns and logistical limitations associated with testing drugs in children; dramatic physiologic/developmental changes from neonate to infant and toddler and differences between children and adults in disease processes that radically influence pharmacokinetics, pharmacodynamics, and drug disposition; and the lack of financial incentive for industry due to the small population ( ; ; ; ). Therefore it is not surprising that pediatric drug development efficacy studies are associated with a high failure rate of 40% ( ; ); major contributing factors are inadequate dosing and unaccounted differences between the pediatric and adult disease processes ( ). Legislation issued by the FDA (the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act) significantly increased the number of drug development studies in children and resulted in an improvement in the rational use of drugs in children, including more than 500 labeling changes. Furthermore, a policy statement by the American Academy of Pediatrics ( ) and the most recent joint policy statement endorsed by the European Academy of Pediatrics and the European Society for Developmental Perinatal and Pediatric Pharmacology ( ) provided ethical, legal, and scientific frameworks for pediatric drug development and a rational use of drugs in children. Although substantial progress has been made, there is still a substantial unmet need for development of pediatric dosage forms.

A major address of pediatric pharmacology research in this century has focused on the challenge of characterizing developmental changes in pharmacokinetics and pharmacodynamics, as well as determining proper pediatric dosing guidelines, particularly the downward scaling of adult doses to children. In the past decade, progress in pediatric drug development and dosing recommendations in children has been made by the application of pharmacometric principles ( ; ; ) and physiologically based pharmacokinetic modeling and simulation becoming an essential part of pediatric clinical pharmacology ( ; ).

Physiology and development

Growth and maturation are seminal features of pediatric development, and it is important to understand that they vary independently ( ; ; ). Growth is an increase in size, often characterized by changes in weight. Maturation is a time-dependent phenomenon often characterized by age. Traditionally, the common metric of maturation was postnatal age (PNA), or the time since birth. With the superiority of neonatal intensive care and the survival of neonates as small as 500 g and 24 weeks’ gestation, which have clearly immature and widely variant degrees of development at birth, it is now well established that PNA is an inadequate metric of organ maturation that actually begins before birth. Postconceptual age (PCA), the sum of gestational age (the period between conception and birth) and PNA, is a superior metric. Because of the inexactitude in determining the date of conception, the alternate metric of postmenstrual age (PMA) is often used instead. Particularly for infants and very small children, the use of PCA or PMA rather than PNA is important in pediatric pharmacology and therapeutics.

Body composition changes dramatically during growth and development ( ). Simply stated, compared with adults, infants have big heads, large torsos, and short, stumpy legs. Developmental changes in pediatric physiology can affect drug disposition. Table 8.1 describes the changes in organ weight that occur during growth. The most significant changes with age are in total body water, the intracellular versus extracellular distribution of body water, and muscle and fat mass ( Tables 8.2 and 8.3 ). Total body water content constitutes 75% of body weight in the full-term newborn and 80% to 85% of body weight in the preterm neonate. This decreases to about 60% at 5 months and remains relatively constant until puberty. Extracellular water redistributes intracellularly during the first year of life. Extracellular fluid is 45% to 50% of body weight in premature and newborn infants, decreasing to 26% at 1 year and 18% in adults. In contrast, body fat increases with age, from 3% in premature neonates and 12% in full-term newborns, to 30% at 1 year of age. “Baby fat” is shed when toddlers start walking and drops to adult levels of about 18%, concomitant with an increase in muscle mass. A major consequence of body composition changes may be differences in drug volume of distribution, with neonates and infants having larger volumes of water-soluble drugs, as described later (see “Volume of Distribution”).

The relative lack of dosing data for many drugs used in pediatrics has necessitated the use of extrapolations from adult dosing. Considerable effort has been expended to provide a scientific basis for such extrapolations, such as volumes of distribution, clearance, renal function, and dose. Basic models for predicting physiologic function and drug dose based on size include the linear per-kilogram model, the surface area model, and the allometric model. It is now increasingly evident and accepted that allometric scaling provides the most accurate information. Throughout nature, many body size relationships are of the form:

where Y is the biological characteristic, W is the body mass, and a and b are empirically derived constants. For physiologic functions such as cardiac output, metabolic rate, oxygen consumption, glomerular filtration rate (GFR), and pharmacologic functions such as drug clearance, the power exponent b is 0.75. For physiologic volumes such as blood volume, lung volume, tidal volume, and stroke volume, and pharmacologic volumes such as the volume of distribution, the power exponent is 1. For time-based physiologic functions such as circulation time, heart rate, and respiratory rate, and pharmacologic functions such as drug elimination half-life, the exponent is 0.25 ( ). This allometric model may then be used to scale metabolic processes across size:

where W _i is the weight of any individual and W _std is the weight of a standardized individual (such as a mythical 70-kg adult). The applicability of scaling will subsequently become apparent.

Pharmacodynamics

Pharmacodynamics refers to the biological effect of a drug, specifically the concentration (usually plasma)-effect relationship (or more precisely, the effect site concentration-effect relationship, although the effect site concentration is rarely actually measured). Far less is known about the developmental aspects of pharmacodynamics than of pharmacokinetics. The concentration-effect relationship defining drug pharmacodynamics is characterized by potency and efficacy. Potency (drug concentration or, less correctly, drug dose that produces a specific effect) is characterized by the ED ₅₀ , defined as the concentration producing half-maximal effect in a graded dose-response (from zero to maximal response) curve in a single experiment, cell, animal, or individual. Potency can also be characterized by the ED ₅₀ , or as the concentration producing an all-or-nothing (quantal) response in a quantal dose-response curve in 50% of a population of cells, animals, or individuals. Efficacy is the maximum possible response at the highest possible drug concentration. The developmental aspects of drug pharmacodynamics are therefore best described by age-dependent changes in potency and efficacy. Often, however, the only information available is age dependence of clinical drug response, which may reflect both pharmacokinetic and pharmacodynamic changes.

True age-related pharmacodynamic changes may be qualitative or quantitative, and they may apply to both therapeutic and adverse effects ( ). One example of quantitative differences in therapeutic response is the effect of warfarin in prepubertal, pubertal, and adult patients. Despite equivalent plasma drug concentrations, warfarin effects on prothrombin fragments 1 and 2 and on the international normalized ratio (INR) were higher in prepubertal patients than in adults. Similarly, augmented response was observed with cyclosporine, in which peripheral blood monocytes from infants had twofold lower proliferation and sevenfold lower interleukin-2 expression compared with older subjects. Examples of age-dependent adverse effects occurring only in children include chloramphenicol toxicity (“gray baby syndrome”), limb deformation from thalidomide during embryogenesis, tetracycline staining of dental enamel, and valproic acid hepatotoxicity, which is increased in young children. Generalized factors leading to age-dependent drug responses include physiology, pathology, host response to disease, adverse drug reactions, and pharmacodynamics ( ).

For drugs used in anesthesia, the best information on developmental pharmacodynamics has been obtained for inhaled anesthetics and, to a lesser extent, certain intravenous anesthetics. The potency of inhaled anesthetics is significantly affected by developmental age. The principal metric of inhaled anesthetic potency (the median effective concentration, or EC ₅₀ ) has been called the minimum alveolar concentration (MAC) and defined as the “minimum alveolar concentration of anesthetic at 1 atmosphere that produces immobility in 50% of those patients or animals exposed to a noxious stimulus,” where the stimulus is usually an incision ( ). Other endpoints have been analogously defined, such as the MAC _AWAKE endpoint, which defines loss (or return) of consciousness. The quantal EC ₅₀ of all inhaled anesthetics is similarly influenced by age, with a common log-linear negative slope (for age older than 1 year) ( ). For decreasing ages younger than 40 years, EC ₅₀ (MAC) increases 6% per decade. Thus the MAC for sevoflurane is conceptually 20% greater at age 10 and 27% greater at age 1 (i.e., 2.16% and 2.29% at ages 10 and 1, respectively, for a MAC of 1.8% at age 40) ( ). A clinical study found the MAC of sevoflurane to be 2.5% in children between 1 and 12 years old and 3.2% in infants 6 to 12 months old, compared with 2% at age 40 ( ; ). The MAC _AWAKE endpoint for sevoflurane was 0.43%, 0.45%, and 0.66% in children 8 to 12 years old, 5 to younger than 8 years, and 2 to younger than 5 years, respectively ( ). The ratio between the MAC _AWAKE endpoint and MAC did not differ with age.

Measures of the age-dependent change in apparent anesthetic potency may be influenced by the clinical drug effect used as the index of response. For example, various electroencephalogram (EEG)-derived parameters (e.g., spectral edge frequency, bispectrum, and bispectral index [BIS]) have been used to measure volatile anesthetic effects in children ( ; ; ). Although there were age-dependent effects of volatile anesthetics on various EEG parameters, the EEG itself was found to be highly age dependent. Specifically, EEG was fundamentally different in infants between 0 and 6 months old, and caution was suggested in the use of BIS to determine volatile anesthetic pharmacodynamics in children ( ; ). Similar results were obtained when EEG-derived parameters were used to evaluate age and propofol effects, and EEG results in children younger than 1 year old were considered inaccurate ( ).

Compared with inhaled anesthetics, much less is known about developmental aspects of intravenous drug pharmacodynamics. In part, this reflects the ease, lack of expense, ubiquity, and real-time availability of measuring end-tidal inhaled anesthetic concentrations, compared with measuring plasma concentrations of intravenous anesthetics. Limited data are available for propofol, which suggests slightly lower sensitivity (diminished potency) in children. Plasma propofol concentration-effect (BIS) curves analyzed in children (mean age of 10 years, range of 6 to 13 years) and adults (mean age of 18 years, range of 14 to 32 years) found graded EC ₅₀ means values of 4 versus 3.3 mcg/mL, respectively. When propofol infusions were targeted to maintain a steady-state BIS of 50, measured mean plasma concentrations were 4.3 ± 1.1 and 3.4 ± 1.2 mcg/mL, respectively ( ). Somewhat lower propofol potency was also reported by others ( ). In contrast, one study found no difference in propofol EC ₅₀ in adults and children, but predicted rather than measured plasma concentrations were used in the analysis, which is a limitation of such studies ( ). Increased propofol EC ₅₀ in children is consistent with diminished EC ₅₀ in older adults ( ). No data are available regarding propofol pharmacodynamics in neonates.

In summary, available data suggest some developmental age-dependence of inhaled and intravenous anesthetic pharmacodynamics, with somewhat lower potency in young children. Nonetheless, developmental changes in drug pharmacodynamics, in general, appear to be much smaller and of less clinical significance than developmental changes in drug pharmacokinetics.

Pharmacokinetic parameters

Pharmacokinetics , which means “drug movement,” is an area of pharmacology that relates to how a drug enters, moves through, and exits the body. It refers to the time course of drug disposition in the body and the processes that affect it. Some have characterized pharmacokinetics as “what the body does to the drug.” These processes are governed by absorption, distribution, metabolism and transport, and excretion. Conceptually, pharmacokinetics is characterized by the fundamental primary parameters of volume of distribution and clearance and by the secondary parameter of half-life (which is proportional to volume of distribution and inversely proportional to clearance).

Volume of distribution

Volume of distribution (V _d ) is a theoretic concept that relates the amount of drug in the body (dose) to the concentration (C) of drug that is measured (in blood, plasma, and unbound in tissue water). Volume of distribution is the volume of fluid “apparently” required to contain the total-body amount of drug homogeneously at a concentration equal to that in plasma (or blood) ( Fig. 8.1 ):

${\text{C}}_{\text{0}}\text{=}{\text{dose (X)/Vd or V}}_{\text{d}}\text{=}{\text{dose (X)/C}}_{\text{0}}$

The volume of distribution does not necessarily correspond to any specific physiologic volume or space. Drugs such as highly water-soluble compounds, which are confined intravascularly, have a small volume of distribution (approximately equal to intravascular volume), whereas lipophilic drugs that distribute to tissues have a large volume of distribution (which may be as large as to exceed total body water). For example, in adults the volume of distribution of gentamicin is 0.2 to 0.3 L/kg, whereas that of digoxin is 8 to 10 L/kg ( Table 8.5 ). Plasma protein binding of drugs decreases the apparent volume of distribution, and tissue binding increases the apparent volume of distribution. The major practical value of volume of distribution lies in the calculation of initial drug dosing (loading):

$\text{Dose (X)}\text{=}{\text{C}}_{\text{0}}\text{×}\text{Vd}$

A major consequence of growth and maturational changes in body composition may be differences in volume of distribution. In general, neonates and infants have larger distribution volumes for water-soluble drugs and smaller volumes for lipophilic drugs. For example, the volume of distribution of gentamicin is 0.45 to 0.7 L/kg in neonates and infants compared with 0.2 to 0.3 L/kg in adults ( ; ).