The process of absorption defines the rate and amount of drug that enters the bloodstream. The parameter F indicates the percentage of dispensed drug available in the systemic circulation, with F = 1 indicating the drug is 100% available. We lack systematic studies of absorption in sick newborns, and differences in absorptive processes are expected but remain unmeasured generally. Some differences in newborns that potentially affect bioavailability include developmental changes in surface area and permeability of gastrointestinal (GI) mucosa, age-dependent changes in acid secretion in the stomach (higher pH than in older children and adults), changes in gastric emptying time and total GI transit time, and the characteristics of GI flora. Drugs such as ranitidine and metoclopramide also affect absorption of other medications by means of the same mechanisms.

“First-pass” pharmacokinetics means the drug is absorbed through the GI mucosa and travels directly to the liver, where it is metabolized and excreted in significant amounts, limiting bioavailability. Different drugs are absorbed at different rates, and different formulations of the same medication may be protected from first-pass metabolism. Drugs also may be given by inhalation, intranasally, intrarectally, topically, intramuscularly, subcutaneously, and intravenously. ¹²

Medications rely on blood flow and drug solubility for distribution to their sites of therapeutic effect. The volume of distribution for a drug is a parameter that relates total amount of drug distributed throughout the body to the serum or plasma concentration.³ It is an attempt to quantify the space in which the drug can go. Strictly defined, it is the hypothetical volume of body fluid necessary to dissolve the total amount of drug as found in the serum. Volume of distribution must be used to estimate the amount of a loading dose or a change in plasma concentration with any bolus dose:

Or, put another way:

Volume of distribution usually is expressed as a function of body weight, with units of volume per kilogram. Major factors that affect distribution volume are plasma protein binding and body composition. ^12,18,29 Changes in body composition happen throughout fetal and newborn life. Total body water decreases with increasing age: 85% in the smallest, most preterm infants; 70% in term infants; and 55% in most adults. Total body water may increase with such conditions as the syndrome of inappropriate antidiuretic hormone (SIADH) excretion, which increases total body water. Extracellular water composes about half this amount in a healthy term neonate. Large water-soluble molecules reach this compartment. Intravascular water composes about 10% of the body weight; protein-bound medications stay in this small compartment. Water-soluble drugs such as penicillins, aminoglycosides, and cephalosporins are distributed in a greater volume in smaller, more preterm infants, therefore requiring a higher loading dose per kilogram, if total body water were the only determinant of volume of distribution.

Plasma protein amounts and binding capacities also differ with gestational and chronologic age. Protein binding is decreased in newborns, because lower amounts of albumin are available than later in life, and fetal albumin has less capacity to bind some drugs. Acidic drugs such as ampicillin, phenytoin, and phenobarbital bind less well, thus increasing the free (available to receptor) fraction of the drug, with resultant increase in effect. Changes in pH also can affect a drug’s affinity for albumin. Fat content varies with gestational age and degree of illness; increased fat content increases the volume of distribution. Lipid-soluble molecules also are distributed in this space.

Of particular concern in newborns is the interaction of circulating unconjugated bilirubin and protein-bound drugs. Several anionic compounds bind to albumin and can displace bilirubin, increasing free bilirubin, thus increasing its potential for toxicity. Bilirubin has a higher affinity for albumin than some other medications; it may displace them from albumin, increasing the medication’s availability and potential to reach toxic levels.

Biotransformation, or drug metabolism, occurs most commonly in the liver. Phase I metabolism describes the nonsynthetic metabolism of medications. Phase II, usually conjugation, or the addition of a substance to a medication, is synthetic metabolism. Oxidation, conjugation, glucuronidation, and hepatic blood flow change with gestational and chronologic age, diseased states, and use of certain medications. For example, oxidation and glucuronidation are decreased in newborns. Drugs such as acetaminophen, phenobarbital, and phenytoin, which require oxidation for elimination, remain available longer and may be transformed to other active metabolites (the neonatal liver metabolizes theophylline to caffeine), or the drug may remain at significant free concentrations for a prolonged period. The possibility of prolonged peak concentrations of available drug or active metabolites for many pharmaceuticals mandates careful monitoring of drug levels and clinical conditions to titrate dose intervals. To further the potential for confusion and trouble and further the argument for careful assessment of levels and clinical signs of effectiveness and toxicity, a decrease in plasma protein binding (or any other change in volume of distribution) may increase the hepatic clearance of a drug.

Drug clearance or elimination occurs by excretion of unaltered drug or biotransformation to an inactive metabolite. Most drug elimination pathways can become saturated if the dose is high enough and dose intervals are too frequent. Most drugs in use in the NICU have therapeutic doses less than those necessary to saturate the elimination system. When clearance mechanisms are not saturated, the Css in plasma is proportional to the dose rate. Clearance equals the rate of drug elimination divided by the drug concentration. ¹⁹ Just as volume of distribution relates to loading dose and initial concentration, clearance relates to a maintenance dose that keeps a drug’s concentration at steady state. So for an ideal drug maintained at steady-state concentration:

Stated another way:

Or, to tailor the dose for a desired steady-state concentration:

The appropriate dosing rate can be calculated if the clinician can specify the desired steady-state plasma concentration and knows the clearance and bioavailability of a drug (from peak and trough levels in a particular patient).

For example, clearance of theophylline in preterm infants is reported to be 0.017 L/kg/hr. If the desired Css = 8 mg/L, assuming F = 1, particularly if the dose is to be given intravenously:

The t _½ is used to predict and interpret the time course of changes in plasma drug concentrations. For example, the time to steady state is 4 to 5 half-lives. The half-life is useful in selecting dose intervals. This concept is illustrated in Figure 10-3.

Loading doses help expedite reaching desired therapeutic concentrations, especially for drugs with long half-lives, in which a desired effect is needed immediately. For drugs with one-compartment distribution that stay in the circulation and are not stored in cells or tissue, the loading dose may be given as a simple single dose. Drugs that are fat soluble or stored intracellularly are more difficult to assess, and therapeutic levels must be included in the loading dose assessment.

If the volume of distribution for theophylline in preterm infants is 0.7 L/kg, and 8 mg/L is the desired concentration, and F, for an intravenous dose, is assumed to be 1, a loading dose can be calculated.

In the 30,000-plus known genes, there are over 4 million “common” variants (occurring in more than 1% of the population), many of which directly affect the function of the coded protein. In addition to the multiple factors like age, gender, disease, and concurrent medications, a patient’s genetic code can cause variation in the response to a particular drug. Once a drug is administered, it is absorbed and distributed to its site of action, then interacts with targets, and is finally metabolized and excreted. The enzymes and other compounds involved in each of these processes are subject to genetic variation that leads to variation in function. Pharmacogenetics is the study of the role of inheritance in the individual variation in drug response. Pharmacogenomics is the study of the influence of multiple genes and their interaction with each other and the environment on drug effects. ^5,24,28

The first description, over 40 years ago, of a genetically caused variation in drug metabolism was for the enzyme responsible for hydrolysis of succinylcholine. One in 3500 people are homozygous for a gene encoding an atypical form of the enzyme butyrylcholinesterase, which is quite slow to hydrolyze the succinylcholine, leading to prolonged muscle paralysis. Concurrently, an enzyme responsible for N-acetylation, another form of drug metabolism, was found to have a common genetic variant, so some patients are fast metabolizers and others are slow metabolizers of drugs such as hydralazine.

The cytochrome P-450 enzymes are important in phase I drug metabolism. One in particular, CYP-450 2D6, responsible for metabolism of many drugs, has been extensively studied. About 5% to 10% of the adult Caucasian population have genetic variants of the enzyme, leading to decreased activity and higher and more prolonged active drug levels.

Recently, a genetic variant in mitochondrial DNA, the A1555G mutation gene, has been linked to risk for hearing loss associated with aminoglycoside toxicity. The risk-additive variant’s frequency in the general population is estimated between 1% and 3%, but among deaf subjects tested, concurrence of deafness with aminoglycoside treatment with this mutation is quite common. This could lead to future testing before use of aminoglycosides. It is unknown whether tight control of aminoglycoside levels would reduce risk for hearing loss. No recommendations can be made until more extensive, population-based studies are done. Such studies must include accounting for drug levels and duration and genotypes in assessment of risk for hearing loss. ²¹

In addition to genetic variation in drug metabolism, the genetic polymorphisms of drug targets—including adrenergic and dopamine receptors and enzymes such as acetylcholinesterase—are likely to have effects on the response to drugs targeting these proteins. This may occur with the use of medications such as bronchodilators, pressors, and inotropes, and ACE-inhibitors such as enalapril and captopril.

The study of pharmacogenetics and pharmacogenomics is new, especially to neonatology, in which little is known about pharmacokinetics and pharmacodynamics of commonly used medications. The genetic revolution that has come with completion of the sequencing of the entire human genome is on its way to reaching neonatology with the availability of rapid analysis of large population-based samples for thousands of genes and their variants and how they relate to drug response. In the future, these studies will lead to improved understanding of individual variation in drug response, which should allow development of strategies to individualize care and help avoid complications resulting from heretofore unexplained genetic variations. The challenge will be to understand how the multiple genes and environmental factors interact in individual infants to alter risk for disease and adverse drug responses in fragile infants.