Janna was a 3-month-old baby who had survived neonatal cardiac surgery with a good prognosis. Not unlike other young children, Janna suffered from gastroesophageal reflux and was receiving cisapride. One morning, she was noted to be fussy while in her swing chair and, within 10 minutes, became unresponsive.

Cisapride was a medication approved by the US Food and Drug Administration (FDA) in 1993 for nighttime heartburn in adults. It was never shown to be effective or safe in children under the age of 16 and therefore had no FDA approval for use in this population (1,2). However, cisapride quickly found a market treating a common neonatal problem, gastroesophageal reflux (GER). There was a flavored syrup formulation that was labeled for use in geriatrics, but 90% of its sales were for use in pediatric patients (3). Hospitalized preterm infants also receive medications for symptoms thought to be associated with GER, including apnea, bradycardia, coughing, choking, and cyanosis (4,5). By 1998, more than 19% of infants in neonatal intensive care units (NICUs) in the United States were receiving cisapride (4).

In 1995, a case report had been published of a particular arrhythmia, prolonged QT interval, in a 64-year-old patient taking high-dose cisapride (6). QT prolongation, although not independently dangerous, can lead to the fatal arrhythmia torsades de pointes, especially during episodes of bradycardia. Additionally, erythromycin, commonly used in infants, was found to carry a particularly high risk of fatal arrhythmia when coadministered with cisapride, both by inhibiting its metabolism and by exaggerating ion channel disturbances that cause QT changes (4). By 2000, after 80 deaths and 341 serious adverse events had been reported, mostly in children, cisapride was pulled from general use in the US market (4,6,7).

Cisapride is just one example of many therapeutics often used in children despite a paucity of safety, dosing, and efficacy data. Trimethoprim/sulfamethoxazole, an antibiotic that was deemed safe to use in children, is another. In the 1950s, physicians recognized that infants who received the antibiotic prophylactically had a much higher incidence of kernicterus, a permanent neurological complication of hyperbilirubinemia. Transient hyperbilirubinemia is present in every newborn, and kernicterus is a complication observed almost exclusively in this population. Therefore, kernicterus had not previously been described during the use of trimethoprim/sulfamethoxazole in adults. After this association was noted, studies in animals found that trimethoprim/sulfamethoxazole displaced bilirubin from albumin, increasing the risk of kernicterus in newborns (8).

In the late 1990s, premature infants often received prophylactic steroids to prevent chronic lung disease. Although steroids never received FDA approval for this indication, several randomized trials did show short-term benefits (9,10). When long-term neurodevelopment was examined, however, steroids were associated with a significant increase in the risk of cerebral palsy (11,12).

In 1963, Dr. Harry Shirkey coined the term “therapeutic orphans” to describe children, owing to the lack of active research dedicated to defining the optimal dosing, safety, and efficacy of therapeutics in this population (13). Historically, up to 75% of drugs have had insufficient labeling for pediatric safety, efficacy, and dosing. This percentage is even higher for drugs used in infants. Infants are at particular risk for inaccurate dosing, and an estimated 90% of patients in NICUs receive at least one medication “off-label” (14). Moreover, medication use in this population is on the rise; currently NICU patients receive a median of eight drugs (15).

It is 8:15 a.m., and Dr. Roberts has seen her first two patients of the morning, with dozens to follow, not uncommon in January. Sarah is a 9-month-old ex-premature infant who weighed 500 g at birth and who now has acute otitis media. Ryan is an obese 17-year-old, weighing 130 kg, who has bacterial sinusitis. Dr. Roberts plans to treat both patients with high-dose amoxicillin to cover for resistant Streptococcus pneumoniae. She steps back into her office to use her calculator to determine the correct dosing for each.

Before 1962, there were no requirements for human testing of new pharmaceuticals. The Kefauver–Harris Amendment (Table 9–1) was partly inspired by the case of thalidomide, a drug widely used to treat morning sickness in pregnant women in the early 1960s (15,16). After its release, thalidomide was found to be teratogenic, resulting in many significant birth defects. The Amendment codified the current three-phase process of investigating new drugs, wherein safety and pharmacokinetic trials are performed in the first phase, efficacy and dosing ranges are established during the second phase, and comparative experimental clinical trials with further refinement on efficacy and dosing are explored during the third phase. Historically, the FDA did not request pediatric studies until Phase III trials had been completed in adults. Although deemed ethically appropriate to conclude adult clinical trials before exposing children to new therapeutics, data were often extrapolated from adults to estimate the pharmacokinetics, safety, and efficacy of new drugs in children (17).

As children develop, however, their continuous changes in physiology affect drug absorption, distribution, metabolism, and excretion. These changes are most evident in premature infants (Table 9–2). As an example, micafungin was found to require up to a fivefold increase in dosing (on a per-kg basis) in premature infants compared with adults (18–20). Age and its effect on organ maturation are of particular importance in dosing, although weight- or body surface area (BSA)-based dosing alone is often entertained. This difficulty is augmented for pediatricians, whose patients can vary in weight by 300-fold.

Drug absorption in children can differ markedly from that in adults, producing unpredictable drug concentrations after oral dosing. Many physiological factors unique to young patients affect drug bioavailability. Gastric pH is elevated in infants because of both the reduced total volume of gastric secretions and reduced parietal cell function. This results in increased absorption of orally administered acid-labile drugs and decreased absorption of drugs that are weak acids (21–23). Gastric emptying time decreases rapidly during the first week of life, whereas intestinal transit time matures rapidly during early infancy (24). Splanchnic blood flow matures during the first 3 weeks of life. These factors contribute to rapidly changing absorption rates during the first several weeks after birth, and by 4 months of age, these processes approach adult levels (14,17,23,25). Gastrointestinal physiology is equivalent to that in adults by age 10–12 years, although erratic eating habits in the adolescent can continue to contribute to skewed bioavailability (23,26,27).

Infants have proportionately less muscle mass and reduced muscle blood flow compared with adults, leading to slowed absorption of intramuscularly administered drugs (17,23,26). Topically applied drugs are affected by differences in skin permeability between adults and infants. Neonatal skin has a thinner stratum, causing increased permeability. The ratio of infants’ BSA to their weight is increased relative to older patients, leading to greater topical absorption (23,27). Infants have a sparse amount of body fat and increased extracellular and total body water compared with older children, affecting the distribution of lipid- and water-soluble drugs. They also have reduced protein binding of drugs, resulting in higher levels of unbound active medication and possible toxicity despite having normal serum concentrations (23,28).

Reduced renal blood flow, lower glomerular filtration rates, and functionally immature renal tubules delay renal excretion of drugs. The liver matures markedly during the first few years of life. The cytochrome P (CYP) 450 metabolic pathway is fully functional by age 3 years (17,27). Conjugation to bile salts, a liver function that aids gastrointestinal and renal excretion, matures at age 3–4 years (14,17,23).

All of these factors contribute to inaccuracies in dosing/safety when extrapolating adult information to children.