• 1938 – FDA empowered with enforcement of truthful labeling and documented safety of drugs. Regardless, demonstration of efficacy was not required, and risk-to-benefit ratio was seldom mentioned. Law did nothing for kids.
• 1962 – Sparked by thalidomide, the Harris-Kefauver Amendments to the Food, Drug and Cosmetic Act required proof of efficacy for the first time. This still did nothing for kids.
• 1997 – First regulations mandating evaluation of drugs for pediatric use!
• Pregnant women and children are the "therapeutic orphans", because very few guidelines exist for proper drug dosing for them. Approximately 70% of PDR entries have no dosing information for pediatric patients.

• Presently, proper drug dosing for kids is still not completely known. Many patients get overdosed. Ex: infants require a dose of 0.0025 mL of atropine, but smallest syringe available is 1 cc!
• Pharmacokinetics
• Kids have problems with bioavailability. One of the reasons for this is that gastric pH is 6-8 at birth (it falls to 1.5-3.0 over several hours). Premature infants have no detectable gastric acid until 32 weeks after birth.
• There is no data on drugs requiring active transport or specific transporters.
• Cutaneous absorption changes with skin maturation.
• Infants have a higher than normal total body water composition until the age of 4-6 months (95% at birth, vs. 60% as adult). This affects V_D.
• In general infants will need higher doses on a mg/kg basis than older kids/adults.
• Infants have a lower amount of proteins in their blood. As such they have an age-dependent changes in free fraction at steady state. This further depends on maturation of the clearance mechanisms (liver, kidneys, etc).
• Hepatic drug clearance: drug uptake by liver is low because transport proteins aren’t there yet, P450 enzymes only at 30-50% of adult activity, conjugation enzymes still being expressed.
• Chronological order of Phase II (conjugation enzymes) development: sulfation, acetylation, glucuronidation, amino acid conjugation, methylation. As such, what may be glucuronidated in an adult is sulfated in an infant.
• Age related changes in metabolism will affect clearance, and therefore will determine dosing strategies.
• Activation vs. detoxification pathways are largely unknown in kids.
• Pharmacodynamics
• Infants have: changes in receptor number, receptor affinity, receptor-effector coupling (ex: infants have so many b -receptors that b -antagonists don’t work very well), and frequency of drug-related adverse events.
• There are many unique clinical challenges mostly found in pediatrics: patent ductus arteriosus, hyaline membrane disease (RDS), breast feeding, etc. Pharmacodynamic approaches to these must be developed.
• It was only recently that physicians have acted upon the fact that infants feel pain (no anesthesia in circumcision or surgeries!!!).
• Adverse effects of drugs in infants due to pharmacodynamic reasons:
• Increased Sensitivity
• Verapamil (cardiorespiratory arrest)
• Morphine (more sensitive to depression of CO₂ responsiveness)
• Valproic acid (increased hepatotoxicity)
• Benzodiazepines (paradoxical excitement, hyperactivity)
• Decreased Sensitivity
• INH hepatitis (absent in patients <20 y/o)
• Acetaminophen (almost never get hepatic necrosis)
• Aminoglycoside nephrotoxicity (rare in infants)
• Digoxin toxicity (infants tolerate higher doses than adults)
• Prenatal drug exposure
• Teratogen – drug that causes developmental problems.
• Teratological manifestations: death of fetus, structurally/biochemically abnormal offspring, developmental delay or small-for-gestational age, decrement of anticipated postnatal function.
• Criteria for recognizing a new teratogenic agent in man:
• (1) abrupt Ý in the incidence of a particular defect or syndrome.
• (2) coincidence of the above with a known environmental change (extensive use of a new drug, etc).
• (3) known exposure to the environmental change early in the pregnancy.
• (4) Absence of other factors common to all pregnancies yielding infants with the characteristic defects.
• Examples: Retinoic acid embryopathy – 1982. defects in CNS, cardiovascular, and ear formation. Due to category X (known to be teratogenic at time of release) drug. Relative risk of malformations ~25.6.

The Future – Fetal Therapy