13.12: Pharmacokinetics in Pediatric Patients: Drug Distribution

Drug distribution in the pediatric population exhibits unique challenges and considerations due to the physiological differences between children, particularly neonates and infants, and adults. A crucial aspect of pediatric pharmacology is understanding how these differences impact the pharmacokinetics of various drugs, necessitating age-specific dosing strategies to ensure efficacy and safety.

Neonates and infants have a higher total body water content, ~75%–90% of their body weight, compared to about ~60% in adults. This increased water content significantly affects the distribution of hydrophilic drugs, leading to lower plasma concentrations when dosed on a weight basis. The implications for drug dosing are profound, as the standard adult dosing regimen may not achieve the desired therapeutic effect in this population. Furthermore, the extracellular fluid (ECF) volume is also higher in neonates (45%) compared to adults (25%–26%), which normalizes to adult values by the age of one year. This transient increase in ECF contributes to the altered distribution patterns seen in early life.

Conversely, the total body fat in neonates and infants is initially lower (12%), peaks at about 30% within the first year, and then gradually decreases to the adult value of 18%. This fluctuation in body fat content influences the distribution of lipophilic drugs, although the age-dependent variability is less pronounced compared to hydrophilic drugs.

Moreover, the concentrations of plasma proteins, such as albumin and α-acid glycoprotein, are lower in neonates and infants. These proteins play a critical role in drug binding; thus, lower levels can increase the unbound fraction of drugs in the plasma, enhancing their pharmacological activity. For example, phenytoin, a commonly used antiepileptic drug, has a higher unbound fraction in younger patients, increasing its efficacy. Additionally, the competition between drugs and bilirubin for albumin-binding sites in neonates can lead to increased unbound drug fractions, further complicating drug distribution and necessitating careful consideration in dosing.

In summary, pediatric drug distribution is influenced by developmental changes in body composition and plasma protein concentrations, requiring tailored dosing regimens to achieve therapeutic drug levels while minimizing the risk of adverse effects. Understanding these pharmacokinetic principles is essential for healthcare professionals involved in the care of pediatric patients, ensuring safe and effective drug therapy.

Drug distribution in children is influenced by changes in plasma protein concentration, total body fat, total body water, and extracellular fluid.

Neonates and infants have a higher total body water content and extracellular fluid than adults.

These can affect the distribution of hydrophilic drugs, resulting in lower plasma concentrations in the pediatric population compared to adults.

In contrast, their total body fat is lower at birth, peaks within a year, and then gradually decreases to match the adult levels. However, the distribution volume of lipophilic drugs is less affected.

They also have lower concentrations of plasma proteins, impacting the distribution of drugs that are highly bound to these proteins.

For instance, in neonates and infants, phenytoin has a higher unbound fraction, increasing its plasma concentration and enabling it to exert better activity.

Additionally, in neonates, bilirubin competes with drugs for albumin-binding sites, displacing drugs and increasing the unbound drug fractions.