What Are Special Considerations for Dosing Medications in Pediatric Populations?

Metabolizing Enzymes and Childhood

Metabolizing enzymes can be separated into three classes that are differentially affected in pediatric development. Class 1 enzymes, such as cytochrome P3A7 (CYP3A7), have their highest expression in the first trimester but have negligible levels by two years of age. Class 2 enzymes, such as CYP2C19, possess a relatively constant expression throughout development. Lastly, class 3 metabolizing enzymes, such as CYP1A2, CYP2C9, CYP3A4, and many UDP-glucuronosyltransferase (UGT) enzymes have minimal expression at birth, but they begin to increase in activity over the weeks following birth and reach sustained pediatric levels by two years of age. These changes in metabolizing enzyme expression impact drugs that undergo extensive hepatic metabolism, such as with sildenafil, whose clearance increases threefold over an infant’s first ten days of life due to increasing CYP3A4 metabolism.

This changing and developing drug metabolism in children translates into a safety issue for pain management selection. The FDA has placed black box warnings against the use of codeine and tramadol for pediatric patients due to reports of fatal overdoses from variable metabolizing enzyme activity in children. Specifically for these two medications, further variation is introduced, as pharmacogenomic aberrations in the CYP2D6 alleles also alter their metabolism, impacting the analgesic and toxic effects of what would have historically been considered normal doses for age/size.

Severe proinflammatory states or cachectic malnutrition can further impact metabolic capacity for pediatric palliative care patients. As the liver is a child’s main conversion center for processing medications into metabolites, attentiveness to hepatic clearance is an important consideration in the care of children receiving palliative care. The bioavailability of certain medications may be altered due to changes in liver blood flow (shunting congenital cardiac conditions, heart failure) or hepatic function (metabolic disorders resulting in cirrhosis). Transdermal or subcutaneous infusion may be considered for children with adequate subcutaneous tissue as this route may bypass the portal vein and therefore avoid reliance on first-pass metabolism.

Renal Considerations in Pediatric Dosing

Elimination is stunted in early development and does not reach adult levels of renal function until around one year of age. This can result in decreased renal clearance in neonates and infants, but upon kidney function development, increased relative kidney mass results in increased clearance in children as compared to adults. Thus dosing of medications, especially those which are primarily renally excreted, should take this into consideration. These clearance differences are vital to understand for accurate dosing, and thus pediatric populations utilize a specialized formula, the Schwartz equation, for estimating pediatric glomerular filtration rate (GFR).

Terminally ill children often have reduced elimination of drugs and metabolites due to diminished fluid intake (resulting in prerenal failure), which may be masked in serum creatinine lab values due to diminished muscle mass in deconditioned pediatric patients at the end of life. Rather than chase lab values, in some cases it may be more practical and more consistent with goals of care (avoiding needlesticks) for pediatric palliative clinicians to be aware of the risk of accumulation of certain drugs and metabolites (such as morphine-6-glucuronide as a major metabolite of morphine) and attentive to the possible clinical signs of such. For example, in monitoring general fluid intake as compared to urinary output and monitoring for adverse effects in children with diminished renal function (confusion, nausea, and myoclonic movements), palliative care providers may then consider clinical adjustments (e.g., rotation to a synthetic opioid such as fentanyl).