Pharmacokinetics in Neonatal Medicine

Drug Absorption and Route of Drug Administration

Absorption specifically refers to the process of drug transfer from its site of administration to the bloodstream (see Fig. 45.2 ). Drugs typically enter the body via intravenous (IV), enteral (per oral, PO), intramuscular, intrapulmonary, subcutaneous, or percutaneous routes and are then absorbed into the circulation as free drug. The route of administration affects the concentration of the drug over time (see Fig. 45.3 ). Bioavailability of a drug refers to the fraction of the administered dose that reaches the circulation but does not consider the rate of drug absorption. Bioavailability is determined by comparing the respective area under the plasma concentration curves (AUC) after a non-IV form of administration with the AUC after an IV administration. IV administration of a drug provides the most consistent, reliable absorption into the circulation and, therefore, defines a bioavailability of 100%.

For enteral medications, the bioavailability depends on biochemical properties of the drug, the formulation, and patient-specific factors such as gastric acidity, gastric emptying time, and intestinal absorption and transit time. Bioavailability is reduced by incomplete absorption and by first-pass metabolism as the drug enters the portal circulation where it can be metabolized in the liver before reaching the systemic circulation. Drugs administered enterally enter the circulation more slowly than IV bolus-administered drugs and therefore achieve a lower maximum drug concentration (C _max ) later after administration (see Fig. 45.3 ). Drug-specific dose adjustment is needed when converting IV to enteral formulations to achieve consistent exposure.

Neonates have unique absorption properties that impact drug concentrations after enteral administration. Reduced gastric acidity can increase absorption of acid-labile molecules (penicillin) and decrease absorption of weak organic acids (phenytoin, phenobarbital). Slower gastric emptying time and intestinal motility can change the time to absorb the drug and amount of drug absorbed. Enteral absorption often improves as infants become older. Absorption of enteral medications is often decreased in infants with GI pathology or changes in perfusion to the GI system. Anticipating differences in bioavailability helps guide dose adjustment when converting between IV and PO route of administration.

Bioavailability after intramuscular (IM) and percutaneous (topical) administration can be affected by tissue mass, perfusion, drug permeability, and surface area. In neonates, reduced muscle perfusion and contractility can limit absorption after IM administration. When drugs are applied topically, the percutaneous absorption of the drug is directly related to the degree of skin hydration and relative surface area and inversely related to the thickness of the stratum corneum. Percutaneous application of medications in premature infants can lead to large systemic drug exposures given their larger surface area and thin stratum corneum.

Drug Distribution and Volume of Distribution

Distribution refers to the process by which drugs move from the central circulations through various compartments and peripheral tissues in the body according to physiochemical properties such as the molecular size, ionization constant, and relative hydrophilic/lipophilic properties (see Fig. 45.2 ). The central compartment typically refers to the vascular space with rapid distribution to the heart, kidney, and liver. From the central compartment, drugs distribute at a slower rate to the peripheral compartment(s) that can include brain, fat, and muscle. From the peripheral tissues, drugs traverse back into the central compartment to be eliminated. Drug distribution depends on drug-specific factors (molecular size, ionization constant, relative hydrophilic/lipophilic properties, protein binding) and infant-specific factors (body composition, membrane/tissue permeability, cardiac output). Distribution is an important concept to understanding PK, because it relates to the maximum drug concentration after a given dose and the volume of distribution (Vd). The kinetics of drug transfer to and from the peripheral and central compartments also affects the kinetics of drug excretion and the shape of the drug concentration curve over time.

The apparent volume of distribution (Vd) for a drug is defined as the hypothetical fluid volume through which the drug is dispersed. It is calculated by dividing the total amount of drug given by the concentration of drug in plasma ( Table 45.1 , Eq. [3] ). Vd does not refer to any physiologic compartment nor the blood volume. Instead, Vd relates to the hypothetical volume of the total compartment that explains the concentration of the drug achieved after administering a given amount.

TABLE 45.1

Simplified Mathematical Equations for Basic Pharmacokinetics (PK) Analysis: Intravenous Drugs That Follow First-Order Kinetics

PK Parameter	Abbreviation	Units	[#] Equation
Drug concentration	[C max ] at end infusion [C t ] at time t	mg / L	$\left[C_{\text{max}}\right]=\frac{\text{Dose mg}}{\text{kg}}÷\text{Vd}\left(\frac{L}{\text{kg}}\right)\max \text{concentration after injection}$ $\left[C_t\right]=\left[C_{\text{max}}\right]\times \left(e^{-\text{Kt}}\right)\text{concentration at time t}$
Volume of distribution	Vd	L / kg	$\text{Vd}=\text{amount drug given}\left(\text{mg}/\text{kg}\right)÷\left(\text{plasma}\right[\text{drug}\left]\text{mg}/L\right)$ $\text{Vd}=\text{CL}÷K_{\text{el}}$
Elimination rate constant	K el	hr −1	$K_{\text{el}}=\left(\text{Ln}{[C}_{t1}\right]-\text{Ln}\left[C_{t2}\right])÷\Delta \text{tor}=\text{Ln}\left[C_{t1}/{\text{C}}_{t2}\right]/\Delta t$ where [C t1 ] = conc at Time 1 or Time 2 and Δt is difference in hours between t 2 -t 1 $K_{\text{el}}=\text{CL}÷\text{Vd}$ $K_{\text{el}}=0.693÷T_{\frac{1}{2}}$
Half-life		hr	$T_{\frac{1}{2}}=0.693÷K_{\text{el}}(\text{note that}0.693=\text{Ln}2,\text{time for exponential two fold decline})$ $T_{\frac{1}{2}}=(0.693\times \text{Vd})÷\text{CL}$
Clearance	CL	L / hr * kg	$\text{CL}=K_{\text{el}}\times \text{Vd}$ $\text{CL}=(0.693\times \text{Vd})÷T_{\frac{1}{2}}$ $\begin{array}{c}\text{CL}=\left(\text{Dose}/\tau \right)÷\text{average steady-state}{\left[\text{drug}\right]}_{\text{ss}}\\ \text{where}\tau \text{is dose interval in hours}\end{array}$
Calculations After Single-Dose Infusions Accounting for Drug Elimination During Infusion
Drug concentration at time t	C t t inf = infusion time (hr) t is any time after infusion end	mg / L	$C_{\text{max}}=\left(R_0/\text{CL}\right)\times (1-e^{-\text{Ktinf}}){\text{where R}}_0=\left(\text{dose}/\text{infusion time}\right)\text{in units}(\text{mg}/\text{kg}\ast \text{hr})$ $C_t=\left(R_0/\text{CL}\right)\times (1-e^{-\text{Ktinf}})\times e^{-\text{Kt}}$ Because CL = Vd × k then rearrange [8] to solve for Vd or dose to achieve [C t ] if [C t ] and t inf are known $\text{Vd}=\left(R_0/[C_t\times K]\right)\times (1-e^{-\text{Ktinf}})\times e^{-\text{Kt}}$ $\text{Dose}=(\text{Vd}\times T_{\text{inf}}\times C_t\times K)÷\left(\right[1-e^{-\text{Ktinf}}]\times e^{-\text{Kt}})$
Calculations After ( n ) Multiple Doses After Bolus Injection or Short Infusion Time Models
Drug concentration after multiple doses ( n )	C max ( n ) Max C after n doses C t (n) C at time t after infusion after n doses C t (ss) C at time t after infusion at steady-state	mg / L	For a bolus injection $C_{\text{max}}\left(n\right)=\left(\text{Dose}/\text{Vd}\right)\times \left[\right(1-e^{-\text{nK}\tau })÷(1-e^{-K\tau }\left)\right](n=\text{doses},\tau =\text{dose interval})$
			$C_t\left(n\right)=\left(\text{Dose}/\text{Vd}\right)\times \left[\right(1-e^{-\text{nK}\tau })÷(1-e^{-K\tau }\left)\right]\times e^{-\text{Kt}}$
			$C_t\left(\text{ss}\right)=\left(\text{Dose}/\text{Vd}\right)\times \left[1/(1-e^{-K\tau })\right]\times e^{-\text{Kt}}(\text{as n}=\infty \text{then}[1-e^{-\text{nK}\tau }]=1)$ For a short infusion time (t inf ) $C_t\left(n\right)=\left(R_0/\text{CL}\right)\times (1-e^{-\text{Ktinf}})\times \left[(1-e^{-\text{nK}\tau })/(1-e^{-K\tau })\right]\times e^{-\text{Kt}}$ $C_t\left(\text{ss}\right)=\left(R_0/\text{CL}\right)\times (1-e^{-\text{Ktinf}})\times \left[1/(1-e^{-K\tau })\right]\times e^{-\text{Kt}}$

Understanding the factors that contribute to variation in Vd is helpful in determining the optimal dose of a medication to achieve a desired peak concentration (C _max ) in a specific patient. An infant with a higher Vd will have a lower peak concentration of drug in circulation. High Vd can indicate that the infant has an increase in total body water and extracellular fluid or that the drug has a wide distribution to peripheral tissues where it also might be sequestered. Gentamicin is a highly polar, hydrophilic molecule that distributes readily in extracellular fluid. Preterm infants have a high body water content and, therefore, require a higher dose of gentamicin to achieve the same peak concentration as a term infant.

Plasma protein binding can have significant effects on distribution. Drugs that exhibit high protein-binding capacity often have smaller Vd, because they bind to plasma proteins and are maintained in the circulation. Protein binding is also affected by availability of binding proteins, differences of binding capacity among different proteins, and increases in bilirubin or free fatty acids that can reduce drug protein binding. Protein binding also influences drug activity and elimination. Drugs that remain unbound to proteins (“free” drugs) are not only pharmacologically active but also more available for metabolism and/or elimination. Neonates typically have a higher proportion of “free drug” compared to total drug due to difference in binding proteins. Increased concentrations of bilirubin and free fatty acids can also compete with drugs for protein binding.

Drug Metabolism

Biotransformation is the process that typically converts lipophilic drug molecules into more polar, hydrophilic derivatives (see Fig. 45.2 ). Polar metabolites are less likely to diffuse across cell membranes, less likely to distribute into peripheral tissues, and more likely to be eliminated from the body. These polar metabolites are typically inactive, although some metabolites exhibit partial activity. Drugs undergo metabolism or biotransformation to polar metabolites by endogenous enzymatic pathways in the liver or less often in the kidneys, intestinal mucosa, or lungs. Biotransformation can also produce active metabolites from prodrugs, as with theophylline or valganciclovir, or toxic metabolites, as in the case of acetaminophen metabolite N -acetyl-p-benzoquinone imine.

The metabolism of drugs is typically classified into two phases, nonsynthetic phase 1 and synthetic or conjugation phase 2. Enzymes responsible for phase 1 metabolism convert a parent drug to a polar metabolite by introducing or unmasking a more polar site typically from oxidation, reduction, hydrolysis, or demethylation. The cytochrome P450 enzymes found in the liver and other tissues are primarily responsible for phase 1 oxidative metabolism. The most common cytochrome P450 drug-metabolizing enzymes are the CYP3A4 and CYP3A5 isoforms that together are responsible for metabolism of about 50% of medications. CYP isoforms are differentially expressed across human development; notably, CYP3A4 and 3A5 are only expressed after birth, whereas CYP3A7 is expressed in the fetus but expression declines after birth.

Enzymes responsible for phase 2 metabolisms typically add an endogenous substance to the drug to form a highly polar metabolite using UDP-glucuronosyltransferase, glutathione S-transferase, N-acetyltransferase, or sulfotransferase. Expression of phase 2 enzymes varies with both postnatal and postmenstrual age. At birth, sulfation is relatively developed; however, acetylation and glucuronidation are not well developed. Glucuronidation is an important pathway for metabolism of morphine and acetaminophen. Morphine clearance is low in neonates, and different morphine-glucuronide metabolites predominate as glucuronidation pathways are underdeveloped at birth. In neonates receiving acetaminophen, sulfation compensates for some of the glucuronidation deficiencies at birth such that sulfate-conjugated metabolites become the predominant excreted form. Phase 2 drug metabolism varies greatly among preterm and term infants in the NICU. While glucuronidation capacity is low after birth, it subsequently increases with weight and postnatal age, resulting in changes in the metabolism of drugs among infants in the NICU.

In general, neonates exhibit reduced hepatic metabolism that leads to increased drug concentrations, delay clearance, and longer half-life of medications that require biotransformation prior to excretion. This delay in hepatic metabolism is due to decreases in production in many drug-metabolizing enzymes and limited uptake of drugs into hepatocytes. Metabolism may also be enhanced or impaired by environmental, genetic, and physiologic factors. Environmental influences include concomitant medications that may induce or inhibit drug-metabolizing enzymes; fluconazole inhibits CYP2C9 and CYP3A4, whereas phenobarbital induces CYP2B and CYP3A. The cytochrome P450 genes also exhibit wide genetic variation explained by single nucleotide polymorphisms that can diminish or enhance enzyme activity and significantly affect drug metabolism. For example, codeine is metabolized to morphine by CYP2D6; children whose CYP2D6 genotype leads to ultra-rapid metabolism of codeine can experience morphine toxicity. Other factors affecting hepatic metabolism include uptake of drugs into hepatocytes, hepatic blood flow, body temperature, and disease states affecting perfusion.

Hepatic processes change rapidly over the first month so dose adjustment is often necessary with advancing postnatal age and maturation. Fentanyl is metabolized by hepatic CYP3A4 mediated N-de-alkalation to norfentanyl. Fentanyl elimination depends on liver blood flow, hepatic uptake, and CYP3A4 activity. Not surprisingly, fentanyl PK is highly variable in neonates, half-life ranges from 317-1266 minutes, and clearance increases threefold in the first 2 weeks of life. In the first 48 hours after birth, fentanyl clearance increases 40% between infants born at 29 weeks’ gestation compared to 41 weeks’ gestation. Understanding the differences in drug metabolism is important to understanding drug exposures in neonates; if neonates cannot effectively metabolize a drug, then higher concentration of active drug can potentiate effects of the drug or lead to toxicity. In the absence of specific drug-metabolizing enzymes, neonates may use alternative pathways and produce different metabolites with different activity or toxicity profiles. As drug-metabolizing capacity improves with age, higher doses are necessary to achieve desired concentration and response.

Drug Excretion

The excretion of active drugs or their metabolites is the process by which drugs are removed from the body. Drug excretion primarily occurs through the kidney and liver (see Fig. 45.2 ). The kidney uses three mechanisms of drug excretion: glomerular filtration, active secretion through the proximal tubules, or distal tubule reabsorption. Glomerular filtration is very low in the first few days after birth and increases with hemodynamic changes and improved renal perfusion. Glomerular filtration also increases with gestational age; preterm infants typically have delayed renal clearance and longer half-life compared to term infants. Disease states common in critically ill newborns such as neonatal encephalopathy, sepsis, acute kidney injury, and congenital heart disease all have been associated with reduced glomerular filtration and reduced drug excretion.

Tubular processes related to drug secretion and reabsorption are also important to renal elimination yet incompletely understood particularly in neonates. Drug secretion in the proximal tubules uses transport systems that typically eliminate organic anions. Secretion transporter proteins secrete drugs that are conjugated with glucuronic acid, glycine, and sulfate, such as penicillin or furosemide. Tubular secretion is less developed in newborns, thereby partially explaining the prolonged half-life of penicillin and furosemide. Membrane transporters in the distal tubule can actively reabsorb drugs from the tubular lumen back into the systemic circulation. Tubular reabsorption is also delayed in neonates. Glomerular filtration rate typically improves with maturation faster than tubular mechanisms.

The liver uses four mechanisms of drug excretion: drug metabolism, excretion into bile, fecal elimination, and enterohepatic recirculation. Hepatic drug elimination can be dependent on hepatic blood flow and the metabolic capacity of liver. Patients with hepatic insufficiency have decreased elimination of drugs because of alterations in protein levels and protein binding, decreased liver blood flow, decreased uptake into hepatocytes, and altered hepatic enzymatic reaction. Patients with hepatic insufficiency, however, exhibit marked variability in drug metabolism and elimination. Infants with hepatic insufficiency typically benefit from lower doses of drugs that are eliminated by hepatic biotransformation and therapeutic drug monitoring when possible.

Regardless of excretion mechanism, the rate at which drugs are eliminated from the circulation is essential to the PK properties of drug clearance (CL), elimination rate constant (K _el ), and half-life ( ) (see formulas in Table 45.1 , Eq. [4.6] ). Drug CL is defined as the volume of blood from which all drug is removed per unit time; K _el represents the elimination rate constant, in other words, the slope of the drug concentration time curve on a semi-logarithmic plot; and is defined as the time it takes to clear half of the drug from plasma. Clearance can be affected by body weight, body surface area, cardiac output, hepatic function, renal function, plasma protein binding, concomitant medications, and variation in expression of drug metabolizing enzymes. At steady state, drug input is equal to drug elimination and, therefore, the dose given (dose/interval) is equal to the amount of drug removed (CL x drug concentration at steady state).