Pediatric Pharmacokinetics
Year: 2013
Type: article
Abstract: After reading this article, the reader should be able toFor many clinicians, the term pharmacokinetics conjures images of algebraic equations and differential calculus long forgotten since the days of training. As a result, pharmacokinetic concepts tend to be perceived as somewhat esoteric by the general health care clinician. What often goes unappreciated is that clinicians are uniquely primed to understand pharmacokinetics because pharmacokinetics are merely the mathematical characterization of anatomical and physiologic processes that determine how drugs get into the body (absorption), where they go (distribution), and how they are removed (metabolism/excretion). Knowledge of anatomy and physiology enhances our understanding of pharmacokinetics in much the same way that knowledge of patient-specific factors (eg, age, genetics, diet, and end-organ function) influences our understanding of disease risk and drug response. It is important to realize that the application of pharmacokinetic-related knowledge is bidirectional in that pharmacokinetic studies can broaden our understanding of biology in areas where this knowledge is incomplete.This article is designed to reintroduce the reader to fundamental pharmacokinetic concepts and frame them in the context of the pediatric patient. Integral to beginning this discussion is a review of some basic pharmacokinetic terms that collectively drive decisions related to selecting the most appropriate dosing regimens for our patients.Like any volume, volume of distribution (Vd) represents a quantitative measure of size or space. In theory, Vd reflects the combined volume of the various compartments and tissues wherein a drug can be found after it enters the body. Factors that influence the extent to which a drug distributes into various tissues include the drugs’ octanol-water partition coefficient, acid dissociation constant, and affinity for plasma and tissue proteins.In practice, Vd represents a mathematical variable that relates the amount of drug administered (ie, the dose) to the resulting plasma concentration (equation 1). In essence, Vd reflects the size of a compartment necessary to account for the concentration that is measured after the total amount of drug has been administered.Imagine a jar of maraschino cherries that has been emptied into a large bowl of punch. If we know that the jar contains 100 cherries (dose) and we observe that every cup of punch in the bowl contains 2 cherries (concentration), we can estimate the volume of the punch bowl:For some drugs, the Vd is small and corresponds to a true biological space (eg, intravascular compartment, extracellular fluid stores, and total body water space). For other drugs that concentrate in tissues, the calculated Vd can be quite large. A Vd that exceeds the total volume of the body may seem nonsensical in a biological context; however, we simply need to recognize that Vd estimates are based on the measurement of drug concentrations in the blood. When tissue concentrations go up and blood concentrations go down, the denominator in equation 1.1 becomes smaller and the value of Vd increases.Irrespective of size, the value of Vd lies in its ability to help us determine the dose of drug to give our patients. If we know the volume of the compartment into which we are delivering drug and the concentration we want to achieve, we can calculate the desired dose (equation 1.2).Our goal is that partygoers receive 5 cherries per cup of punch. We have established that the bowl contains 50 cups. Thus, we can calculate the number of cherries we need to add to the bowl to achieve the desired concentration of cherries:Simply stated, clearance reflects a rate of change. In a pharmacokinetic context, clearance represents the fraction of the total Vd from which drug is cleared in any given unit of time. Biologically, clearance reflects the sum total of all physiologic processes that are working together to remove the drug from that compartment.Consider our 50-cup punch bowl from the last example. Now imagine a partygoer plucking cherries from the bowl. If our partygoer removes 10 cherries per hour and the bowl contains 5 cherries per cup, then the bowl is being cleared of cherries at a rate of 2 cups per hour. Add a second partygoer with the same affinity and capacity for consuming cherries and the equivalent of 4 cups per hour are being cleared of cherries.Apart from the innate ability of an organ (eg, kidney or liver) to remove the drug, there are other biologic factors that influence clearance rates, such as the degree of plasma protein binding, tissue extraction ratios, and cardiac output. Clearance is relevant to the practitioner because it helps to determine the frequency with which a drug must be delivered to sustain the concentrations desired in the plasma.At the start of the party we added 250 cherries to our bowl of punch. The 2 partygoers we described are removing a combined 20 cherries per hour. To ensure that other partygoers interested in drinking the punch receive 5 cherries per cup, we can add 20 cherries back to the bowl every hour or 10 cherries every ½ hour or 40 cherries every 2 hours and so on.For drugs administered by any route other than direct intravenous instillation, factors related to both the drug and the patient influence the degree to which the drug reaches the systemic circulation. These factors can include the disintegration characteristics of the dosage form, the dissolution properties of the drug, the stability of the drug at the absorption site, and the degree to which the drug serves as a substrate for transporters and drug-metabolizing enzymes (DMEs) that may be encountered before the drug reaches the systemic circulation (eg, first-pass effect). The fraction of the administered dose that makes it into the blood as intact drug defines bioavailability. For drugs given intravenously, 100% of the administered dose reaches the systemic circulation; thus, the bioavailability is 1. For drugs given by any other route (eg, sublingual, oral, rectal, and percutaneous), the bioavailability usually is less than 1, depending on the drug and host-related factors. Understanding the concept of bioavailability is clinically relevant because it allows us to understand that comorbidities (eg, diarrheal disease, Zollinger-Ellison syndrome, and psoriasis), dietary changes, formulation manipulation (eg, crushing tablets and preparing oral liquids), and other factors can alter the dose-exposure relationship.The concept of bioavailability is relevant also to our understanding of pharmacokinetic because the availability of the drug represents an unknown modifier that influences the estimates of Vd and clearance. Recall that our calculation of Vd relies on the concentrations we observe in the blood. When concentrations are low, we do not know whether it is because the drug has moved out of the circulation and into the tissues or because the drug never made it into the circulation in the first place. Thus, a more accurate representation of equations 1.0 and 1.1 is as follows:Similarly, the term clearance is more accurately represented as clearance/bioavailability given the relationship between clearance and Vd (see the “Half-life” section).The half-life (t½) of a drug is the amount of time required for the total amount of drug in the body or the blood to decrease by half (Fig 1 left). This pharmacokinetic parameter allows us to determine the fraction of drug that has been removed from the body and consequently the fraction of drug that remains. If the t½ is the time it takes concentrations in the body or blood to decrease by half, 50% of the drug will remain after 1 t½, 25% will remain after 2 t½, 12.5% after 3 t½, 6.25% after 4 t½, and 3.125 after 5 t½. Thus, approximately 97% of the drug will have left the system after 5 t½. Both Vd and clearance influence the t½ of a drug as described by equation 1.5. Alternatively, the elimination rate constant derived from the slope of the log-transformed plasma concentration versus the time curve can be used to calculate the t½ according to equation 1.6 (Fig 1 right).Although t½ is perhaps the easiest pharmacokinetic parameter to understand, it is also subject to a number of assumptions, namely, that the drug conforms to a 1-compartment model and demonstrates first-order elimination.Setting aside discussions about more complex, multiple-compartment pharmacokinetic models, we can examine the clinical importance of t½, which informs our decisions related to drug-dosing intervals to maximize efficacy and limit toxicity. The t½ can vary from hours to days and even months among different medications. Propranolol, a nonselective β-blocker commonly used to treat pediatric supraventricular tachycardia (SVT), has a t½ that ranges from 4 to 6 hours in children. By contrast, amiodarone, a class 3 antiarrhythmic agent used to treat refractory SVT, has a t½ of nearly 60 days after long-term administration. As expected, amiodarone requires less frequent dosing compared with the β-blockers.Although drugs with relatively long t½ offer the advantage of simplified dosing schemes, they are accompanied by increased complexities associated with toxicity management should adverse effects arise. By extension, patients who experience a protracted t½ owing to comorbidities that decrease clearance or expand the Vd can develop toxicity if the dose or dosing interval is not adjusted to account for these changes. For example, a postoperative cardiac patient who has poor renal perfusion and who requires antibiotics for concerns of sepsis may require a less frequent dosing interval for vancomycin, an antibiotic that is cleared renally.In patients with transient reductions in renal clearance, such as the postoperative patient described, not only do newly added drugs need to be dosed appropriately, but existing medications in the patient’s regimen should be reevaluated for the need to adjust doses or dosing intervals to avoid toxicity. This consideration is particularly relevant for drugs with a narrow therapeutic index (ie, where the amount of drug that causes therapeutic efficacy is only slightly lower than the amount that causes toxicity). If desirable plasma concentrations have been defined for these drugs, therapeutic drug monitoring is highly recommended. When measuring drug levels, proper timing is essential for accurate therapeutic monitoring. For instance, if a digoxin drug level is obtained before the drug has completely distributed into tissues, the measured value will appear falsely elevated and may lead to improper adjustments of the dose.The parameter t½ also allows us to determine how long it will take to achieve steady state. When drugs are administered at constant intervals, they accumulate in the body until the amount administered in a given period is equal to the amount eliminated in the same period. When this plateau occurs, the drug in the body has achieved steady state (the rate in equals the rate out). Drug accumulates in a similar fashion to that described for decay, so that concentrations are greater than 97% of where they will be at steady state after 5 t½ irrespective of the frequency with which the drug is dosed (Fig 2).Adherence to regular dosing intervals is essential to achieve and maintain a steady state. Whenever the dose or dosing interval changes, another 4 to 5 t½ must pass to achieve a new steady state. Thus, poor drug adherence, which occurs frequently with adolescent patients, will cause large fluctuations in drug concentrations due to a failure to achieve or maintain steady state. As an example, strict adherence to immunosuppressive medication use is of utmost importance after organ to avoid the renal rate has in the last long-term renal in the adolescent due to medication is the of drug from the of or application into the systemic circulation. 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For example, an who has and end-organ (eg, renal being for sepsis will require a more protracted dosing interval due to a lower than As described, these require monitoring of drugs with a narrow therapeutic index and with (eg, and given the of renal this to drugs that on renal for clearance until the and used to treat of are of drugs that of elimination in this that of until the clearance of pediatric drug is but understanding the physiology of the should the in the of which are relevant to proper our knowledge has in the last 20 knowledge remain that to the of drugs to our pediatric patients. The of new knowledge will have an on and pediatric drug to for review of the
Source: Pediatrics in Review
DOI: 10.1542/pir.34-6-258
Authors: J. Wagner, S. M. Abdel-Rahman
Institutions: Children's Mercy Hospital, University of Missouri–Kansas City
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4205396676