Review: therapeutic drug monitoring in pediatrics.

Abstract

Therapeutic drug monitoring (TDM) can be defined as the measurement of drug concentrations in biologic fluids to assess whether they correlate with the patient’s clinical condition and whether the dosage or dosage intervals need to be changed. This is done to optimize the management of patients receiving drug therapy for the alleviation or prevention of disease. Therapeutic drug monitoring is a relatively new service in the clinical pharmacology and toxicology laboratory and has evolved from being a luxury to a necessity. The principles of TDM were developed in the 1960s. Advances in research and knowledge and increasingly sophisticated laboratory methods led to an expansion of TDM (1–3). A drug must meet the following criteria to be eligible for monitoring: There should be a clinically interpretable correlation between the serum drug concentration and its pharmacologic effect. This usually implies a clinically significant correlation between the serum drug concentration and its concentration in the target tissue (1). There should be a better correlation between the plasma drug concentration and the pharmacologic effect than between the drug dosage and the pharmacologic effect. A narrow margin should exist between serum concentrations that cause toxic effects and concentrations that produce therapeutic effects. The serum concentration resulting from a given drug dose is unpredictable as a result of inter- and intraindividual differences in drug absorption, distribution, and elimination. Such poor correlation between serum concentration and drug dosage has been shown with clomipramine used in treatment of enuresis (2). The pharmacologic effects of drugs are not readily measurable (e.g., suppression of seizure activity is difficult to monitor clinically when administering anticonvulsant drugs). There must be a rapid and reliable method for the analysis of the drug. The criteria for monitoring drugs in children are the same as those for adults (6), but several additional factors must be considered. Neonates, infants, and children undergo major and rapid age-related physiologic and biochemical changes, especially during the first year of life, resulting in different clinical pharmacokinetic and pharmacodynamic parameters from adults (Table 1). Recent indications are that approximately 12% of all drugs prescribed in the United States are for children age 9 years and younger (4). Further, review of drug-dosing habits in neonatal intensive care units has shown that the average number of drugs administered to premature infants weighing less than 1,000 g varies from institution to institution but is usually in the range of 15 to 20 drugs; infants weighing more than 2,500 g usually receive 4 to 10 drugs during their hospital stay. Obviously, drug concentrations in many of these patients need to be monitored by the laboratory, and the possibility of drug interactions needs to be considered. Thus, it is important to have a clear understanding of not only the principles of TDM but also the additional factors inherent in and specific to pediatric clinical pharmacology. Table 1 Pharmacokinetic parameters of drugs commonly used in children When administering drugs to children, age-related differences in drug absorption, distribution, metabolism, and clearance should be taken into account to optimize drug efficacy and to avoid toxicity. There are major differences not only between adults and children but also between neonates and pre- and postpubertal children. The following are some important differences between adults and children: Changes in gastric pH and gastric emptying time during the neonatal period lead to variation in the absorption of many drugs. Differences in body composition (neonates are composed of less body fat and more water) lead to differences in the apparent volume of distribution between neonates, children, and adults (Table 2). Table 2 Some factors affecting drug distribution and disposition Slow total drug clearance in premature infants and neonates is due to immature hepatic and renal function. Immaturity of the hepatic microsomal enzyme system produces slow biotransformation of many drugs in premature infants and neonates, requiring a lower mg/kg dosage to achieve therapeutic concentrations. Greater microsomal enzyme activity in prepubertal children than in postpubertal children and adults necessitates a higher mg/kg dosage to achieve similar serum concentrations of some drugs.