Clinical Pharmacokinetics in Neonates

Abstract

Recent concern over toxic effects of drugs in newborns, infants and children have stressed the need for better knowledge of drug kinetics during development. The present review focuses on the available data on clinical pharmacokientics in the neonate. Despite the lack of systematic approaches on drug disposition during the first month of life, the body of data currently available indicates profound differences in drug disposition between neonates and older infants, children and adults. In terms of physiological and anatomical factors the neonate has to be considered as a 'unique drug recipient'. For all the specific variables which govern the drug kinetic pattern (absorption, blood esterase activity, plasma protein binding, metabolic degradation and renal excretion), there are clear difference between neonates and older infants and children. Such differences are not always unidirectional. In the case of absorption, they depend on the maturational stage, but more on the physico-chemical properties of the individual compound. Esterase activiy and renal excretion are also related to the physico-chemical properties of the drug, but are more clearly linked with the development stage. Plasma protein blinding is generally reduced, and depends on several factors, not all of which are as yet clearly identified and understood. Biotransformation activities are usually very low, but may be increased several-fold by exposure to inducing agents. Hydroxylating activity and conjugation with glucronic acid appear to be the two metabolic pathways which are most defective at birth, while sulphate and gylcine conjugation, and dealkylation activities are close to the adult pattern. The material reviewed is fragmentary and does not always permit a comparison of the data obtained in newborns with those reported for adults. Differences in the methodology used and in the kinetic criteria further complicate the matter. It is, however, clearly emerging that drug disposition may vary greatly in the newborn in relation to its developmental age. The reported differences may be relevant for clinical practice and stress the need for more detailed information on drug kinetics in the neonate. Such information may be achieved by carefully planned clinical trials, but more meaningfully, and more profitably for the individual patient, by a very carefully, well integrated monitoring of the neonate a risk. By such an approach, where drug plasma levels are related to drug effects and to the pathophysiological condition, the significance of various factors on drug disportion during development will be better clarified, thus allowing a more rational and safer therapy in the newborn.

Theophylline population pharmacokinetics from routine monitoring data in very premature infants with apnoea

“…The significant influence of both weight and postnatal age on CL agreed with the population study of Moore et al [6] and aligns with the fact that these demographic factors are closely related to the degree of development of major drug clearance organs such as the liver and kidneys [13]. In contrast to another report [14], postnatal age was better than the number of theophylline treatment days, or postconceptional age in modelling clearance.…”

Comparative pharmacokinetics of SCE-2787 and related antibiotics in experimental animals

“…The levels of SCE-2787 and ceftazidime in plasma in young dogs were lower than those in mature dogs. It has been shown that the volume of extracellular fluids per kilogram of body weight in young animals and humans is larger than that in mature animals and humans: the V of ,B-lactam antibiotics at steady state in the infants is generally greater than that in the adults (5,9). This may be due to the fact that the CLp and Vin young dogs were larger than those in mature dogs ( Table 1).…”

Pharmacokinetics in the infant.

“…The area of pediatric pharmacokinetics has blossomed since the 1970s, when advances in the development of sensitive and specific drug assays began. Pharmacokinetic parameters such as clearance (CL), volume of distribution (V) and half-life (t112) have been described for many therapeutic agents used in the newborn and young infant (1)(2)(3)(4)(5)(6) and numerous reviews are devoted to this subject (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). However, quantitation of clinical effects and pharmacodynamic response as modified by development and disease are areas that have lagged behind description of pharmacokinetics in this age group (10).…”