Abstract
There are several reasons why drug research in children remains challenging, in spite of legal and regulatory initiatives providing incentives to pharmaceutical companies applying for market authorization. The population designated as 'children' is not a homogeneous group, but consists of a range of ages and weights varying from premature neonates weighing less than 500 grams to 17-year old adolescents with a body weight over 100 kg. Especially in the younger age groups sufficient information concerning the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs is lacking. This may lead to under- or overdosing. No generally applicable formula exists to calculate the optimal dose or dose interval for various age groups, since the development of the organ systems responsible for absorption, distribution, metabolism and excretion is not linearly related to age or weight. In addition, the sensitivity of the end organs, determining pharmacodynamics (PD) can vary during development, which may lead to unexpected, sometimes adverse effects.
Before conducting a randomised clinical trial (RCT) to evaluate the efficacy of a drug in children, it is important not only to determine the adequate sample size, but also to determine the optimal dosage. To limit the patient burden of these PKPD studies, the number of subjects, the number of samples per subject and the amount of blood per sample should be minimized, and the timing of sampling should be flexible. The emergence of new laboratory techniques and statistical tools such as NONMEM® allows for the collection and analysis of sparse and unbalanced data, enabling the implementation of (observational) PKPD studies in the paediatric clinic.
The PharmaCool study is an example of a study in which the population PK of drugs frequently used in term neonates with hypoxic ischemic encephalopathy due to perinatal asphyxia undergoing moderate hypothermia (i.e. antibiotics, antiepileptics, analgesics, and sedatives) is described. In this multi-center observational cohort study performed in the Netherlands and Belgium, 12 neonatal intensive care units collaborated to obtain valid data to optimize the dosing of these drugs in this specific patient population.
