Clinical pharmacology in neonates: Small size, huge variability

Drug therapy is a powerful tool for improving neonatal outcome. Despite this, neonatologists still routinely prescribe off-label compounds developed for adults and extrapolate doses from those used for children or adults. Knowledge integration through pharmacokinetic modeling is a method that could improve the current situation. Such predictive models may convert neonatal pharmacotherapy from explorative to confirmatory. This can be illustrated by research projects related to the prediction of neonatal renal clearance and neonatal glucuronidation. This type of model will also improve the current knowledge of neonatal (patho)physiology. In the meanwhile, the fields of clinical pharmacology (e.g. pharmacokinetic/pharmacodynamic modeling and pharmacogenetics) and neonatology (e.g. whole-body cooling and the lower limit of viability) have both matured, resulting in new research topics. However, in order for the modeling and the newly emerging topics to become effective tools, they need to be tailored to the specific characteristics of neonates. Consequently, the field of neonatal pharmacotherapy needs dedicated neonatologists who continue to raise the awareness that off-label practices, eminence-based dosing regimens and the absence of neonatal drug formulations all reflect suboptimal care

Endotracheal instillation of prostacyclin in preterm infants with persistent pulmonary hypertension

Does endotracheal instilled prostacyclin (epoprostenol) improve oxygenation in preterm infants with persistent pulmonary hypertension? Four preterm infants were studied. Prostacyclin (50 ng x kg(-1)) was injected as an endotracheal bolus. In two patients the prostacyclin bolus was repeated and in one patient prostacyclin was administered continuously. Oxygenation was evaluated through the oxygenation index and the ratio of arterial oxygen tension to the fraction of inspired oxygen. The mean arterial blood pressure was used to evaluate systemic circulation. The oxygenation index (+/-SD) decreased significantly from 39 (+/-13.3) to 7 (+/-2.5) and the ratio of arterial oxygen tension to the fraction of inspired oxygen (+/-SD) increased significantly from 47 (+/-13) to 218 (+/-67), most likely related to a reduction of the pulmonary vascular resistance with a reversal of the extrapulmonary shunting at the ductus arteriosus and atrial level. The blood pressure did not change. All effects were reversed on drug withdrawal. Repeated or continuous endotracheal administration of prostacyclin in three children demonstrated a sustained response without tachyphylaxis, and without overt side-effects. Endotracheal instillation of prostacyclin resulted in an improved oxygenation without systemic vascular repercussions in four preterm infants with persistent pulmonary hypertension. Repeated or continuous administration showed a sustained response and no overt side-effects were noticed

Phenobarbital Increases Midazolam Clearance in Neonates Treated with Hypothermia: Do We Really Need to Know?

The clinical management and subsequent outcome of pediatric and neonatal patients can improve significantly with the availability of effective and safe medicines if appropriately investigated in the relevant population [1]. This is also the case for neonates treated with hypothermia for perinatal asphyxia. However, the vast majority of medicines are developed with adult pathophysiology in mind and are not guided by neonatal (patho)physiology. Drug development is mainly driven by adult indications, subsequently tailored or repurposed for use in neonates, with exogenous surfactant as the latest but hopefully not last example of drug discovery specific to neonates [2]

CYP3A5 variant allele frequencies in Dutch Caucasians

BACKGROUND: Enzymes of the cytochrome P450 3A (CYP3A) family are responsible for the metabolism of >50% of currently prescribed drugs. CYP3A5 is expressed in a limited number of individuals. The absence of CYP3A5 expression in approximately 70% of Caucasians was recently correlated to a genetic polymorphism (CYP3A5*3). Because CYP3A5 may represent up to 50% of total CYP3A protein in individuals polymorphically expressing CYP3A5, it may have a major role in variation of CYP3A-mediated drug metabolism. Using sequencing, have been identified (Hustert et al. Pharmacogenetics 2001;11:773-9; Kuehl et al. Nat Genet 2001;27:383-91) variant alleles *2 through *7 for CYP3A5. Detection of CYP3A5 variant alleles, and knowledge about their allelic frequency in specific ethnic groups, is important to establish the clinical relevance of screening for these polymorphisms to optimize pharmacotherapy. METHODS: In a group of 500 healthy Dutch Caucasian blood donors, we determined the allelic frequency of the CYP3A5*2, *3, *4, *5, *6, and *7 alleles by use of newly developed PCR-restriction fragment length polymorphism assays. RESULTS: The frequency of the defective CYP3A5*3 allele in the Dutch Caucasian population was 91%, followed by the CYP3A5*2 (1%) and CYP3A5*6 (0.1%) alleles. The CYP3A5*4, *5, and *7 alleles were not detected. CONCLUSIONS: On the basis of its allelic frequency, screening for the CYP3A5*3 allele in the Caucasian population is extremely relevant. In addition, screening for the CYP3A5*2 allele may be taken into consideration in individuals heterozygous for the CYP3A5*3 allele. The CYP3A5*4, *5, *6, and *7 alleles have low allelic frequencies that do not support initial screening