John N. van den Anker

Survey of unlicensed and off label drug use in paediatric wards in European countries

Abstract Objective: To determine the extent of use of unlicensed and off label drugs in children in hospital in five European countries. Design: Prospective study of drugs administered to children in general paediatric medical wards over four weeks. Setting: Childrens wards in five hospitals (one each in the United Kingdom, Sweden, Germany, Italy, and the Netherlands). Subjects: Children aged 4 days to 16 years admitted to general paediatric medical wards. Main outcome measure: Proportion of drugs that were used in an unlicensed or off label manner. Results: 2262 drug prescriptions were administered to 624 children in the five hospitals. Almost half of all drug prescriptions (1036; 46%) were either unlicensed or off label. Of these 1036, 872 were off label and 164 were unlicensed. Over half of the patients (421; 67%) received an unlicensed or off label drug prescription. Conclusions: Use of off label or unlicensed drugs to treat children is widespread. This problem is likely to affect children throughout Europe and requires European action. Key messages Many drugs are not tested in children, which means that they are not specifically licensed for use in children Licensed drugs are often prescribed outside the terms of the product license (off label) in relation to age, indication, dose of frequency, route of administration, or formulation Over two thirds (67%) of 624 children admitted to wards in five European hospitals received drugs prescribed in an unlicensed or off label manner 39% of the 2262 drug prescriptions given to children were off label The problem of off label and unlicensed drug prescribing in children is a European problem that requires European action

Cytochrome P450 3A: ontogeny and drug disposition.

The maturation of organ systems during fetal life and childhood exerts a profound effect on drug disposition. The maturation of drug-metabolising enzymes is probably the predominant factor accounting for age-associated changes in non-renal drug clearance. The group of drug-metabolising enzymes most studied are the cytochrome P450 (CYP) superfamily. The CYP3A subfamily is the most abundant group of CYP enzymes in the liver and consists of at least 3 isoforms: CYP3A4, 3A5 and 3A7. Many drugs are mainly metabolised by the CYP3A subfamily. Therefore, maturational changes in CYP3A ontogeny may impact on the clinical pharmacokinetics of these drugs.CYP3A4 is the most abundantly expressed CYP and accounts for approximately 30 to 40% of the total CYP content in human adult liver and small intestine. CYP3A5 is 83% homologous to CYP3A4, is expressed at a much lower level than CYP3A4 in the liver, but is the main CYP3A isoform in the kidney. CYP3A7 is the major CYP isoform detected in human embryonic, fetal and newborn liver, but is also detected in adult liver, although at a much lower level than CYP3A4. Substrate specificity for the individual isoforms has not been fully elucidated. Because of large interindividual differences in CYP3A4 and 3A5 expression and activity, genetic polymorphisms have been suggested. However, although some gene mutations have been identified, the impact of these mutations on the pharmacokinetics of CYP3A substrates has to be established.Ontogeny of CYP3A activity has been studied in vitro and in vivo. CYP3A7 activity is high during embryonic and fetal life and decreases rapidly during the first week of life. Conversely, CYP3A4 is very low before birth but increases rapidly thereafter, reaching 50% of adult levels between 6 and 12 months of age. During infancy, CYP3A4 activity appears to be slightly higher than that of adults. Large interindividual variations in CYP3A5 expression and activity were observed during all stages of development, but no apparent developmental pattern of CYP3A5 activity has been identified to date.Profound changes occur in the activity of CYP3A isoforms during all stages of development. These changes have, in many instances, proven to be of clinical significance when treatment involves drugs that are substrates, inhibitors or inducers of CYP3A. Investigators and clinicians should consider the impact of ontogeny on CYP3A in both pharmacokinetic study design and data interpretation, as well as when prescribing drugs to children.

Glucuronidation in Humans Pharmacogenetic and Developmental Aspects

During human development impressive changes in drug disposition occur. An important determinant of drug clearance is metabolism, something that is not only determined by ontogenic regulation but also by genetic processes which add to the variability of drug metabolism during different stages of childhood. Therefore, an understanding of the developmental regulation of different metabolic pathways, together with information on the genetic determinants of drug metabolism, will increase the knowledge of inter- and intraindividual variability in drug disposition during childhood.Conjugation has historically received less attention than cytochrome P450 metabolism. An important group of conjugation reactions are catalysed by the uridine 5′-diphosphate (UDP)-glucuronosyltransferases (UGTs); to date at least 10 different UGT isoforms have been identified. The UGTs are not only involved in the metabolism of many drugs [e.g. morphine, paracetamol (acetaminophen)] but also capable of the biotransformation of important endogenous substrates (e.g. bilirubin, ethinylestradiol) and several xenobiotics. Isoform specificity for these substrates has, however, not been fully characterised.Serious adverse events associated with chloramphenicol toxicity in the neonate have highlighted the importance of developmental changes in UGT activity. However, isoform-specific differences preclude the generalisation of a simple developmental pattern for UGT activity. UGT2B7 is the only UGT isoform for which ontogeny has been characterised both in vitro and in vivo, using morphine as the probe drug. However, no general developmental pattern for the individual UGT isoforms which might be of value for the clinician is currently available.Genetic polymorphisms have been identified for the UGT family. Not only for the UGT1A gene, which reduces bilirubin glucuronidation, leading to genetic hyperbilirubinaemia (the Crigler-Najjar and Gilbert’s syndromes), but also for 3 other UGT isoforms. However, the impact of these genetic differences on drug metabolism remains to be established because of overlapping isoform specificity of the drugs studied, as well as a lack of specific probe substrates to test the activity of individual UGT isoforms in relation to these gene mutations.Clearly, an information gap exists regarding the developmental and genetic aspects of UGT regulation and its potential impact on therapy. More research is needed on the pharmacogenetics and ontogeny of the UGTs for effective translation of scientific information into clinically applicable knowledge.

Guidelines on Paediatric Dosing on the Basis of Developmental Physiology and Pharmacokinetic Considerations

The approach to paediatric drug dosing needs to be based on the physiological characteristics of the child and the pharmacokinetic parameters of the drug. This review summarises the current knowledge on developmental changes in absorption, distribution, metabolism and excretion and combines this knowledge with in vivo and in vitro pharmacokinetic data that are currently available. In addition, dosage adjustments based on practical problems, such as child-friendly formulations and feeding regimens, disease state, genetic make-up and environmental influences are presented.Modification of a dosage based on absorption, depends on the route of absorption, the physico chemical properties of the drug and the age of the child. For oral drug absorption, a distinction should be made between the very young and children over a few weeks old. In the latter case, it is likely that practical considerations, like appropriate formulations, have much greater relevance to oral drug absorption.The volume of distribution (Vd) may be altered in children. Hydrophilic drugs with a high Vd in adults should be normalised to bodyweight in young children (age <2 years), whereas hydrophilic drugs with a low Vd in adults should be normalised to body surface area (BSA) in these children. For drugs that are metabolised by the liver, the effect of the Vd becomes apparent in children <2 months of age. In general, only the first dose should be based on the Vd subsequent doses should be determined by the clearance. Pharmacokinetic studies on renal and liver function clarify that a distinction should be made between maturation and growth of the organs. After the maturation process has finished, the main influences on the clearance of drugs are growth and changes in blood flow of the liver and kidney. Drugs that are primarily metabolised by the liver should be administered with extreme care until the age of 2 months. Modification of dosing should be based on response and on therapeutic drug monitoring. At the age of 2–6 months, a general guideline based on bodyweight may be used. After 6 months of age, BSA is a good marker as a basis for drug dosing. However, even at this age, drugs that are primarily metabolised by cytochrome P450 2D6 and uridine diphosphate glucuronosyltransferase should be normalised to bodyweight.In the first 2 years of life, the renal excretion rate should be determined by markers of renal function, such as serum creatinine and p-aminohippuric acid clearance. A dosage guideline for drugs that are significantly excreted by the kidney should be based on the determination of renal function in first 2 years of life. After maturation, the dose should be normalised to BSA.These guidelines are intended to be used in clinical practice and to form a basis for more research. The integration of these guidelines, and combining them with pharmacodynamic effects, should be considered and could form a basis for further study.

More Codeine Fatalities After Tonsillectomy in North American Children

In 2009 we reported the fatal case of a toddler who had received codeine after adenotonsillectomy for obstructive sleep apnea syndrome. The child was an ultra-rapid metabolizer of cytochrome P4502D6 (CYP2D6). We now report 3 additional fatal or life-threatening cases from North America. In the 2 fatal cases, functional gene duplications encoding for CYP2D6 caused a significantly greater production of potent morphine from its parent drug, codeine. A severe case of respiratory depression in an extensive metabolizer is also noted. These cases demonstrate that analgesia with codeine or other opioids that use the CYP2D6 pathway after adenotonsillectomy may not be safe in young children with obstructive sleep apnea syndrome.

The pharmacokinetics and safety of micafungin, a novel echinocandin, in premature infants

Background: Candidal fungal infection rates in neonates are increasing and are a significant cause of mortality, especially in low birth weight infants. Micafungin is an echinocandin that works by inhibiting 1,3-β-D-glucan synthase, an enzyme responsible for fungal cell wall synthesis. The objective of this study was to determine the safety and pharmacokinetics of micafungin in premature infants. Methods: This was a phase I, single-dose, multicenter, open-label, sequential-dose trial of intravenous micafungin investigating 3 doses (0.75 mg/kg, 1.5 mg/kg and 3.0 mg/kg) in 18 premature infants weighing >1000 g (n = 6 in each dosage group). A further 5 infants (500–1000 g) were enrolled in the 0.75 mg/kg dosage group only. Results: The mean ± standard deviation gestational age in the >1000 g dosage group was 26.4 ± 2.4 weeks and, on entry, patients had one or more of a variety of underlying conditions, including sepsis, pneumonia and other infections caused by Candida or other species. Micafungin pharmacokinetics in preterm infants appears linear. However, premature infants >1000 g on average displayed a shorter half-life (8 hours) and a more rapid rate of clearance (approximately 39 mL/h per kg) compared with published data in older children and adults. All doses of micafungin were well tolerated and no serious drug-related adverse events were observed. Conclusions: Single doses of micafungin, ranging up to 3.0 mg/kg, appear well tolerated in premature infants weighing >1000 g. The drugs elimination half-life and total plasma clearance in preterm infants appear dissimilar to published values for these parameters in older children and adults. The reason(s) for this apparent difference remain to be investigated.

Impact of obesity on drug metabolism and elimination in adults and children.

The prevalence of obesity in adults and children is rapidly increasing across the world. Several general (patho)physiological alterations associated with obesity have been described, but the specific impact of these alterations on drug metabolism and elimination and its consequences for drug dosing remains largely unknown.In order to broaden our knowledge of this area, we have reviewed and summarized clinical studies that reported clearance values of drugs in both obese and non-obese patients. Studies were classified according to their most important metabolic or elimination pathway. This resulted in a structured review of the impact of obesity on metabolic and elimination processes, including phase I metabolism, phase II metabolism, liver blood flow, glomerular filtration and tubular processes.This literature study shows that the influence of obesity on drug metabolism and elimination greatly differs per specific metabolic or elimination pathway. Clearance of cytochrome P450 (CYP) 3A4 substrates is lower in obese as compared with non-obese patients. In contrast, clearance of drugs primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT), glomerular filtration and/or tubular-mediated mechanisms, xanthine oxidase, N-acetyltransferase or CYP2E1 appears higher in obese versus non-obese patients. Additionally, in obese patients, trends indicating higher clearance values were seen for drugs metabolized via CYP1A2, CYP2C9, CYP2C19 and CYP2D6, while studies on high-extraction-ratio drugs showed somewhat inconclusive results. Very limited information is available in obese children, which prevents a direct comparison between data obtained in obese children and obese adults.Future clinical studies, especially in children, adolescents and morbidly obese individuals, are needed to extend our knowledge in this clinically important area of adult and paediatric clinical pharmacology.

Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus

Our objective was to study the pharmacokinetics of ibuprofen in premature infants with patent ductus arteriosus on day 3 and day 5 after birth.

Rising Opioid Prescribing in Adult U.S. Emergency Department Visits: 2001–2010

OBJECTIVES The objective was to describe trends in opioid and nonopioid analgesia prescribing for adults in U.S. emergency departments (EDs) over the past decade. METHODS Data from the National Hospital Ambulatory Medical Care Survey (NHAMCS) 2001 through 2010 were analyzed. ED visits for adult patients (≥18 years of age) during which an analgesic was prescribed were included. Trends in the use of six commonly prescribed opioids, stratified by Drug Enforcement Agency (DEA) schedule, as well as nonopioid analgesics were explored, along with the frequency of pain-related ED visits. For 2005 through 2010, data were further divided by whether the opioid was administered in the ED versus prescribed at discharge. RESULTS Between 2001 and 2010, the percentage of overall ED visits (pain-related and non-pain-related) where any opioid analgesic was prescribed increased from 20.8% to 31.0%, an absolute increase of 10.2% (95% confidence interval [CI] = 7.0% to 13.4%) and a relative increase of 49.0%. Use of DEA schedule II analgesics increased from 7.6% in 2001 to 14.5% in 2010, an absolute increase of 6.9% (95% CI = 5.2% to 8.5%) and a relative increase of 90.8%. Use of schedule III through V agents increased from 12.6% in 2001 to 15.6% in 2010, an absolute increase of 3.0% (95% CI = 2.0% to 5.7%) and a relative increase of 23.8%. Prescribing of hydrocodone, hydromorphone, morphine, and oxycodone all increased significantly, while codeine and meperidine use declined. Prescribing of nonopioid analgesics was unchanged, 26.2% in 2001 and 27.3% in 2010 (95% CI = -1.0% to 3.4%). Hydromorphone and oxycodone had the greatest increase in ED administration between 2005 and 2010, while oxycodone and hydrocodone had the greatest increases in discharge prescriptions. There was no difference in discharge prescriptions for nonopioid analgesics. The percentage of visits for painful conditions during the period increased from 47.1% in 2001 to 51.1% in 2010, an absolute increase of 4.0% (95% CI = 2.3% to 5.8%). CONCLUSIONS There has been a dramatic increase in prescribing of opioid analgesics in U.S. EDs in the past decade, coupled with a modest increase in pain-related complaints. Prescribing of nonopioid analgesics did not significantly change.

Unlicensed and off label prescription of drugs to children: population based cohort study

Editorial by Banner and pp 1311, 1312 Drugs are subject to licensing procedures to ensure their quality, efficacy, and safety, but many drugs used to treat children in hospital are either not licensed for use in children (“unlicensed”) or are prescribed outside the terms of the product licence (“off label”).1 Little is known about such prescribing in general practice, so we conducted a cohort study in primary care in the Netherlands to investigate the subject. We retrieved data from the integrated primary care information project, a longitudinal observational database containing information from computer based patient records of 150 general practitioners in the Netherlands. The system complies with European Union guidelines on the use of medical data for medical research and has been proved valid for pharmacoepidemiological research.2 Within the dynamic population of children (0-16 years) registered in 1998, …