Pharmacology of enalapril in children: a review

Enalapril is an angiotensin-converting enzyme (ACE) inhibitor that is used for the treatment of (paediatric) hypertension, heart failure and chronic kidney diseases. Because its disposition, efficacy and safety differs across the paediatric continuum, data from adults cannot be automatically extrapolated to children. This review highlights paediatric enalapril pharmacokinetic data and demonstrates that these are inadequate to support with certainty an age-related effect on enalapril/enalaprilat pharmacokinetics. In addition, our review shows that evidence to support effective and safe prescribing of enalapril in children is limited, especially in young children and heart failure patients; studies in these groups are either absent or show conflicting results. We provide explanations for observed differences between age groups and indications, and describe areas for future research

Proenkephalin A as a marker for glomerular filtration rate in critically ill children: Validation against gold standard iohexol GFR measurements

Objectives: Accurate determination of glomerular filtration rate (GFR) is important. Several endogenous biomarkers exist for estimating GFR, yet, they have limited accuracy, especially in the paediatric population. Proenkephalin A 119-159 (PENK) is a novel and promising GFR marker, but its relation with age in children remains unknown. Also, the value of PENK has never been validated against measured GFR (mGFR) in children when compared to traditional GFR markers including serum creatinine (SCr), SCr-based estimated GFR (eGFR) and cystatin C (cysC). Methods: Critically ill children and term-born neonates were included in this single-centre, prospective study. Iohexol-based mGFR, SCr, and cysC were determined in each patient. eGFR was calculated using the bedside Schwartz equation, incorporating SCr and height. Spearman correlation coefficients were calculated to determine the correlation between mGFR and PENK, SCr, cysC and eGFR. Results: For 97 patients (56 children and 41 neonates), mGFR, SCr, cysC and PENK levels were available. PENK levels were higher in young children and decreased to adult PENK reference values around two years of age. PENK levels were highly correlated with mGFR (ρ=-0.88, p<0.001), and similar to mGFR-eGFR correlation (ρ=-0.87, p<0.001). For cysC and SCr the correlation with mGFR was lower (ρ=-0.77 and ρ=-0.46, respectively. Both p<0.001). Conclusions: The correlation of PENK with mGFR was as good as SCr-based eGFR-mGFR correlation. To determine the added value of PENK in paediatric clinical care and prior to implementation, PENK reference values are needed and the development and validation of a paediatric PENK-based eGFR equation is necessary

Assessing causality by means of the Naranjo scale in a paediatric patient with life threatening respiratory failure after alemtuzumab administration

Background: Alemtuzumab is a T cell depleting antibody agent used as induction immunosuppressant therapy in solid organ transplant recipients. In addition, it is being increasingly used to treat severe or glucocorticoid-resistant graft rejection. Despite the effectiveness of the treatment, severe adverse events have been reported related to alemtuzumab administration. We present a similar event illustrating the severity of this adverse drug reaction (ADR) and we highlight the structure causality assessment provides in approaching such a case. Case presentation: We report a case of life-threatening respiratory failure after alemtuzumab administration in a 17 year old paediatric kidney transplant recipient. He developed near fatal severe respiratory and circulatory failure based on acute respiratory distress syndrome (ARDS) with diffuse alveolar oedema and haemoptysis hours after his second alemtuzumab administration. As it was questionable whether alemtuzumab could be regarded as th

Guiding future paediatric drug studies based on existing pharmacokinetic and efficacy data: Cardiovascular drugs as a proof of concept

Introduction: Off-label drug use in the paediatric population is common, and the lack of high-quality efficacy studies poses patients at risk for failing pharmacotherapy. Next to efficacy studies, pharmacokinetic (PK) studies are increasingly used to inform paediatric dose selection. As resources for paediatric trials are limited, we aimed to summarize existing PK and efficacy studies to identify knowledge gaps in available evidence supporting paediatric dosing recommendations, thereby taking paediatric cardiovascular drugs as proof of concept. Methods: For each cardiovascular drug, paediatric indication and prespecified age group, together comprising one record, the authorized state was assessed. Next, for off-label records, the highest level of evidence was scored. High-quality efficacy studies were defined as meta-analysis or randomized controlled trials. Other comparative research, noncomparative research or consensus-based expert opinions were considered low quality. The level of evidence for PK studies was scored per drug and per age group, but regardless of indication. Results: A total of 58 drugs included 417 records, of which 279 (67%) were off-label. Of all off-label records, the majority (81%) were not supported by high-quality efficacy studies, but for 140 of these records (62%) high-quality PK studies were available. Conclusion: We demonstrated that for the majority of off-label cardiovascular drugs, only low-quality efficacy studies were available. However, high-quality PK studies were frequently available. Combining these PK data with extrapolation of efficacy data from adults may help to close the current information gap and prioritize the drugs for which clinical studies and safety data are urgently needed

Maturation of glomerular filtration rate in term-born neonates: an individual participant data meta-analysis

Background: The evidence from individual studies to support the maturational pattern of glomerular filtration rate (GFR) in healthy term-born neonates is inconclusive. We performed an individual participant data (IPD) meta-analysis of reported measured GFR (mGFR) data aimed to establish neonatal GFR reference values. Furthermore, we aimed to optimise neonatal creatinine-based GFR estimations. Methods: We identified studies reporting mGFR measured by exogenous markers or creatinine clearance (CrCL) in healthy term-born neonates. The relationship between postnatal age and clearance was investigated using cubic splines with generalized additive linear mixed models. From our reference values, we estimated an updated coefficient for the Schwartz equation (eGFR(ml/min/1.73m2)=(k*height (cm))/serum creatinine(mg/dl)). Results: Forty-eight out of 1521 screened articles reported mGFR in healthy term-born neonates, and 978 mGFR values from 881 neonates were analysed. IPD were available for 367 neonates and the other 514 neonates were represented by 41 aggregated data points as means/medians per group. GFR doubled in the first five days after birth from 19.6 (95%CI 14.7;24.6) ml/min/1.73m2 to 40.6 (95%CI 36.7;44.5) ml/min/1.73m2, then more gradually increased to 59.4 (95%CI 45.9;72.9) ml/min/1.73m2 by four weeks of age. A coefficient of 0.31 to estimate GFR best fitted the data. Conclusions: These reference values for healthy term-born neonates show a biphasic increase in GFR with the largest increase between days 1 and 5. Together with the re-examined Schwartz equation, this can help identify altered GFR in term-born neonates. To enable widespread implementation of our proposed eGFR equation, validation in a large cohort of neonates is required

Quality of Active versus Spontaneous Reporting of Adverse Drug Reactions in Pediatric Patients: Relevance for Pharmacovigilance and Knowledge in Pediatric Medical Care

For drug safety in pediatric patients, knowledge about adverse drug reactions (ADRs) is essential to balance benefits and risks, especially because of the high incidence of off-label drug use. However, underreporting of ADRs is a serious problem, leading to a deficit in knowledge affecting clinical practice. The aim of this study is to find a method by which we can improve the quantity of ADR reporting while maintaining or improving the quality of the ADR reports. This was done in several steps. First, health care providers were educated to increase awareness of ADRs. Thereafter, a novel active supporting system was introduced, where reporting ADRs was simplified; if clinical physicians suspected an ADR, they only had to send the name or hospital number of the patient, the observed ADR, and the suspected drug to a supportive team. This team collects all information needed about the possible ADR from the patient&rsquo;s medical records and hospital charts. With this information, the supportive team fills in the forms necessary for reporting ADRs to the nationwide pharmacovigilance centre Lareb. With this system, the quantity of ADR reports from both inpatients and outpatients rose dramatically. Subsequently, the quality of the obtained ADR reports was measured using the ClinDoc and vigiGrade systems. This study shows there is no loss of quality of the ADR reports in the active reporting system compared to spontaneous reporting systems. Based on the data of the present study, we suggest that an active reporting system has the potential to increase our knowledge about ADRs in pediatric patients