Insufficient Stability of Clavulanic Acid in Widely Used Child-Appropriate Formulations.

Amoxicillin-clavulanic acid (AMC) belongs to the WHO Essential Medicines List for children, but for optimal antimicrobial effectiveness, reconstituted dry powder suspensions need to be stored in a refrigerated environment. Many patients in low- and middle-income countries who are sold AMC suspensions would be expected not to keep to the specified storage conditions. We aimed to assess the stability of both ingredients in liquid formulations and dispersible tablets, combined with nationally representative data on access to appropriate storage. Degradation of amoxicillin (AMX) and clavulanic-acid (CLA) was measured in suspensions and dispersible tablets commercially available in Switzerland at different ambient temperatures (8 °C vs. 28 °C over 7 days, and 23 °C vs. 28 °C over 24 h, respectively). Data on access to refrigeration and electricity were assessed from the USAID-funded Demographic and Health Survey program. In suspensions, CLA degraded to a maximum of 12.9% (95% CI -55.7%, +29.9%) at 8°C and 72.3% (95% CI -82.8%, -61.8%) at a 28 °C ambient temperature during an observation period of 7 days. Dispersible tablets were observed during 24 h and CLA degraded to 15.4% (95% CI -51.9%, +21.2%) at 23 °C and 21.7% (-28.2%, -15.1%) at a 28 °C ambient temperature. There is relevant degradation of CLA in suspensions during a 7-day course. To overcome the stability challenges for all active components, durable child-appropriate formulations are needed. Until then, prescribers of AMC suspensions or pharmacists who sell the drug need to create awareness for the importance of proper storage conditions regarding effectiveness of both antibiotics and this recommendation should be reflected in the WHO Essential Medicines List for children

A Pediatric Covariate Function for CYP3A-Mediated Midazolam Clearance Can Scale Clearance of Selected CYP3A Substrates in Children

Recently a framework was presented to assess whether pediatric covariate models for clearance can be extrapolated between drugs sharing elimination pathways, based on extraction ratio, protein binding, and other drug properties. Here we evaluate when a pediatric covariate function for midazolam clearance can be used to scale clearance of other CYP3A substrates. A population PK model including a covariate function for clearance was developed for midazolam in children aged 1– 17 years. Commonly used CYP3A substrates were selected and using the framework, it was assessed whether the midazolam covariate function accurately scales their clearance. For eight substrates, reported pediatric clearance values were compared numerically and graphically with clearance values scaled using the midazolam covariate function. For sildenafil, clearance values obtained with population PK modeling based on pediatric concentration-time data were compared with those scaled with the midazolam covariate function. According to the framework, a midazolam covariate function will lead to systemically accurate clearance scaling (absolute prediction error (PE) < 30%) for CYP3A substrates binding to albumin with an extraction ratio between 0.35 and 0.65 when binding < 10% in adults, between 0.05 and 0.55 when binding > 90%, and with an extraction ratio ranging between these values when binding between 10 and 90%. Scaled clearance values for eight commonly used CYP3A substrates were reasonably accurate (PE < 50%). Scaling of sildenafil clearance was accurate (PE < 30%). We defined for which CYP3A substrates a pediatric covariate function for midazolam clearance can accurately scale plasma clearance in children. This scaling approach may be useful for CYP3A substrates with scarce or no available pediatric PK information

Useful pharmacodynamic endpoints in children: selection, measurement, and next steps.

Pharmacodynamic (PD) endpoints are essential for establishing the benefit-to-risk ratio for therapeutic interventions in children and neonates. This article discusses the selection of an appropriate measure of response, the PD endpoint, which is a critical methodological step in designing pediatric efficacy and safety studies. We provide an overview of existing guidance on the choice of PD endpoints in pediatric clinical research. We identified several considerations relevant to the selection and measurement of PD endpoints in pediatric clinical trials, including the use of biomarkers, modeling, compliance, scoring systems, and validated measurement tools. To be useful, PD endpoints in children need to be clinically relevant, responsive to both treatment and/or disease progression, reproducible, and reliable. In most pediatric disease areas, this requires significant validation efforts. We propose a minimal set of criteria for useful PD endpoint selection and measurement. We conclude that, given the current heterogeneity of pediatric PD endpoint definitions and measurements, both across and within defined disease areas, there is an acute need for internationally agreed, validated, and condition-specific pediatric PD endpoints that consider the needs of all stakeholders, including healthcare providers, policy makers, patients, and families.Pediatric Research advance online publication, 11 April 2018; doi:10.1038/pr.2018.38

C-reactive protein point-of-care testing in children with cough : qualitative study of GPs' perceptions

Background: Point-of-care C-reactive protein (CRP) testing is widely accepted in Dutch general practice for adult patients with acute cough, but GPs' perceptions of its use in children with suspected lower respiratory tract infection (LRTI) are unknown. Knowledge of these perceptions is important when considering broadening its indication to use in children. Aim: To explore the perceptions of Dutch GPs of the addition of point-of-care CRP testing to the diagnostic evaluation of children, and compare these to their perceptions of use in adults. Design & setting: A qualitative study in general practice in the Netherlands. Method: Semi-structured interviews were held with 11 GPs. Interviews were analysed using open coding and a thematic approach. Results: GPs' perceptions of the addition of point-of-care CRP testing to diagnostic process in children with suspected LRTI differ from their perceptions of this in adults. Five themes were identified: patient characteristics; vulnerability of the child; clinical presentation; availability of evidence; the impact of the procedure; and use of point-of-care CRP testing as a communication tool. Conclusion: Differences between the perceptions of using point-of-care CRP testing in children and adults need to be addressed when considering the possible implementation of this diagnostic instrument

C-reactive protein point-of-care testing in children with cough: qualitative study of GPs' perceptions

Background: Point-of-care C-reactive protein (CRP) testing is widely accepted in Dutch general practice for adult patients with acute cough, but GPs’ perceptions of its use in children with suspected lower respiratory tract infection (LRTI) are unknown. Knowledge of these perceptions is important when considering broadening its indication to use in children. Aim: To explore the perceptions of Dutch GPs of the addition of point-of-care CRP testing to the diagnostic evaluation of children, and compare these to their perceptions of use in adults. Design & setting: A qualitative study in general practice in the Netherlands Method: Semi-structured interviews were held with 11 GPs. Interviews were analysed using open coding and a thematic approach. Results: GPs’ perceptions of the addition of point-of-care CRP testing to diagnostic process in children with suspected LRTI differ from their perceptions of this in adults. Five themes were identified: patient characteristics; vulnerability of the child; clinical presentation; availability of evidence; the impact of the procedure; and use of point-of-care CRP testing as a communication tool. Conclusion: Differences between the perceptions of using point-of-care CRP testing in children and adults need to be addressed when considering the possible implementation of this diagnostic instrument