Pharmacokinetics-Based Pediatric Dose Evaluation and Optimization Using Saliva - A Case Study.

Understanding pharmacokinetics (PK) in children is a prerequisite to determine optimal pediatric dosing. As plasma sampling in children is challenging, alternative PK sampling strategies are needed. In this case study we evaluated the suitability of saliva as alternative PK matrix to simplify studies in infants, investigating metamizole, an analgesic used off-label in infants. Six plasma and 6 saliva PK sample collections were scheduled after a single intravenous dose of 10 mg/kg metamizole. Plasma/saliva pharmacometric (PMX) modeling of the active metabolites 4-methylaminoantipyrine (4-MAA) and 4-aminoantipyrine (4-AA) was performed. Various reduced plasma sampling scenarios were evaluated by PMX simulations. Saliva and plasma samples from 25 children were included (age range, 5-70 months; weight range, 8.7-24.8 kg). Distribution of metamizole metabolites between plasma and saliva was without delay. Estimated mean (individual range) saliva/plasma fractions of 4-MAA and 4-AA were 0.32 (0.05-0.57) and 0.57 (0.25-0.70), respectively. Residual variability of 4-MAA (4-AA) in saliva was 47% (28%) versus 17% (11%) in plasma. A simplified sampling scenario with up to 6 saliva samples combined with 1 plasma sample was associated with similar PK parameter estimates as the full plasma sampling scenario. This case study with metamizole shows increased PK variability in saliva compared to plasma, compromising its suitability as single matrix for PK studies in infants. Nonetheless, rich saliva sampling can reduce the number of plasma samples required for PK characterization, thereby facilitating the conduct of PK studies to optimize dosing in pediatric patients.

Model-driven survival prediction after congenital heart surgery.

OBJECTIVES: The objective of the study was to improve postoperative risk assessment in congenital heart surgery by developing a machine-learning model based on readily available peri- and postoperative parameters. METHODS: Our bicentric retrospective data analysis from January 2014 to December 2019 of established risk parameters for dismal outcome was used to train and test a model to predict postoperative survival within the first 30 days. The Freiburg training data consisted of 780 procedures; the Heidelberg test data comprised 985 procedures. STAT mortality score, age, aortic cross-clamp time and postoperative lactate values over 24 h were considered. RESULTS: Our model showed an area under the curve (AUC) of 94.86%, specificity of 89.48% and sensitivity of 85.00%, resulting in 3 false negatives and 99 false positives.The STAT mortality score and the aortic cross-clamp time each showed a statistically highly significant impact on postoperative mortality. Interestingly, a child's age was barely statistically significant. Postoperative lactate values indicated an increased mortality risk if they were either constantly at a high level or low during the first 8 h postoperatively with an increase afterwards.When considering parameters available before, at the end of and 24 h after surgery, the predictive power of the complete model achieved the highest AUC. This, compared to the already high predictive power alone (AUC 88.9%) of the STAT mortality score, translates to an error reduction of 53.5%. CONCLUSIONS: Our model predicts postoperative survival after congenital heart surgery with great accuracy. Compared with preoperative risk assessments, our postoperative risk assessment reduces prediction error by half. Heightened awareness of high-risk patients should improve preventive measures and thus patient safety.

Pharmacokinetics of a microdosed cocktail of three direct oral anticoagulants in children with congenital heart defects: study protocol for a single-centre clinical trial (DOAC-Child).

INTRODUCTION: Direct oral anticoagulants (DOACs) are direct inhibitors of coagulation factor Xa and are frequently used in adults for different indications such as deep vein thrombosis or non-valvular atrial fibrillation. Paediatric patients might benefit as well from DOACs because the simplicity and convenience of their use is likely to decrease physical and psychological stress related to invasive procedures associated with phenprocoumon and heparin therapy. Thus, it is expected that the future use of DOACs will ultimately improve compliance and overall safety of anticoagulant therapies in paediatric populations. To assure safe and effective use the clinical pharmacology and pharmacokinetics (PK) of these drugs need to be evaluated in children. METHODS AND ANALYSIS: This study is a single-centre, open-label, clinical trial in a paediatric population with non-cyanotic congenital heart defects. After having obtained informed consent from the parents, each participant will receive a single oral administration of a drinkable solution of a microdose cocktail of three FXa inhibitors consisting of apixaban (12.5 µg), rivaroxaban (12.5 µg), edoxaban (50 µg), plus a microdose of the two probe drugs midazolam (10 µg) and yohimbine (25 µg). Serial blood samples (n=up to 20) will be collected at specified time points before and up to 25 hours after cocktail administration. The primary PK endpoint will be the area under the plasma concentration time curve of apixaban, rivaroxaban and edoxaban. Secondary PK outcomes will be Cmax, tmax, t1/2, Cl/F and Vss/F. Safety and tolerability of the microdose cocktail will be evaluated as well by a collection of adverse events. ETHICS: This study has been approved by the responsible Ethics Committee of the Medical Faculty of Heidelberg University. DISSEMINATION: Study results will be presented at international scientific meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: EudraCT 2019-001759-38 16, DRKS00021455.

Efficacy and Safety of NSAIDs in Infants: A Comprehensive Review of the Literature of the Past 20 Years.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in infants, children, and adolescents worldwide; however, despite sufficient evidence of the beneficial effects of NSAIDs in children and adolescents, there is a lack of comprehensive data in infants. The present review summarizes the current knowledge on the safety and efficacy of various NSAIDs used in infants for which data are available, and includes ibuprofen, dexibuprofen, ketoprofen, flurbiprofen, naproxen, diclofenac, ketorolac, indomethacin, niflumic acid, meloxicam, celecoxib, parecoxib, rofecoxib, acetylsalicylic acid, and nimesulide. The efficacy of NSAIDs has been documented for a variety of conditions, such as fever and pain. NSAIDs are also the main pillars of anti-inflammatory treatment, such as in pediatric inflammatory rheumatic diseases. Limited data are available on the safety of most NSAIDs in infants. Adverse drug reactions may be renal, gastrointestinal, hematological, or immunologic. Since NSAIDs are among the most frequently used drugs in the pediatric population, safety and efficacy studies can be performed as part of normal clinical routine, even in young infants. Available data sources, such as (electronic) medical records, should be used for safety and efficacy analyses. On a larger scale, existing data sources, e.g. adverse drug reaction programs/networks, spontaneous national reporting systems, and electronic medical records should be assessed with child-specific methods in order to detect safety signals pertinent to certain pediatric age groups or disease entities. To improve the safety of NSAIDs in infants, treatment needs to be initiated with the lowest age-appropriate or weight-based dose. Duration of treatment and amount of drug used should be regularly evaluated and maximum dose limits and other recommendations by the manufacturer or expert committees should be followed. Treatment for non-chronic conditions such as fever and acute (postoperative) pain should be kept as short as possible. Patients with chronic conditions should be regularly monitored for possible adverse effects of NSAIDs.

US drug shortages compared to the World Health Organization's Model List of Essential Medicines for Children: A cross-sectional study.

PURPOSE: To describe US drug shortages affecting medications on the 2019 World Health Organization (WHO) Model List of Essential Medicines for Children (EMLc). METHODS: Drug shortage data from January 2014 to December 2019 were obtained from the University of Utah Drug Information Service. Shortage data for drugs on the EMLc were analyzed for the type of drug, American Hospital Formulary Service category, reason for the shortage, duration of the shortage, marketing status (generic vs brand name), and whether the agent was a single- or multisource drug. RESULTS: From 2014 to 2019, a total of 209 drug shortages impacted medications on the EMLc, of which 77 (36.8%) remained unresolved by 2019. Of all active shortages, 13 (6.2%) began before 2014. Resolved shortages had a median duration of 5.9 months (interquartile range [IQR], 3.6-13.2 months) while active shortages had a median duration of 18.3 months (IQR, 10.9-33.5 months; P ≤ 0.0001). The therapeutic categories most impacted by drug shortages were anti-infective agents (27.3%), central nervous system agents (12.9%), and antineoplastic agents (11.0%). The reason for the shortage was not reported in 46.4% of cases. When a reason was provided, the most common reason was manufacturing problems (29.2%) followed by supply/demand mismatch (15.8%). CONCLUSION: US drug shortages affected many medications on the WHO EMLc. Future studies should examine the global shortage climate and implications for patient care.

Plasma concentration guided dosing of drugs used for the treatment of childhood leukaemias: protocol for a systematic review.

INTRODUCTION: Childhood leukaemia is the most common type of cancer in children and represents among 25% of the diagnoses in children <15 years old. Childhood survival rates have significantly improved within the last 40 years due to a rapid advancement in therapeutic interventions. However, in high-risk groups, survival rates remain poor. Pharmacokinetic (PK) data of cancer medications in children are limited and thus current dosing regimens are based on studies with small sample sizes. In adults, large variability in PK is observed and dose individualisation (plasma concentration guided dosing) has been associated with improved clinical outcomes; whether this is true for children is still unknown. This provides an opportunity to explore this strategy in children to potentially reduce toxicities and ensure optimal dosing. This paper will provide a protocol to systematically review studies that have used dose individualisation of drugs used in the treatment of childhood leukaemias. METHODS AND ANALYSIS: Systematic review methodology will be applied to identify, select and extract data from published plasma guided dosing studies conducted in a paediatric leukaemia cohort. Databases (eg, Ovid Embase, Ovid MEDLINE, Ovid Cochrane) and clinical trial registries (CENTRAL, ClinicalTrials.gov and ISRCTN) will be used to perform the systematic literature search (up until February 2021). Only full empirical studies will be included, with primary clinical outcomes (progression-free survival, toxicities, minimal residual disease status, complete cytogenetic response, partial cytogenetic response and major molecular response) being used to decide whether the study will be included. The quality of included studies will be undertaken, with a subgroup analysis where appropriate. ETHICS AND DISSEMINATION: This systematic review will not require ethics approval as there will not be collection of primary data. Findings of this review will be made available through publications in peer-reviewed journals and conference presentations. Gaps will be identified in current literature to inform future-related research. PROSPERO REGISTRATION NUMBER: CRD42021225045.

Treatment of pulmonary arterial hypertension in children.

Pulmonary arterial hypertension (PAH) is a devastating illness causing already significant morbidity in childhood. Currently approved treatment options for children comprise the endothelin receptor antagonist bosentan, as well as the phosphodiesterase-5 inhibitor sildenafil. But PAH treatment has advanced significantly over the past decade, and new classes of targeted drug therapies, such as stimulators of the soluble guanylate cyclase (riociguat) or prostacyclin receptor agonists (selexipag), are currently evaluated regarding their efficacy and safety in children, in order to limit off-label use. Due to the different etiologies in children, such as PAH-CHD, there is no evidence that initial combination therapy in children is superior to a mono-therapy with respect to survival. Special attention should also be paid to the pharmacology of PAH drugs in children, which might be impacted by ontogeny or drug-drug-interactions. Therapeutic drug monitoring may be useful in pediatric patients. There is a clear need for more controlled studies of PAH medications, alone or in combination therapy in the pediatric age group. Data from clinical trials as well as from patient registries should be pooled to optimize drug development and evaluation, trial design, and evidence-based pharmacotherapy in pediatric patients with PAH. In this review, the current treatment options of pediatric PAH are summarized, and an overview of new treatment concepts, which are already evaluated in adults, is presented.

Monitoring the recovery time of children after tonsillectomy using commercial activity trackers.

An observational prospective feasibility study in which children received a tracker 2 weeks before a tonsillectomy and were required to wear it until four weeks postoperatively. The parents used a diary to log the estimated steps of their child. As primary endpoint, the compliance of complete datasets was compared between the tracker and the diary. As secondary endpoints, the agreement of steps between tracker and diary, and the recovery time after tonsillectomy were analyzed.Twenty-four patients (50% male) with a median age of 6 years were recruited. The tracker had a complete dataset compliance of 91.7% in the pre-operative and 58.3% in postoperative period, whereas the diary's compliance was 62.5% in the pre-operative and 12.5% in the postoperative period. The difference of 29.2% and 45.8% in the pre-operative and postoperative periods between the tracker and the diary was significant (p < 0.005). The tracker and diary had a mean agreement difference of 1063 steps per day. Mean recovery time was 21 days after tonsillectomy.Conclusion: The results of this pilot study support the use of a tracker in terms of compliance and practicability. Consumer-level activity trackers are a viable alternative to conventional manual logging for clinical use in pediatric research.Trial registration: ClinicalTrials.gov Identifier: NCT03174496 What is known: • Consumer-level activity trackers are already used in clinical research to monitor steps and physical activity. • The use of consumer-level activity trackers in clinical studies has mostly been validated in the adult population. What is new: • This study proves the feasibility of using physical activity trackers in a pediatric population before and after a surgical intervention. • Recovery of a patient could be assessed with an activity tracker.

Personalised therapeutic management of epileptic patients guided by pathway-driven breath metabolomics.

Background: Therapeutic management of epilepsy remains a challenge, since optimal systemic antiseizure medication (ASM) concentrations do not always correlate with improved clinical outcome and minimal side effects. We tested the feasibility of noninvasive real-time breath metabolomics as an extension of traditional therapeutic drug monitoring for patient stratification by simultaneously monitoring drug-related and drug-modulated metabolites. Methods: This proof-of-principle observational study involved 93 breath measurements of 54 paediatric patients monitored over a period of 2.5 years, along with an adult's cohort of 37 patients measured in two different hospitals. Exhaled breath metabolome of epileptic patients was measured in real time using secondary electrospray ionisation-high-resolution mass spectrometry (SESI-HRMS). Results: We show that systemic ASM concentrations could be predicted by the breath test. Total and free valproic acid (VPA, an ASM) is predicted with concordance correlation coefficient (CCC) of 0.63 and 0.66, respectively. We also find (i) high between- and within-subject heterogeneity in VPA metabolism; (ii) several amino acid metabolic pathways are significantly enriched (p < 0.01) in patients suffering from side effects; (iii) tyrosine metabolism is significantly enriched (p < 0.001), with downregulated pathway compounds in non-responders. Conclusions: These results show that real-time breath analysis of epileptic patients provides reliable estimations of systemic drug concentrations along with risk estimates for drug response and side effects.

Drug-drug and drug-food interactions in an infant with early-onset SCN2A epilepsy treated with carbamazepine, phenytoin and a ketogenic diet.

Sodium channel 2 subunit α (SCN2A) mutations cause difficult-to-treat early-onset epilepsy. Effective treatment includes high-dose phenytoin or carbamazepine ± ketogenic diet (KD). We describe an infant with early-onset SCN2A-epilepsy with subtherapeutic carbamazepine concentration during transition from phenytoin treatment to avoid long-term neurotoxicity. The transition from high-dose phenytoin (20 mg kg-1 d-1 , concentration: ≥20 mg/L) with KD, to carbamazepine (50-75 mg kg-1 d-1 , concentration: 9-12 mg/L) lasted 85 days, which we suspected was due to significant drug-drug and/or drug-food interactions. Model-based analysis of carbamazepine pharmacokinetics quantified significant time- and dose-dependent phenytoin-mediated CYP3A4 induction and carbamazepine concentration-dependent auto-induction (apparent clearance increased up to 2.5/3-fold). Lower carbamazepine concentrations under KD were modelled as decreased relative bioavailability (44%), potentially related to decreased fraction absorbed (unexpected for this lipophilic drug), increased intestinal/hepatic metabolism and/or decreased protein-binding with KD. This suggests importance of carbamazepine-concentration monitoring during KD-introduction/removal and necessity of high carbamazepine doses to achieve therapeutic concentrations, especially in infants treated with high-dose phenytoin.