A majority of therapeutics are not available as suitable dosage forms for administration to pediatric patients. The first part of this review provides an overview of clinical and technological challenges and opportunities in the development of child-friendly dosage forms such as taste masking, tablet size, flexibility of dose administration, excipient safety and acceptability. In this context, developmental pharmacology, rapid onset of action in pediatric emergency situations, regulatory and socioeconomic aspects are also reviewed and illustrated with clinical case studies. The second part of this work discusses the example of Orally Dispersible Tablets (ODTs) as a child-friendly drug delivery strategy. Inorganic particulate drug carriers can thereby be used as multifunctional excipients offering a potential solution to address unique medical needs in infants and children while maintaining a favorable excipient safety and acceptability profile in these vulnerable patient populations.

Despite significant improvements in survival following preterm birth in recent years, the neurodevelopmental burden of prematurity, with its long-term cognitive and behavioral consequences, remains a significant challenge in neonatology. Neuroprotective treatment options to improve neurodevelopmental outcomes in preterm infants are therefore urgently needed. Alleviating inflammatory and oxidative stress (OS), melatonin might modify important triggers of preterm brain injury, a complex combination of destructive and developmental abnormalities termed encephalopathy of prematurity (EoP). Preliminary data also suggests that melatonin has a direct neurotrophic impact, emphasizing its therapeutic potential with a favorable safety profile in the preterm setting. The current review outlines the most important pathomechanisms underlying preterm brain injury and correlates them with melatonin’s neuroprotective potential, while underlining significant pharmacokinetic/pharmacodynamic uncertainties that need to be addressed in future studies.

Background: Juvenile idiopathic arthritis (JIA) is one of the most common pediatric inflammatory rheumatic diseases (PiRDs). Uncontrolled disease activity is associated with decreased quality of life and chronic morbidity. Biologic disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKi) have considerably improved clinical outcomes. For optimized patient care, understanding the efficacy-safety profile of biologics in subgroups of JIA is crucial. This systematic review based on published randomized controlled trials (RCTs) aims to assess efficacy and safety data for bDMARDs and JAKi with various JIA subgroups after 3 months of treatment.Methods: Data for American College of Rheumatology (ACR) pediatric (Pedi) 30, 50, and/or 70 responses after 3 months of treatment were selected from RCTs investigating bDMARDs or JAKi in JIA according to predefined inclusion/exclusion criteria. Treatment and control arms were compared by calculating risk ratios (RRs) with 95% confidence intervals (CIs), and proportions of overall, serious adverse events (AEs) and infections were analyzed. Forest plots were generated to summarize efficacy and safety endpoints across studies, JIA subgroups, and type of biologics.Results: Twenty-eight out of 41 PiRD RCTs investigated bDMARD or JAKi treatments in JIA. 9 parallel RCTs reported ACR Pedi 30, 50, and/or 70 responses 3 months after treatment initiation. All treatment arms showed improved ACR Pedi responses over controls. RRs ranged from 1.05 to 3.73 in ACR Pedi 30, from 1.20 to 7.90 in ACR Pedi 50, and from 1.19 to 8.73 in ACR Pedi 70. An enhanced effect for ACR Pedi 70 was observed with infliximab combined with methotrexate in PJIA vs. methotrexate monotherapy. A slightly higher risk of gastrointestinal AEs and infections was observed with treatment arms compared to placebo or methotrexate monotherapy.Conclusion: Investigated bDMARDs and JAKi showed superior treatment responses compared to controls after 3 months of treatment, which were more pronounced in ACR Pedi 50 and 70 than in ACR Pedi 30. Higher susceptibility to infections associated with bDMARDs or JAKi vs. control arms must be weighed against efficacious treatment of the underlying disease and prevention of disease-related damage. Additional RCTs are warranted to further inform development and utilization of biologics in JIA.

The antiparasitic drug ivermectin is approved for persons > 15 kg in the US and EU. A pharmacometric (PMX) population model with clinical PK data was developed (i) to characterize the effect of the patient-friendly ivermectin formulation CHILD-IVITAB on the absorption process and (ii) to evaluate dosing for studies in children < 15 kg. Simulations were performed to identify dosing with CHILD-IVITAB associated with similar exposure coverage in children ≥ 15 kg and < 15 kg as observed in adults receiving the reference formulation STROMECTOL^®. A total of 448 ivermectin concentrations were available from 16 healthy adults. The absorption rate constant was 2.41 h⁻¹ (CV 19%) for CHILD-IVITAB vs. 1.56 h⁻¹ (CV 43%) for STROMECTOL^®. Simulations indicated that 250 µg/kg of CHILD-IVITAB is associated with exposure coverage in children < 15 kg consistent with that observed in children ≥ 15 kg and adults receiving 200 µg/kg of STROMECTOL^®. Performed analysis confirmed that CHILD-IVITAB is associated with faster and more controlled absorption than STROMECTOL^®. Simulations indicate that 250 µg/kg of CHILD-IVITAB achieves equivalent ivermectin exposure coverage in children < 15 kg as seen in children ≥ 15 kg and adults.

Understanding adalimumab pharmacokinetics (PK) in pediatric inflammatory rheumatic diseases (PIRD) could facilitate individualized treatment strategies. This pharmacometric (PMX) analysis, utilizing prospectively collected data, aimed to develop a PMX model investigating associations between disease‐specific factors and adalimumab exposure in PIRD. PK data originating from a prospective two‐center study including 36 children with PIRD (weight IQR: 33‐55 kg) receiving subcutaneous adalimumab (IQR: 30‐40 mg biweekly; n = 28 at steady state, n = 8 after first dose, i.e., treatment naïve) were analyzed. A total of 72 adalimumab concentrations were available for PMX analysis, measured at 1‐9 days and 10‐14 days post‐dose. In addition to disease type (juvenile idiopathic arthritis [JIA] vs idiopathic uveitis) and disease activity (inactive/mild/minimal/moderate/severe), associations between methotrexate (MTX) co‐administration and duration of adalimumab treatment with apparent clearance (CL/F) were investigated. A one‐compartment model with standard allometric scaling adequately described adalimumab concentration–time data, with higher inter‐individual variability in apparent clearance (63%). CL/F showed trends of association with disease type (52% higher in JIA vs idiopathic uveitis, P < .1), disease activity (12% higher in active vs inactive disease, P < .1), and duration of adalimumab (higher with longer duration, P < 0.1) but not MTX co‐administration (n.s.). However, none of these factors could be incorporated into the model with sufficient precision, except for bodyweight. While this PMX analysis suggests disease‐specific factors may influence adalimumab exposure in children with PIRD, additional prospective studies are warranted to further characterize influence of disease‐specific factors on drug exposure and their effects on drug response with goal to facilitate implementation of personalized dosing strategies in pediatric rheumatology. What is already known on this topic Adalimumab is a monoclonal antibody directed against tumor necrosis factor alpha (TNFα), used for treatment of various inflammatory diseases, including pediatric inflammatory rheumatic diseases (PIRD). Data on adalimumab PK in children with PIRD is limited, indicating the need for further clinical research to support development and implementation of personalized treatment in pediatric clinical practice. What this study adds Applying standard weight‐based allometric scaling, a one‐compartment model with first‐order absorption and elimination adequately described available prospectively collected adalimumab concentration–time data in patients with PIRD. Higher CL/F was seen (i) in children with JIA versus those with idiopathic uveitis, (ii) in children with active disease, and (iii) with prolonged duration of adalimumab treatment. How this study might affect research, practice, or policy Disease‐specific factors can influence adalimumab exposure in children with PIRD, but (a priori) dose individualization based on these factors is not directly supported by our investigation (high remaining inter‐individual variability). A posteriori dose individualization based on adalimumab exposure (e.g., by PMX‐based therapeutic drug monitoring) may be promising to avoid adalimumab over‐ and underexposure, particularly after achievement of remission/inactive disease in children with PIRD. Together with increasing knowledge on exposure–response relationships in PIRD, the developed PMX model may be applied to optimize and personalize tapering or dose escalation in PIRD patients. This research identified disease‐specific factors that can influence adalimumab exposure, which in turn can inform design and set‐up of larger prospective clinical studies.