Pediatric Dose Research Articles

Physiologically-based pharmacokinetic models versus allometric scaling for prediction of tyrosine-kinase inhibitor exposure from adults to children

PurposeModel-based methods can predict pediatric exposure and support initial dose selection. The aim of this study was to evaluate the performance of allometric scaling of population pharmacokinetic (popPK) versus physiologically based pharmacokinetic (PBPK) models in predicting the exposure of tyrosine kinase inhibitors (TKIs) for pediatric patients (≥ 2 years), based on adult data. The drugs imatinib, sunitinib and pazopanib were selected as case studies due to their complex PK profiles including high inter-patient variability, active metabolites, time-varying clearances and non-linear absorption.MethodsPediatric concentration measurements and adult popPK models were derived from the literature. Adult PBPK models were generated in PK-Sim® using available physicochemical properties, calibrated to adult data when needed. PBPK and popPK models for the pediatric populations were translated from the models for adults and were used to simulate concentration-time profiles that were compared to the observed values.ResultsTen pediatric datasets were collected from the literature. While both types of models captured the concentration-time profiles of imatinib, its active metabolite, sunitinib and pazopanib, the PBPK models underestimated sunitinib metabolite concentrations. In contrast, allometrically scaled popPK simulations accurately predicted all concentration-time profiles. Trough concentration (Ctrough) predictions from the popPK model fell within a 2-fold range for all compounds, while 3 out of 5 PBPK predictions exceeded this range for the imatinib and sunitinib metabolite concentrations.ConclusionBased on the identified case studies it appears that allometric scaling of popPK models is better suited to predict exposure of TKIs in pediatric patients ≥ 2 years. This advantage may be attributed to the stable enzyme expression patterns from 2 years old onwards, which can be easily related to adult levels through allometric scaling. In some instances, both methods performed comparably. Understanding where discrepancies between the model methods arise, can further inform model development and ultimately support pediatric dose selection.

Knowledge and Perception of Paediatric Drug Dosing: Impact of Paediatric Drug Dosing Workshop.

Paediatric patients frequently encounter medication errors caused by the requirement for individualised drug dose estimates based on weight, age variance, and drug pharmacokinetics. One thing contributing to drug dosing errors is the lack of healthcare personnel's knowledge of paediatric drug dosing. The present study aimed to evaluate the knowledge and perception regarding the workshop on paediatric drug dosing among undergraduate pharmacy students. A prospective pre-post study was conducted. A virtual workshop on paediatric drug dosing was designed and developed by the clinical pharmacy lecturer from Universiti Sultan Zainal Abidin (UniSZA) for pharmacy students. An online questionnaire with 15 questions regarding knowledge of paediatricdrug dosing and perception of the virtual workshop on paediatricdrug dosing was used to evaluate pharmacy students' knowledge pre- and post-workshop. Twenty-six students took part in the study (100%). In the pre-workshop on paediatric drug dosing calculation, most students had poor knowledge of the paediatric drug dosing calculation, scored 8 out of 15, 26.92% between 9 to 11 and only 11.54% scored ≥ 12. There was a statistically significant difference in median knowledge score between pre- and post-workshop (p< 0.05). Among the students, 73.08% stated that they strongly agreed that the online workshop attracted their attention and 76.92% of students strongly agreed that they were able to calculate paediatricdrug dosing after joining the online workshop. Results demonstrate that pharmacy students have insufficient knowledge of paediatric drug dosing calculations. Virtual workshop is one strategy that could improve the pharmacy students' knowledge.

Age-based diagnostic reference levels and achievable doses for paediatric CT: a survey in Shanghai, China

Computed tomography (CT) is extensively utilised in medical diagnostics due to its notable radiographic superiority. However, the cancer risk associated with CT examinations, particularly in children, is of significant concern. The assessment of cancer risk relies on the radiation dose to examinees. Diagnostic reference levels (DRLs) and achievable doses (ADs) were used to assess the level of radiation dose in CT examinations widely. Although the national DRLs of paediatric CT have been explored in China, few local DRLs at the city level have been assessed. To set up the local DRLs and ADs of paediatric CT, we investigated the radiation dose level for paediatric CT in Shanghai. In this survey, a total of 3061 paediatric CT examinations underwent in Shanghai in 2022 were selected by stratified sampling, and the dose levels in terms of volume CT dose index (CTDIvol) and the dose-length product (DLP) were analysed by 4 age groups. The DRLs and ADs were set at the 75th and 50th percentile of the distribution and compared with the previous studies at home and abroad. The survey results revealed that, for head scan, the DRLs of CTDIvol were from 25 to 46 mGy, and the levels of DLP were from 340 to 663 mGy·cm. For chest, the DRLs of CTDIvol were from 2.2 to 8.3 mGy, and the levels of DLP were from 42 to 223 mGy·cm. For abdomen, the DRLs of CTDIvol were from 6.3 to 16 mGy, and the levels of DLP were from 181 to 557 mGy·cm. The ADs were about 60% lower than their corresponding DRLs. The levels of radiation doses in children-based hospitals were higher than those in other medical institutions (P < 0.001). In conclusion, there was still potential for reducing radiation dose of paediatric CT, emphasising the urgent need for optimising paediatric CT dose in Shanghai.

Posaconazole in paediatric malignancy and haematopoietic stem cell transplant: dosing to achieve therapeutic concentration.

Posaconazole is increasingly used for the treatment and prophylaxis of invasive fungal infections in immunocompromised children. We aimed to review evidence for paediatric posaconazole dosing regimens focusing on attainment of target concentrations and frequency of adverse effects. In May 2023, the Cochrane, Embase, MEDLINE and PubMed databases were searched for articles reporting posaconazole dosing in children with malignancy or post-haematopoietic stem cell transplantation. Studies reporting the attainment of target serum concentrations were included. Overall, 24 studies were included. Eighteen studies of the oral suspension consistently reported poor attainment of target concentrations for prophylaxis (≥0.7 µg/mL, 12%-78%) despite high daily doses of 14-23 mg/kg/day (max. 1200 mg/day). Target attainment was significantly affected by gastric pH and food intake. Six studies of the delayed-release tablet (DRT) reported 58%-94% achieved concentrations ≥0.7 µg/mL, with the majority using lower doses of 4-12 mg/kg/day (max. 300 mg/day). Similarly, one study of powder for oral suspension found 67%-100% achieved target concentrations with a dose of 6 mg/kg/day (max. 300 mg/day). As expected, the IV formulation had high attainment of prophylaxis targets (81%-90%) with 6-10 mg/kg/day (max. 400 mg/day). All formulations were well tolerated, and no relationship between adverse effects and posaconazole concentrations was identified. The required posaconazole dose in immunocompromised children varies depending on the formulation. The IV infusion had the highest attainment of therapeutic concentration followed by the DRT and powder for suspension. By contrast, the oral suspension had low attainment of target concentrations despite higher daily doses.

Current practices of craniospinal irradiation techniques in Turkey: a comprehensive dosimetric analysis

ObjectiveThis study evaluates various craniospinal irradiation (CSI) techniques used in Turkish centers to understand their advantages, disadvantages and overall effectiveness, with a focus on enhancing dose distribution.MethodsAnonymized CT scans of adult and pediatric patients, alongside target volumes and organ-at-risk (OAR) structures, were shared with 25 local radiotherapy centers. They were tasked to develop optimal treatment plans delivering 36 Gy in 20 fractions with 95% PTV coverage, while minimizing OAR exposure. The same CT data was sent to a US proton therapy center for comparison. Various planning systems and treatment techniques (3D conformal RT, IMRT, VMAT, tomotherapy) were utilized. Elekta Proknow software was used to analyze parameters, assess dose distributions, mean doses, conformity index (CI), and homogeneity index (HI) for both target volumes and OARs. Comparisons were made against proton therapy.ResultsAll techniques consistently achieved excellent PTV coverage (V95 > 98%) for both adult and pediatric patients. Tomotherapy closely approached ideal Dmean doses for all PTVs, while 3D-CRT had higher Dmean for PTV_brain. Tomotherapy excelled in CI and HI for PTVs. IMRT resulted in lower pediatric heart, kidney, parotid, and eye doses, while 3D-CRT achieved the lowest adult lung doses. Tomotherapy approached proton therapy doses for adult kidneys and thyroid, while IMRT excelled for adult heart, kidney, parotid, esophagus, and eyes.ConclusionModern radiotherapy techniques offer improved target coverage and OAR protection. However, 3D techniques are continued to be used for CSI. Notably, proton therapy stands out as the most efficient approach, closely followed by Tomotherapy in terms of achieving superior target coverage and OAR protection.

NF1 mutation-driven neuronal hyperexcitability sets a threshold for tumorigenesis and therapeutic targeting of murine optic glioma.

With the recognition that noncancerous cells function as critical regulators of brain tumor growth, we recently demonstrated that neurons drive low-grade glioma initiation and progression. Using mouse models of neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG), we showed that Nf1 mutation induces neuronal hyperexcitability and midkine expression, which activates an immune axis to support tumor growth, such that high-dose lamotrigine treatment reduces Nf1-OPG proliferation. Herein, we execute a series of complementary experiments to address several key knowledge gaps relevant to future clinical translation. We leverage a collection of Nf1-mutant mice that spontaneously develop OPGs to alter both germline and retinal neuron-specific midkine expression. Nf1-mutant mice harboring several different NF1 patient-derived germline mutations were employed to evaluate neuronal excitability and midkine expression. Two distinct Nf1-OPG preclinical mouse models were used to assess lamotrigine effects on tumor progression and growth in vivo. We establish that neuronal midkine is both necessary and sufficient for Nf1-OPG growth, demonstrating an obligate relationship between germline Nf1 mutation, neuronal excitability, midkine production, and Nf1-OPG proliferation. We show anti-epileptic drug (lamotrigine) specificity in suppressing neuronal midkine production. Relevant to clinical translation, lamotrigine prevents Nf1-OPG progression and suppresses the growth of existing tumors for months following drug cessation. Importantly, lamotrigine abrogates tumor growth in two Nf1-OPG strains using pediatric epilepsy clinical dosing. Together, these findings establish midkine and neuronal hyperexcitability as targetable drivers of Nf1-OPG growth and support the use of lamotrigine as a potential chemoprevention or chemotherapy agent for children with NF1-OPG.

Efficacy and safety of empiric treatment with omeprazole continuous infusion in critically ill children with gastrointestinal bleeding.

Gastrointestinal bleeding (GI) is a prevalent condition among pediatric patients, with a reported incidence of 6.4%, often severe enough to require admission to the pediatric intensive care unit (PICU). There are multiple therapies utilized in the management of GI bleeding in pediatrics, among which continuous intravenous (IV) infusion of omeprazole is used off-label without standard pediatric dosing recommendations. Reviewing the current literature reveals a lack of studies assessing the efficacy, safety, and appropriate dosing regimen of continuous omeprazole infusion in children with GI bleeding. This study aimed to evaluate the efficacy and safety of continuous IV omeprazole infusion in comparison to other therapeutic modalities in children. This study is a single-center, retrospective chart review of children admitted to the PICU at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. The treatment group included pediatric patients with GI bleeding and receiving omeprazole IV continuous infusion over ≥24 h while the control group included pediatric patients with GI bleeding managed using other therapies. Primary outcomes were the efficacy of omeprazole continuous infusion in stopping GI bleeding, and PICU length of stay (LOS). Secondary outcomes included instances of rebleeding post- therapy discontinuation, transfusion requirements, and the safety of omeprazole continuous infusion. The study included 81 critically ill pediatric patients, 22 of whom received continuous infusion omeprazole while 59 received other therapies. The results indicated that patients in the control group had a significantly shorter PICU LOS (8 vs. 18.5 days, p < 0.001) and bleeding episode (4 vs. 10.5 days, p < 0.001) than those in the treatment group. However, no significant differences were observed between the two groups regarding secondary outcomes. The treatment group had a significantly lower all-cause mortality rate during hospitalization compared to the control group (16 patients [72.7%] vs. 56 patients [94.9%], respectively, p = 0.005). Empirical use of omeprazole continuous intravenous infusion in children with GI bleeding was not favorable in terms of shortening PICU LOS and duration of GI bleeding. Our study results provide evidence supporting the safety and tolerability of omeprazole continuous infusion. Additional larger studies are necessary to determine the implication of such results.

Pharmacometric in silico studies used to facilitate a national dose standardisation process in neonatology - application to amikacin.

Pharmacometricin silicoapproaches are frequently applied to guide decisions concerning dosage regimes during the development of new medicines. We aimed to demonstrate how such pharmacometric modelling and simulation can provide a scientific rationale for optimising drug doses in the context of the Swiss national dose standardisation project in paediatrics using amikacin as a case study. Amikacin neonatal dosage is stratified by post-menstrual age (PMA) and post-natal age (PNA) in Switzerland and many other countries. Clinical concerns have been raised for the subpopulation of neonates with a post-menstrual age of 30-35 weeks and a post-natal age of 0-14 days ("subpopulation of clinical concern"), as potentially oto-/nephrotoxic trough concentrations (Ctrough>5 mg/l) were observed with a once-daily dose of 15 mg/kg. We applied a two-compartmental population pharmacokinetic model (amikacin clearance depending on birth weight and post-natal age) to real-world demographic data from 1563 neonates receiving anti-infectives (median birth weight 2.3 kg, median post-natal age six days) and performed pharmacometric dose-exposure simulations to identify extended dosing intervals that would ensure non-toxic Ctrough(Ctrough<5 mg/l) dosages in most neonates. In the subpopulation of clinical concern, Ctrough<5 mg/l was predicted in 59% versus 79-99% of cases in all other subpopulations following the current recommendations. Elevated Ctroughvalues were associated with a post-natal age of less than seven days. Simulations showed that extending the dosing interval to ≥36 h in the subpopulation of clinical concern increased the frequency of a desirable Ctroughbelow 5 mg/l to >80%. Pharmacometricin silicostudies using high-quality real-world demographic data can provide a scientific rationale for national paediatric dose optimisation. This may increase clinical acceptance of fine-tuned standardised dosing recommendations and support their implementation, including in vulnerable subpopulations.

Advancing pediatric head CT dose prediction: correlating patient size metrics with AP and LAT dimensions in Moroccan population

This study aims to establish comprehensive relationships between patient size, focusing on effective diameter (Deff) and water-equivalent diameter (Dw), in conjunction with anterior-posterior (AP) and lateral (LAT) dimensions. The primary goal is to refine precise patient dose estimations in pediatric head computed tomography (CT) examinations. Our examination involved a dataset of 105 pediatric head CT images sourced from a Moroccan pediatric university hospital. These images, selected from the central scanning range, underwent quantification for LAT, AP, Deff, and Dw, with measurements carried out using RadiAnt Dicom Viewer for lateral and anteroposterior dimensions. Our analytical approach encompassed modeling Deff and Dw as functions of LAT, AP, and combined AP + LAT dimensions. Additionally, Dw was modeled as a function of Deff and calculated Size Specific Dose Estimates (SSDE) based on Dw was compared to SSDE computed from one single dimension. The outcomes revealed strong correlations among Deff, Dw, and fundamental geometric dimensions (LAT, AP, and AP + LAT), as indicated by consistently high coefficients of determination (R² > 0.8). SSDE calculated from Dw shows impressive correlation with SSDE computed from a single dimension (R² > 0.9). This study offers insights into the relationships between patient size and critical dimensions, identifying high correlations that can represent a significant advancement in predicting doses for pediatric head CT examinations. This introduces the potential for streamlining the determination of head diameter and dose by relying on a single dimension, thereby enhancing the efficiency of dose predictions by facilitating the monitoring of radiation exposure of this population in clinical routine.

Paediatric cancer risks associated with chest computed tomography (CT) scans: comparison of routine chest and COVID-19 diagnosis CT protocols

The aim of this study is to compare the radiation dose and cancer incidence risk associated with two chest Computed Tomography (CT) protocols: routine chest CT (RC-CT) and COVID-19 Diagnosis CT protocol (CD-CT). The study included 254 pediatric patients divided into three age groups: G1 (&lt;5), G2 (5–&lt;10), and G3 (10–15). The effective diameter, volumetric CT dose index (CTDIvol), dose length product (DLP), size specific dose estimate (SSDE), organ doses, and cancer incidence risk were calculated for the two protocols. Organ doses (mSv) and effective dose (mSv) were estimated using the National Cancer Institute dosimetry system for CT (NCICT) software. Estimation of cancer incidence risks were conducted according to the Biological Effects of Ionizing Radiation (BEIR) VII report. The oldest group (G3) in two protocols exhibited the greatest values for CTDIvol, DLP, effective dose and SSDE. The results showed that CD-CT protocol resulted in statistically significant (p &lt; 0.05) lower organ doses and cancer incidence risk. The cancer incidence risk for both protocols did not exceed the reference levels reported in literature surveys on pediatric CT chest radiation dose for all age groups. It can be concluded that the choice of CT protocol can significantly impact the radiation dose received by pediatric patients during CT imaging, highlighting the importance of carefully selecting the appropriate protocol to minimize radiation exposure.

Ethanol Content of Medications and Its Effect on Blood Alcohol Concentration in Pediatric Patients.

Ethanol is a common excipient used in liquid medications to enhance solubility and inhibit -bacterial growth. While the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have released guidance for how much ethanol is acceptable in medicines, many medications contain more than the recommended amount. The objective of this study was to determine what effect these medications would have on blood alcohol concentration (BAC) for pediatric patients, defined as those medications that would increase the BAC by ≥2.5 mg/dL. A list of medications dispensed to pediatric patients from a single hospital over a period of 4 months was obtained. The package inserts of these medications were reviewed to determine ethanol content. Typical doses were used to determine the amount of ethanol pediatric patients weighing 10, 20, and 40 kg would receive. The theoretical BAC was then calculated for each medication containing ethanol. Seven hundred ninety-six medications were dispensed for pediatric patients during the study period, of which 33 contained ethanol. Seven medications would be projected to increase the BAC above 2.5 mg/dL with a normal pediatric dose. While most medications do not contain ethanol, we found 7 that contained enough ethanol to potentially raise the BAC above 2.5 mg/dL. Health care practitioners should consider the ethanol content of medications prior to recommending them in children and when assessing overdoses.

Clinical pharmacokinetics of leriglitazone and a translational approach using PBPK modeling to guide the selection of the starting dose in children.

Leriglitazone is a unique peroxisome proliferator-activated receptor-gamma (PPARγ) agonist that crosses the blood-brain barrier in humans and clinical trials have shown evidence of efficacy in neurodegenerative diseases. At clinical doses which are well-tolerated, leriglitazone reaches the target central nervous system (CNS) concentrations that are needed for PPARγ engagement and efficacy; PPARγ engagement is also supported by clinical and anti-inflammatory biomarker changes in the Cerebrospinal fluid in the CNS. Plasma pharmacokinetics (PK) of leriglitazone were determined in a phase 1 study in male healthy volunteers comprising a single ascending dose (SAD) and a multiple ascending dose (MAD) at oral doses of 30, 90, and 270 mg and 135 and 270 mg, respectively. Leriglitazone was rapidly absorbed with no food effect on overall exposure and showed a linear PK profile with dose-exposure correlation. A physiologically based pharmacokinetic (PBPK) model was developed for leriglitazone based on phase 1 data (SAD part) and incorporated CYP3A4 (fmCYP3A4 = 24%) and CYP2C8-mediated (fmCYP2C8 = 45%) metabolism, as well as biliary clearance (feBIL = 19.5%) derived from invitro data, and was verified by comparing the observed versus predicted concentration-time profiles from the MAD part. The PBPK model was prospectively applied to predict the starting pediatric doses and was preliminarily verified with data from five pediatric patients.

Knowledge and Awareness Level Healthcare Professionals about Adult and Pediatric Basic Life Support

Objective: This study aimed to evaluate healthcare professionals' knowledge levels and attitudes toward adult and pediatric basic life support in a tertiary university hospital.&#x0D; Methods: The data of the research was collected by questionnaire method. A total of 351 healthcare professionals who agreed to participate in the study and filled out the questionnaire form were included in the analysis of the study. Twenty-nine questions about adult and pediatric basic life support were asked to the participants; each group was analyzed in terms of gender, age groups, working unit, working time, and duties.&#x0D; Results: The study was completed with 351 participants, mostly women, working in the emergency department and surgical sciences as research assistants, nurses, and health technicians, working for less than 5 years, and mostly over 26 years old. Most participants had received training in basic life support, used automatic external defibrillators, and performed cardiopulmonary resuscitation before. The rate of correct answers to questions about general information about adult and pediatric basic life support, circulation, airway, defibrillation rhythms, and doses of drugs were low. A statistical difference was found in the total questionnaire score regarding duty, working time, and their department.&#x0D; Conclusion: The level of knowledge of healthcare professionals on adult and pediatric basic life support is inadequate and out of date and should be improved with education and training programs

Optimization of Routine Pediatric Computed Tomography Examinations in Hawassa City, Sidama Regional State, Ethiopia

Computed tomography (CT) has considerable impact in patient care. However, it is the most irradiating medical imaging technique in diagnostic radiology department. Optimization of pediatric CT is not well-practiced in developing countries. Protocols for some age groups were missed, and scan parameters are not adapted to the patient body size and age group. Furthermore, there are no established diagnostic reference levels to enhance dose optimization for pediatric patients at the local, regional, and national levels. Therefore, this study aimed to assess the optimization of routine pediatric CT examinations in Hawassa city, Ethiopia. A total of 360 pediatric dose records were reviewed for routine pediatric CT performed between January 1st, 2021 - May 30th, 2022. The data were analyzed using the statistical package for social science version 25 software. The Local Diagnostic Reference Levels (LDRLs) were established at the 75th percentile of CT dose quantities. The average KVp, mAs, and scan length used for pediatric head, chest, and abdomen CT were (112.8, 260.6, and 19.8), (112.9, 64.7, and 31.5), and (113.3, 79.4, and 32.9) respectively. The range of the established LDRLs in terms of volumetric CT dose index for the head, chest, and abdomen CT were (31.5 to 47, 2.3 to 6.1, 1.7 to 4.7) mGy. Whereas the range in terms of dose length product per scan for the head, chest, and abdomen CT were (723.4 to 1126.7, 55.9 to 258.9, and 38.1 to 242.5) mGy cm respectively. The obtained results show that the LDRLs for volumetric CT does index for head and chest CT were equivalent to the international studies. Whereas the local DRLs in terms of dose length product per scan were higher than the reports other studies except in Japan where the values for chest CT were comparable to the results of this study. Finally, the findings suggested that non-optimized pediatric head and chest CT were performed across all age groups.

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.

Daptomycin Dose Optimization in Pediatric Staphylococcus aureus Bacteremia: A Pharmacokinetic/Pharmacodynamic Investigation.

Daptomycin is an antibiotic with Gram-positive activity, including methicillin-resistant Staphylococcus aureus, for which optimal pediatric dosing is unknown. This study aimed to evaluate daptomycin exposures achieved with package label dosing and to identify dosing regimens necessary to enhance efficacy and minimize toxicity in children with S. aureus bacteremia. Monte Carlo simulations were performed to determine probability of target attainment (PTA) for six pediatric age cohorts. Area under the curve to minimum inhibitory concentration ratio (AUC0-24:MIC) ≥666 was used to determine the PTA for efficacy (PTAE). Minimum concentration (Cmin) ≥24.3mg/L determined the PTA for toxicity (PTAT). Acceptable dosing regimens were those which achieved the combined target of ≥90% PTAE and ≤5% PTAT. Package label dosing of daptomycin yielded insufficient efficacy with only 26.3% PTAE in children 13-24 months, 39.5% PTAE in children 2-6 years, 30.1% PTAE in children 7-11 years, and 50.1% PTAE in adolescents ≥12 years. To achieve the combined efficacy and safety target, doses of 18-24mg/kg in children 3-12 months, 20-24mg/kg in children 13-24 months, 19-24mg/kg in children 2-6 years, 17-19mg/kg in children 7-11 years, and 10-14mg/kg in adolescents ≥12 years are necessary. Package label dosing resulted in suboptimal exposure for the majority of pediatric patients in all age groups evaluated. If targeting validated efficacy and safety endpoints, daily daptomycin doses of at least 20mg/kg in children ≤6 years, 17mg/kg in children 7-11 years, and 10mg/kg in adolescents ≥12 years are necessary. Clinical studies evaluating these higher doses are needed.

Assessment of Dosing Strategies for Pediatric Drug Products.

Pediatric drug dosing is challenged by the heterogeneity of developing physiology and ethical considerations surrounding a vulnerable population. Often, pediatric drug dosing leverages findings from the adult population; however, recent regulatory efforts have motivated drug sponsors to pursue pediatric-specific programs to meet an unmet medical need and improve pediatric drug labeling. This paradigm is further complicated by the pathophysiological implications of obesity on drug distribution and metabolism and the roles that body composition and body size play in drug dosing. Therefore, we sought to understand the landscape of pediatric drug dosing by characterizing the dosing strategies from drug products recently approved for pediatric indications identified using FDA Drug Databases and analyze the impact of body size descriptors (age, body surface area, weight) on drug pharmacokinetics for several selected antipsychotics approved in pediatric patients. Our review of these pediatric databases revealed a dependence on body size-guided dosing, with 68% of dosing in pediatric drug labelings being dependent on knowing either the age, body surface area, or weight of the patient to guide dosing for pediatric patients. This dependence on body size-guided dosing drives the need for special consideration when dosing a drug in overweight and obese patients. Exploratory pharmacokinetic analyses in antipsychotics illustrate possible effects of drug exposure when applying different dosing strategies for this class of drugs. Future efforts should aim to further understand the pediatric drug dosing and obesity paradigm across pediatric age ranges and drug classes to optimize drug development and clinical care for this patient population.

Assessment of effective dose and cancer risk for pediatric chest and pelvis CT procedures in the central region of Saudi Arabia

BackgroundCT accounts for the highest radiation dose among various imaging modalities. Children are more susceptible to the harmful effects of radiation because of their higher cell-division rate and the likelihood of longer lifespans. Therefore, it is important to monitor pediatric CT doses to minimize their potential risks. AimThe objective of this study was to evaluate the radiation doses received by pediatrics undergoing trunk CT procedures and to estimate the associated cancer risk. MethodsA total of 255 pediatric patients who underwent chest (92 cases), abdomen & pelvis (133 cases), and chest-abdomen-pelvis (CAP) scans (30 cases) from hospitals within the central region of Saudi Arabia were categorized into four age groups: <1 year, 1–5 years, 6–10 years, and 11–15 years. The averages and ranges of DLP and CTDIvol from each procedure were measured and compared with international reports. The effective dose and cancer risk from each procedure were also reported. ResultsThe mean and range DLP (mGy.cm) for chest, abdomen & pelvis, and CAP examinations were found to be 131.5 (13.8–375.5), 244 (10.5–1353), and 94.2 (23.5–239), respectively. The mean and range CTDIvol (mGy) for chest, abdomen & pelvis, and CAP examinations were found to be 5.5 (1–33.8), 5.5 (0.9–18.6), and 3.6 (1.3–24.8) in order. The effective dose (mSv) and associated cancer risk (case/10,000 cases) for chest, abdomen & pelvis, and CAP ranges between (2.31–3.37; 1.27–1.85), (4.19–6.89; 2.30–3.78), and (1.89–3.58; 1.04–1.97), respectively. ConclusionEstimations of effective doses and cancer risk were conducted for pediatric patients aged <1 through 15 years who underwent chest, abdomen & pelvis, and CAP procedures. The documented dose levels in this study were relatively elevated compared to similar reports, revealing substantial variations even within the same procedure and age group category. Therefore, prioritizing dose optimization practices becomes crucial to mitigate potential radiation-induced cancer risks.

Public support for and concerns regarding pediatric dose optimization for seizures in emergency medical services: An exception from informed consent (EFIC) trial.

Federal regulations allow exception from informed consent (EFIC) to study emergent conditions when obtaining prospective consent is not feasible. Little is known about public views on including children in EFIC studies. The Pediatric Dose Optimization for Seizures in EMS (PediDOSE) trial implements age-based, standardized midazolam dosing for pediatric seizures. The primary objective of this study was to determine public support for and concerns about the PediDOSE EFIC trial. The secondary objective was to assess how support for PediDOSE varied by demographics. We conducted a mixed-methods study in 20 U.S. communities. Participants reviewed information about PediDOSE before completing an online survey. Descriptive data were generated. Univariable and multivariable logistic regression analysis identified factors associated with support for PediDOSE. Reviewers identified themes from free-text response data regarding participant concerns. Of 2450 respondents, 79% were parents/guardians, and 20% had a child with previous seizures. A total of 96% of respondents supported PediDOSE being conducted, and 70% approved of children being enrolled without prior consent. Non-Hispanic Black respondents were less likely than non-Hispanic White respondents to support PediDOSE with an adjusted odds ratio (aOR) of 0.57 (95% CI 0.42-0.75). Health care providers were more likely to support PediDOSE, with strongest support among prehospital emergency medicine clinicians (aOR 5.82, 95% CI 3.19-10.62). Age, gender, parental status, and level of education were not associated with support of PediDOSE. Common concerns about PediDOSE included adverse effects, legal and ethical concerns about enrolling without consent, and potential racial bias. In communities where this study will occur, most respondents supported PediDOSE being conducted with EFIC and most approved of children being enrolled without prior consent. Support was lowest among non-Hispanic Black respondents and highest among health care providers. Further research is needed to determine optimal ways to address the concerns of specific racial and ethnic groups when conducting EFIC trials.

Paediatric indications and dosing guidance for advanced targeted treatments in Australia.

As with adults, paediatric patients may benefit from a number of advanced targeted therapies for inflammatory skin disease. This brief report aims to be an accessible reference tool with respect to regulatory approval and reimbursement of these treatments within Australia.