Dosing In Pediatric Patients Research Articles

7317 CAHtalyst Pediatric: Results From The Randomized, Double-Blind, Placebo-Controlled Period Of A Phase 3 Trial Of Crinecerfont, A Corticotropin-Releasing Factor Type 1 Receptor Antagonist, In Children And Adolescents With Classic Congenital Adrenal Hyperplasia

Abstract Disclosure: K. Sarafoglou: Consulting Fee; Self; Neurocrine Biosciences, Inc., Crinetics Pharmaceuticals, Eton Pharmaceuticals, Spruce Biosciences. Research Investigator; Self; Neurocrine Biosciences, Inc., Adrenas Therapeutics, Spruce Biosciences. M.S. Kim: Advisory Board Member; Self; Spruce Biosciences. Research Investigator; Self; Neurocrine Biosciences, Inc., Diurnal, Spruce Biosciences. M. Lodish: None. E.I. Felner: None. L. Martinerie: None. N.J. Nokoff: Advisory Board Member; Self; World Athletics. Consulting Fee; Self; Ionis Pharmaceuticals Inc., Neurocrine Biosciences, Inc. M. Clemente: Consulting Fee; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Novo Nordisk. Research Investigator; Self; Eli Lilly & Company, Novo Nordisk. P.Y. Fechner: Consulting Fee; Self; Neurocrine Biosciences, Inc., Eton Pharmaceuticals. Research Investigator; Self; Neurocrine Biosciences, Inc., Diurnal, Spruce Biosciences. M.G. Vogiatzi: Consulting Fee; Self; Adrenas Therapeutics, Eton Pharmaceuticals. Research Investigator; Self; Neurocrine Biosciences, Inc., Spruce Biosciences. P.W. Speiser: Advisory Board Member; Self; Adrenas Therapeutics, Chan Zuckerberg's Rare as One Initiative. Consulting Fee; Self; Roche Diagnostics. Research Investigator; Self; Neurocrine Biosciences, Inc.. Speaker; Self; Medscape, Wolters Kluter Publishing. J. Sturgeon: Employee; Self; Neurocrine Biosciences, Inc. E. Roberts: Employee; Self; Neurocrine Biosciences, Inc. G.S. Jeha: Employee; Self; Neurocrine Biosciences, Inc. J.L. Chan: Employee; Self; Neurocrine Biosciences, Inc. R. Farber: Employee; Self; Neurocrine Biosciences, Inc.. Introduction: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a genetic disorder characterized by cortisol deficiency and excess adrenal androgens, typically requires management with supraphysiological glucocorticoid (GC) doses. Crinecerfont is a novel oral CRF1 antagonist that reduced elevated ACTH and adrenal androgens in patients with 21OHD in 14-day, open-label Phase 2 studies. This Phase 3 study (CAHtalyst Pediatric: NCT04806451) evaluated whether crinecerfont can reduce androstenedione (A4) levels and supraphysiological GC doses in pediatric patients with 21OHD. Methods: Children and adolescents (2-17 yrs) with classic 21OHD, stable GC regimens at doses >12 mg/m2/d in hydrocortisone equivalents (HCe), A4 >midpoint of reference range, and 17-hydroxyprogesterone (17-OHP) >2x upper limit of normal (ULN) were randomized (2:1) to either crinecerfont (25, 50, or 100 mg BID based on weight) or placebo for 28 weeks. GC dosing was maintained stable for 4 weeks and then reduced, if possible, based on A4 levels to achieve a dose of 8-10 mg/m2/d while maintaining A4 control (≤120% of baseline or ≤ULN) by week 28. Results: In the 103 randomized participants (53 male; mean [range] age: 12 [4-17] yrs), demographics and baseline characteristics were similar between treatment arms (69 crinecerfont, 34 placebo). Mean baseline GC dose was 16.4 mg/m2/d HCe (92% on HC alone, 8% on a predniso[lo]ne-containing regimen). Baseline A4 (mean±SD) was 431±461 ng/dL and 17-OHP was 8682±6847 ng/dL. Over 95% completed the double-blind treatment period. At week 4 (end of GC-stable period), crinecerfont led to greater reductions in A4 vs placebo (least squares mean difference [LSMD]: -268 ng/dL; p=0.0002) (primary endpoint) and 17-OHP (LSMD: -6421 ng/dL; p<0.0001) (key secondary endpoint). At week 28, the crinecerfont arm had a greater percent reduction in GC dose while maintaining A4 control, vs placebo (LSMD: -24%; p<0.0001) (key secondary endpoint). Moreover, 30% of participants on crinecerfont achieved a protocol-defined physiological GC dose (≤11 mg/m2/d) while maintaining A4 control, vs 0% on placebo (nominal p=0.0009). The most common treatment-emergent adverse events (AEs) in the crinecerfont arm were headache (25% vs 6% for placebo), pyrexia (23% vs 24%), and vomiting (15% vs 30%). There were few serious AEs (5% overall) with none assessed as related to study drug. Conclusions: Crinecerfont, an oral CRF1 antagonist, represents a novel treatment option to improve androgen control in pediatric patients with classic 21OHD. In the largest interventional Phase 3 study conducted to date in these patients, crinecerfont led to a significant decrease in A4 while the GC dose was stable, enabling a significant percent reduction of supraphysiological GC doses while maintaining A4 control by 28 weeks. Crinecerfont was well tolerated overall. Presentation: 6/2/2024

Comparison between the intraoperative CT O-arm and C-arm related to radiation dose and accuracy in scoliosis surgery: A review study

Pedicle screw placement is a vital scoliosis therapy operation that aims to address spinal abnormalities while avoiding consequences including neurological damage caused by misplaced screws. Accurate imaging is required for precise screw insertion, with intraoperative CT (O-arm) and fluoroscopy (C-arm) being the principal modalities used. This review assesses various modalities based on their radiation dosages and accuracy. It comprises research published between 2012 and 2020 that evaluates both effective dose and accuracy for pediatric and adult patients. According to the review, the O-arm outperforms the C-arm in terms of accuracy, resulting in shorter procedure times for both pediatric and adult patients. The O-arm's sophisticated 3-D imaging capacity enhances screw insertion accuracy, reducing the likelihood of problems and the need for additional procedures. Furthermore, using pediatric low-dose protocols and techniques like the Detachable Pedicle Marker and Probe (DPMPs) with pulsed fluoroscopy can reduce radiation exposure while still ensuring precise screw placement. The review suggests that the O-arm has considerable advantages over the C-arm, such as improved image quality and lower radiation risk. This leads to enhanced patient safety and procedural outcomes. Overall, the O-arm's capacity to produce high-quality 3-D pictures makes it an invaluable tool in pedicle screw insertion, resulting in more accurate surgical outcomes and reducing the risk of problems associated with spinal deformity repairs.

Efficacy and Safety of Naldemedine for Opioid-Induced Constipation in Children.

Background: Naldemedine, a peripherally acting opioid μ receptor antagonist, is effective for prevention of opioid-induced constipation (OIC); however, evidence on its use in children is limited. Objective: To evaluate the efficacy and safety of naldemedine in pediatric patients with OIC. Design, Setting/Subjects: Retrospective analysis of 32 pediatric patients with OIC treated with naldemedine in a single institution in Japan from June 2017 to March 2021. Measurements: Efficacy was evaluated in 13 evaluable patients with bowel movement (BM) response, defined as those with at least three BMs in the first 7 days after naldemedine initiation and an increase of at least one BM from baseline. Safety was evaluated by examining adverse events (AEs) based on the Common Terminology Criteria for AEs (v5.0). Results: BM response was recorded in 11 of the 13 patients (85%), and the number BMs per day significantly increased from 0.43 before naldemedine to 1.00 after naldemedine (p = 0.025). The most common AE was diarrhea, observed in 16 of the 32 patients (50%), and all instances were grade 1 or 2. In three of the 16 patients, naldemedine was discontinued owing to worsening diarrhea. Conclusions: In pediatric patients, naldemedine resulted in a high rate of BM response and increased the BM frequency, indicating its efficacy. In some patients, grade 2 diarrhea required naldemedine discontinuation, suggesting that it should be used with caution in pediatric patients. Further studies are warranted to determine the optimal naldemedine dose in pediatric patients.

Impact of Age and Concurrent Antiseizure Medication Use on Lacosamide Dose to Concentration Ratio and Dosing in Pediatric Patients.

To evaluate age, adjunctive antiseizure medication (ASM), and specific ASMs on lacosamide (LCM) weight normalized dose-to-concentration ratio (DCR) and US Food and Drug Administration (FDA) dosing guidelines in pediatric patients. Patients 1 mo to ≤18 years with a LCM serum concentration between October 2009 and June 2017 were considered. Demographics, LCM DCR, and adjunctive ASM were recorded. LCM DCR/hr was used as a surrogate for clearance. Data were stratified by age (1 mo-< 2 yr; ≥ 2-6 yr; ≥ 6-12 yr; and ≥12-≤18 yr), FDA dosing weights, and ASM potential to interaction with LCM. There were 646 sera (380 patients) with median dose 8.36 mg/kg/day (IQR, 5.92-11.16). 50.2% of doses were within FDA-weight guidelines; however, 40.4% exceeded recommendations. Most (81.3%) LCM concentrations were between 2 and 12 mg/L. A difference existed in DCR between ages, with those <2 years having the highest DCR (p < 0.001). Moving across age groups, the DCR decreases by 30.7%, 50.5%, and 63.4%. There was a weak (r2 = 0.073) but significant (p < 0.001) negative correlation between DCR and age. 84.8% received adjunctive ASM consisting of at least one of 31 different ASMs. DCR was higher with adjunctive ASMs compared with monotherapy [0.061 (0.039-0.095) vs 0.043 (0.030-0.062)], respectively (p < 0.001) and was greatest with inducers. Phenobarbital increased DCR by 2.6-fold, topiramate by 72.1%, and clobazam by 32.6%. Inhibitors had no effect. The correlation between age and DCR was weak, accounting for 6% of variability. Strong inducers significantly increased DCR. Synergy may exist when multiple inducers are given. Weak inhibitors did not affect DCR. Those ≥6 to 11 kg, ≥30 to 50 kg, and those given strong inducers may require larger -initial LCM doses. Serum concentrations should be used to individualize dosing, especially in those receiving strong inducers.

Ketorolac Dose Ceiling Effect for Pediatric Headache in the Emergency Department

OBJECTIVE This study sought to demonstrate a non-inferiority analgesic ceiling effect previously ­demonstrated within adults for pediatric patients receiving a maximum ketorolac dose of 15 mg. METHODS We conducted a retrospective cohort study of pediatric ED patients weighing at least 60 kg treated with 30 mg (pre-intervention) or 15 mg (post-intervention) intravenous (IV) ketorolac for headache. The primary outcome included patient-reported pain scores. Additional outcomes included demographic variables, adjunct medication use and adverse effects. Categorical data were evaluated using a χ2 test, and numerical data were evaluated using an ANOVA F test and Welch 2-sample t test. RESULTS The pre- and post-intervention groups included 216 and 62 patients, respectively. Overall demographics were similar between the groups (72.3% female, 49.3% White/Caucasian, mean age 15.5 years, mean weight 79.2 kg, and mean baseline 10-point pain score 7.5). Twelve (5.6%) in the pre-intervention group required rescue analgesic compared with 2 patients (3.2%) in the post-intervention group (p = 0.416). In the pre-intervention group, 198 patients (91.7%) received nausea medication compared with 52 patients (83.9%) in the post-intervention group (p = 0.087). Mean 10-point pain scores following ketorolac administration decreased by 3.9 in the pre-intervention group compared with 5.1 in the post-intervention group (p = &amp;lt; 0.001). Common (0.9%) or rare (0.9%) side effects were infrequent and only seen in the pre-intervention group patients. CONCLUSIONS Truncating the maximum intravenous ketorolac dose in pediatric patients at least 60 kg in weight to 15 mg compared with 30 mg results in effective analgesia in pediatric patients with headache. Future research could explore differences in admission rates, treatment of other indications, or treatment with multiple-dose regimens.

Dosing of Venetoclax in Pediatric Patients with Relapsed Acute Myeloid Leukemia: Analysis of Developmental Pharmacokinetics and Exposure-Response Relationships

This work aimed to characterize the pharmacokinetics and exposure-response relationships of venetoclax in pediatric patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) to identify venetoclax doses to be administered to pediatric patients in the phase 3 study. Data from 121 patients across three phase 1 studies enrolling pediatric patients with R/R malignancies were utilized to develop a population pharmacokinetic model to describe venetoclax pharmacokinetics in pediatric patients. Individual patient average venetoclax plasma concentration up to the event of interest, derived based on the population pharmacokinetics analysis, was used to evaluate the exposure-response relationships to efficacy (complete response) and safety (neutropenia and thrombocytopenia) endpoints for patients with AML who received venetoclax in combination with azacitidine, decitabine, or cytarabine (n = 36). The population pharmacokinetic model was then used to simulate exposures in pediatric age- and weight-based subgroups to identify the venetoclax doses for pediatric patients. The pharmacokinetic data were adequately described by the two-compartment population pharmacokinetic model with first-order absorption and elimination. The model accounted for cytochrome P450 3A developmental changes using a maturation function and incorporated allometric scaling to account for growth and body size effect. Weight was identified as a statistically significant covariate on clearance and volume of distribution and retained in the final model. Population pharmacokinetic estimates were comparable to previously reported estimates in adults. Exposure-response analyses suggested that the clinical efficacy of venetoclax in combination with high-dose cytarabine (HDAC) is maximized at 600 mg adult-equivalent, and higher doses are unlikely to enhance clinical efficacy. Venetoclax 600 mg adult-equivalent was selected for further development in combination with HDAC. Additionally, venetoclax 400 mg adult-equivalent was selected for bridging/maintenance therapy in combination with azacitidine. Flat exposure-response relationships were observed with Grade ≥3 neutropenia and thrombocytopenia. Doses were selected based on weight (allometric scaling) for children aged ≥2 years old and based on weight and CYP3A ontogeny for children aged <2 years. The selected age- and weight-based dosing scheme of venetoclax is projected to achieve venetoclax exposures in pediatric subgroups comparable to those observed in adults receiving venetoclax 400 mg or 600 mg. This work characterized the pharmacokinetics and exposure-response relationships of venetoclax in pediatric patients and guided the selection of pediatric dosing regimens in support of the venetoclax phase 3 trial in pediatric AML (NCT05183035). NCT03236857, NCT03181126, and NCT03194932.

Assessing pediatric antibiotic knowledge and practices among community pharmacists in Palestine: implications for antibiotic use and resistance

BackgroundAntibiotics are widely used in the pediatric population, and their inappropriate use contributes to antibiotic resistance, which is a growing concern in developing countries. Therefore, this national cross-sectional study aimed to assess community pharmacists’ knowledge, attitudes and practices regarding appropriate antibiotic use and dosing in pediatric patients and to explore the barriers to such use in Palestine.MethodsA questionnaire-based survey was conducted among community pharmacists on the West Bank, Palestine, from September 2022 to March 2023. The survey assessed the pharmacists’ sociodemographic characteristics; knowledge, practices, and attitudes toward antibiotic use; and understanding of antibiotic dosing. The data were analyzed using descriptive statistics, and the factors affecting pharmacists’ knowledge were evaluated.ResultsThe study included 301 community pharmacists, with an average age of 30.06 years, who were primarily female (75.1%). The majority of the pharmacists (80.1%) correctly believed that antibiotics are effective against bacterial infections. However, 18.3% believed that antibiotics are effective against viruses. While 61.8% knew that antibiotics kill germs, 32.0% were unaware that not all antibiotics require refrigeration. Furthermore, 67.8% were aware that antibiotics do not speed up recovery from diarrhea. Over 99% of the participants recognized that antibiotic resistance developed due to various resistant mechanisms. The majority (78.7%) believed that each infection needed a different antibiotic. Pharmacists demonstrated reasonable knowledge of antibiotic dosing in case scenarios. Knowledge was positively correlated with years of experience (P = 0.001).ConclusionsThis study revealed that community pharmacy professionals have a good understanding of antibiotic usage in pediatric patients. The findings suggest that professional expertise and quality training improve healthcare services. However, the results may not be universally applicable, as identifying knowledge gaps is necessary to help with the development of focused interventions. Therefore, ongoing educational initiatives, awareness campaigns and antibiotic stewardship programs are recommended.

The determination of coefficients for size specific effective dose for adult and pediatric patients undergoing routine computed tomography examinations.

The effective dose resulting from computed tomography (CT) scans provides an assessment of the risk associated with stochastic effects but does not account for the patient's size. Advances in Monte Carlo simulations offer the potential to obtain organ dose data from phantoms of varying stature, enabling derivation of a size-specific effective doses (SEDs) representing doses to individual patients. This study aimed to compute size-specific k-conversion factors for SED in routine CT examinations for adult and pediatric patients of different sizes. Radiation interactions were simulated for adult and pediatric phantom models of various sizes using National Cancer Institute CT version 3.0.20211123. Subsequent calculations of SED were performed, and coefficients for SED were derived, considering the variations in body sizes. The results revealed a strong correlation between effective diameter and weight, observed with size-specific k-conversion factors for adult and pediatric phantoms, respectively. While size-specific k-conversion factors for CT brain remained constant in adults, values for pediatric cases varied. When using the tube current modulation (TCM) system, size-specific k-conversion factors increased in larger phantoms and decreased in smaller ones. The extent of this increase or decrease correlated with the set TCM strength. This study provides coefficients for estimating SEDs in routine CT exams. Software utilizing look-up tables of coefficients can be used to provide dose information for CT scanners at local hospitals, offering guidance to practitioners on doses to individual patients and improving radiation risk awareness in clinical practice.

Systematic Review and Meta-Analysis of Adjuvant Radiation Dose for Pediatric Patients (≤22 years) with Nonmetastatic Intracranial Ependymomas

Ependymomas are the third most common brain tumors in children. Standard of care is surgery followed by adjuvant radiotherapy. Controversy in the literature still exists over optimal radiotherapy dose. We completed a systematic review and meta-analysis to determine the optimal dose for local control (LC), event-free survival (EFS), and overall survival (OS) in pediatric patients. We searched MEDLINE (PubMed), Cochrane Database of Systematic Reviews, and Web of Science through January 2024. We included cohort studies that compared adjuvant radiotherapy of ≤54Gy to >54Gy in pediatric patients (≤22 years) with non-metastatic intracranial ependymomas. We assessed study quality using the Newcastle-Ottawa Quality Assessment Scale of Cohort Studies. We pooled studies using a random effects meta-analysis for hazard ratios (HR), 95% confidence intervals (CI), and assessed statistical heterogeneity via I2. When HRs were unavailable, we transformed risks using established methods. We narratively summarized qualitative outcomes. Seven studies met our inclusion criteria, covering a combined 1321 patients. Studies included a range of doses from 45-66.6Gy. Compared with >54Gy, we found no difference in LC for those receiving ≤54Gy (HR=0.83, 95% CI 0.56-1.24, I2=49.1%), in EFS (HR=1.02, 95% CI 0.95-1.09, I2=0.00%), and OS (HR=0.99, 95% CI 0.82-1.20, I2=37.5%). Two studies reported on subtotal resection by radiotherapy dose, neither study reporting statistical differences in LC, EFS, or OS, though the number of patients was small (n≤30). Five studies reported on late effects, with brainstem radionecrosis, radiation-induced vasculopathy, and secondary tumors being the most frequent. Overall study quality was high, though lower scores were consistently seen in comparability of cohorts. No studies reported on molecular subgroups. We found no difference in LC, EFS, or OS for those treated with ≤54Gy compared to >54Gy. There was insufficient data to complete a subgroup meta-analysis on radiotherapy dosing based on extent of resection or molecular subgroups.

A Retrospective Analysis of Micafungin Prophylaxis in Children Under 12 Years Undergoing Chemotherapy or Hematopoietic Stem Cell Transplantation.

Literature is limited regarding ideal micafungin dosing in pediatric patients with hematologic malignancies receiving chemotherapy or hematopoietic stem cell transplantation. Micafungin is an intravenous echinocandin with activity against Candida and Aspergillus species and has a favorable safety profile compared with other antifungal classes. Our objective was to evaluate the breakthrough invasive fungal infection (IFI) rate in pediatric patients who received a prophylactic micafungin course at our institution. A single-center, retrospective study was conducted between January 1, 2011, and July 31, 2017, to determine the IFI rate in patients receiving micafungin prophylaxis. Patients with suspected IFI were evaluated for probable or proven infection based on European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group Consensus Group invasive fungal disease definitions. Statistical analyses were descriptive. A total of 170 prophylactic micafungin courses from 129 unique patients ages <12 years at a median dose of 3 mg/kg daily were identified. The rate of probable or proven breakthrough IFIs was 2.4% as determined by clinical, radiologic, microbiologic, and histopathologic criteria. A low rate of breakthrough IFI was seen with micafungin prophylaxis that is consistent with prior published adult hematopoietic stem cell transplantation studies. Micafungin was well tolerated, with liver function test elevations being transient in most cases and thought to be related to alternative factors.

Effect of Omega-3 Fatty Acids Supplementation in Pediatric Patients with Type 1 Diabetes Mellitus

Abstract Background Omega-3 fatty acids (O3FAs) are polyunsaturated fatty acids derived from fish oil. Beneficial effects of O3FA supplementation in a wide range of disease condition have been well studied. However; the role of O3FA in management of type 1 diabetes mellitus (T1DM) remains unclear and controversial. Objectives Therefore, we performed a randomized-controlled trial to assess the effect of oral O3FAssupplementation on glycemic control and lipid profile in pediatric patients with T1DM. Methods This study included 70 children and adolescents with T1DM. Patients were randomly assigned into two groups; intervention group and received oral O3FAs capsules (1 gram daily). The other group did not receive any supplementation and served as a control group. Both groups were followed-up for 6 months with assessment of fasting blood glucose (FBG), HbA1c and fasting lipids. Results Supplementation with O3FAs was safe and well-tolerated. After 6 months, O3FAs adjuvant therapy for the intervention group resulted in a significant decrease of systolic blood pressure, insulin dose, FBG, HbA1c, triglycerides, total cholesterol and LDL-cholesterol compared with baseline levels and compared with the control group (p &amp;lt; 0.05). On the other hand, T1DM patients without O3FAs adjuvant therapy (control group) had higher blood glucose levels and HbA1c at study end compared with baseline levels (p &amp;lt; 0.001). Conclusions O3FAs as an adjuvant therapy to insulin improved blood glucose levels, glycemic control and dyslipidemia leading to reduction in insulin dose in pediatric patients with T1DM.

Model-Informed individualized dosage regimen of sirolimus in pediatric patients with intractable lymphatic malformations

Intractable lymphatic malformations (iLM) pose a significant threat to affected children, demonstrating limited responses to conventional treatments. Sirolimus, effectively inhibiting endothelial cell proliferation in lymphatic vessels, plays a crucial role in iLM treatment. However, the drug's narrow therapeutic window and substantial interindividual variability necessitate customized dosing strategies. This study aims to establish a Population Pharmacokinetic Model (PopPK model) for sirolimus in pediatric iLM patients, identifying quantitative relationships between covariates and sirolimus clearance and volume of distribution. Initial dosages are recommended based on a target concentration range of 5–15 ng/mL. Retrospective data from our institution, encompassing 53 pediatric patients with 275 blood concentration results over the past five years (average age: 4.64 ± 4.19 years), constituted the foundation of this analysis. The final model, adopting a first-order absorption and elimination single-compartment model, retained age as the sole covariate. Results indicated a robust correlation between apparent clearance (CL/F) at 5.56 L/h, apparent volume of distribution (V/F) at 292.57 L, and age. Monte Carlo simulation guided initial dosages for patients aged 0–18 years within the target concentration range. This study presents the first PopPK model using a large Therapeutic Drug Monitoring (TDM) database to describe personalized sirolimus dosing for pediatric iLM patients, contributing to pharmacokinetic guidance and potentially improving long-term clinical outcomes.

Estimation of Organ Doses in Pediatric Patients for Different Imaging Protocols and Examinations

In this study, the Volume Computed Tomography Dose Index (CTDIvol) Dose Length Product (DLP), effective patient doses (ED), and organ doses were calculated for pediatric patients aged 0, 1, 5, and 10 years undergoing computed tomography (CT) examinations using the VirtualDose program, a software designed for reporting such doses. The study utilized a Toshiba Aquilion 16 CT scanner. Head, chest, and pelvis CT scans were simulated with commonly used kVp, mAs, and pitch values. The results indicated a significant difference in organ doses between standard and low-dose protocols. When kVp and mAs values were increased, ED and organ doses increased by an average of 2.5 times. Conversely, when kVp and mAs values were held constant and pitch value was increased, ED and organ doses decreased by an average of 2 times. Physicians requesting pediatric CT scans should continuously evaluate the requested examinations based on their benefits and risks. To reduce organ doses, scanning protocols should be reviewed, and low-dose protocols should be preferred. Additionally, newer generation devices that provide lower dose scanning should be utilized.

Development and validation of individualized tacrolimus dosing software for Chinese pediatric liver transplantation patients: a population pharmacokinetic approach.

We aim to describe the population pharmacokinetics (PPK) of tacrolimus in Chinese pediatric patients under 4years old after liver transplantation and to develop individualized tacrolimus dosing software. A total of 663 blood concentrations from 85 patients aged 4.57months to 3.97years were collected in this study. PPK analysis was performed using a nonlinear mixed effects modeling approach with the software, Phoenix. Using C#, an individualized tacrolimus dosing software was created. The software was then used to predict the concentrations of another ten pediatric liver transplantation patients to verify the accuracy of said software. The predictive error (PE) and the absolute predictive error (APE) for each predicted time point were computed. A one-compartment model with first-order elimination best fitted the data. The apparent volume of distribution (V/F) and apparent clearance (CL/F) were 198.65 L and 2.41 L/h. Postoperative days (POD), total bilirubin (TBIL), and the use of voriconazole significantly influenced tacrolimus apparent clearance. The incorporation of an increasing number of actual blood drug concentrations into the prediction resulted in a decrease in both PE (72%, 17%, 7%) and APE (87%, 53%, 26%). A qualified PPK model of tacrolimus was developed in Chinese pediatric patients. The individualized tacrolimus dosing software could be used as a suitable tool for the personalization of tacrolimus dosing for pediatric patients after liver transplantation.

Patient-specific radiation dose for Chinese pediatric patients undergoing whole-body PET/CT examinations

Objective. To assess potential variations in the absorbed dose between Chinese and Caucasian children exposed to 18F-FDG PET scan and to investigate the factors contributing to dose differences, this work employed patient-specific phantoms and our compartment model for calculating the patient-specific absorbed dose in Chinese children. Approach. Data of 29 Chinese pediatric patients undergoing whole-body 18F-FDG PET/CT studies were retrospectively collected, including PET images for activity distributions and corresponding CT images for organ segmentation and phantom construction. A biokinetic compartment model was implemented to obtain cumulated activities. Absorbed radiation dose for both CT and PET component were calculated using Monte Carlo simulations. Regression models were fitted to time integrated activity coefficient (TIAC) and organ absorbed dose for each patient. Main results. TIACs of all the organs in our compartment model and the organ dose for 12 organs were correlated with patients’ weight. Young children have significantly large uptake in brain compared to adults. The distinctions of anatomical and biological characteristics between Chinese and Caucasian children contribute to variations in the absorbed dose of 18F-FDG PET scans. PET contributed more in organ dose than CT did in most organs, especially in brain and bladder. The average effective dose (± SD) was 4.5 mSv (± 1.12 mSv), 7.8 mSv (± 3.2 mSv) and 12.3 mSv (± 3.5 mSv) from CT, PET and their sum respectively. PET contributed 1.7 times higher than CT. Significance. To the best of our knowledge, this work represents the first attempt to estimate patient-specific radiation doses from PET/CT for Chinese pediatric patients. TIACs derived from our methodology in both age groups exhibited significant differences from the that reported in ICRP 128. Substantial differences in absorbed and effective doses were observed between Chinese and Caucasian children across all age groups. These disparities are attributed to markedly distinct anatomical and pharmacokinetic characteristics among adults and pediatric patients, and different racial groups. The application of data derived from adults to pediatric patients introduces considerable uncertainty. Our methodology offers a valuable approach not only for estimating pharmacokinetic characteristics and patient-specific radiation doses in pediatric patients undergoing 18F-FDG studies but also for other cohorts with similar characteristics.

A Quality Initiative to Improve Appropriate Medication Dosing in Pediatric Patients with Obesity.

Emerging evidence supports the use of alternative dosing weights for medications in patients with obesity. Pediatric obesity presents a particular challenge because most medications are dosed based on patient weight. Additionally, building system-wide pediatric obesity safeguards is difficult due to pediatric obesity definitions of body mass index-percentile-for-age via the Center for Disease Control growth charts. We describe a quality initiative to increase appropriate medication dosing in inpatients with obesity. The specific aim was to increase appropriate dosing for 7 high-risk medications in inpatients with obesity ≥2 years old from 37% to >74% and to sustain for 1 year. The Institute for Healthcare Improvement model for improvement was used to plan interventions and track outcomes progress. Interventions included a literature review to establish internal dosing guidance, electronic health record (EHR) functionality to identify pediatric patients with obesity, a default selection for medication weight with an opt-out, and obtaining patient heights in the emergency department. Appropriate dosing weight use in medication ordered for patients with obesity increased from 37% to 83.4% and was sustained above the goal of 74% for 12 months. Implementation of EHR-based clinical decision support has increased appropriate evidence-based dosing of medications in pediatric and adult inpatients with obesity. Future studies should investigate the clinical and safety implications of using alternative dosing weights in pediatric patients.

Vancomycin AUC0-24 estimation using first-order pharmacokinetic methods in pediatric patients.

The optimal dosing and monitoring of vancomycin in pediatrics is still unknown but has evolved to emphasize area under the curve over 24 h (AUC0-24) over minimum concentration (Cmin) monitoring. Real-world data supporting the feasibility of two-concentration kinetics with first-order equations for the estimation of vancomycin AUC0-24 in pediatric patients are lacking. To describe the interplay of vancomycin dose, AUC0-24, and Cmin using first-order equations within four pediatric age groups. This is a single-center, retrospective cohort study analyzing pediatric patients (<18 years) receiving intravenous vancomycin between 2020 and 2022. Included patients received at least 24 h of intravenous vancomycin with two concentrations obtained within 96 h of therapy initiation. Patients with baseline renal dysfunction were excluded. Patients were divided into four age categories: neonates (≤28 days), infants (29 days to <1 year), children (1-12 years), and adolescents (13-17 years). First-order equations were utilized to estimate pharmacokinetic parameters and AUC0-24. Overall, 219 patients (median age of 6 years [IQR 1-12]) met inclusion criteria. The median vancomycin daily dose was 30 mg/kg in neonates, 70 mg/kg in infants and children, and 52 mg/kg in adolescents. Median Cmin and AUC0-24 values among all age groups were 8.68 mg/L and 505 mg * h/L, respectively. For AUC0-24 values outside of the therapeutic range (400-600 mg * h/L), more values were SUPRAtherapeutic (>600 mg * h/L) than SUBtherapeutic (<400 mg * h/L). The overall trend within our data showed suboptimal correlation between Cmin and AUC0-24. However, 71% of patients with Cmin values of 5-10 mg/L had an AUC0-24 within the therapeutic range of 400-600 mg * h/L, whereas 23 patients (92%) with a SUPRAtherapeutic AUC0-24 had a Cmin value ≥15 mg/L. Approximately 10% of patients experienced acute kidney injury. Our data describe the relationship between vancomycin dose, Cmin, and AUC0-24 in pediatric patients. We demonstrated the feasibility of using first-order equations to estimate AUC0-24, using two concentrations obtained at steady state to monitor efficacy and safety in pediatric patients receiving intravenous vancomycin. Our data showed suboptimal correlation between AUC0-24 and Cmin, which indicates that Cmin should not be used as a surrogate marker for a therapeutic AUC0-24 in pediatric patients. In alignment with the 2020 vancomycin consensus guidelines, we suggest utilizing AUC0-24 for efficacy and safety monitoring.

A population pharmacokinetic model using allometric scaling for baricitinib in patients with juvenile idiopathic arthritis.

Baricitinib is approved for the treatment of rheumatoid arthritis (RA) in more than 70 countries, and juvenile idiopathic arthritis (JIA) in the European Union. Population pharmacokinetic (PK) models were developed in a phase 3 trial to characterize PK in pediatric patients with JIA and identify weight-based dosing regimens. The phase 3, randomized, double-blind, placebo-controlled withdrawal, efficacy and safety trial, JUVE-BASIS, enrolled patients (aged 2 to <18 years) with polyarticular course JIA. During a safety/PK period, baricitinib concentration data from age-based dose cohorts were compared to concentrations from adult patients receiving 4-mg QD. PK data were used to develop a population PK model with allometric scaling to determine a weight-based posology in pediatric patients with JIA that matched the adult 4-mg exposure. Baricitinib plasma concentrations from 217 pediatric patients were used to characterize PK. Based on the adult model, pediatric PK was best described using a 2-compartment model with allometric scaling on clearance and volume of distribution and renal function (estimated with glomerular filtration rate [GFR], a known covariate affecting PK of baricitinib) on clearance. The PK modeling suggested the optimal dosing regimen based on weight for pediatric patients as: 2-mg QD for patients 10 to <30 kg and 4-mg QD for patients ≥30 kg. The use of a population PK model of baricitinib treatment in adult patients with RA, with the addition of allometric scaling for weight on clearance and volume terms, was useful to predict exposures and identify weight-based dosing in pediatric patients with JIA.

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.

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.