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Fosphenytoin (FOS) and its active form, phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA) are commonly used second-line treatments of status epilepticus. However, limited information is available regarding LEV and VPA concentrations following high intravenous doses, particularly in young children. The Established Status Epilepticus Treatment Trial, a blinded, comparative effectiveness study of FOS, LEV, and VPA for benzodiazepine-refractory status epilepticus provided an opportunity to investigate early drug concentrations. Patients aged ≥2 years who continued to seizure despite receiving adequate doses of benzodiazepines were randomly assigned to FOS, LEV, or VPA infused over 10 minutes. A sparse blood-sampling approach was used, with up to 2 samples collected per patient within 2 hours following drug administration. The objective of this work was to report early drug exposure of PHT, LEV, and VPA and plasma protein binding of PHT and VPA. Twenty-seven children with median (interquartile range) age of 4 (2.5-6.5) years were enrolled. The total plasma concentrations ranged from 69 to 151.3 μg/mL for LEV, 11.3 to 26.7 μg/mL for PHT and 126 to 223 μg/mL for VPA. Free fraction ranged from 4% to 19% for PHT and 17% to 51% for VPA. This is the first report in young children of LEV concentrations with convulsive status epilepticus as well as VPA concentrations after a 40 mg/kg dose. Several challenges limited patient enrollment and blood sampling. Additional studies with a larger sample size are required to evaluate the exposure-response relationships in this emergent condition.

The primary objective of this work was to characterize the pharmacokinetics (PK) of systemic clofarabine (clo-fara) in pediatric allogeneic hematopoietic cell transplantation (HCT) recipients receiving either nucleoside monotherapy or a dual nucleoside analog preparative regimen. Fifty-one children (median age, 4.9 years; range, .25 to 14.9 years) undergoing allogeneic HCT for a variety of malignant and nonmalignant disorders underwent PK assessment. Plasma samples were collected over the 4 to 5 days of clo-fara treatment and quantified for clo-fara, using a validated liquid chromatography/tandem mass spectrometry assay. Nonlinear mixed-effects modeling was used to develop the population PK model, including identification of covariates that influenced drug disposition. In agreement with previously published models, a 2-compartment PK model with first-order elimination best described the PK of clo-fara. Final parameter estimates for clo-fara were consistent with previous reports and were as follows: clearance (CL), 23 L/h/15 kg; volume of the central compartment, 42 L/15 kg; volume of peripheral compartment, 47 L/15 kg; and intercompartmental CL, 9.8 L/h/15 kg. Unexplained variability was acceptable at 33%, and the additive residual error (reflective of the assay) was estimated to be 0.36 ng/mL. Patient-specific factors significantly impacting clo-fara CL included actual body weight and age. The covariate model was able to estimate clo-fara CL with good precision in children spanning a wide age range from infancy to early adulthood and demonstrates the need for variable dosing in children of different ages. For example, the dose required for a 6-month and 1-year old was approximately 43% and 17% lower, respectively, than the typical 40 mg/m2dose to achieve the median AUC0-24of 1.04 mg·h/L in the study population. Despite the known renal elimination of clo-fara, no significant clinical parameters for renal function were retained in the final model (P> .05). Coadministration of fludarabine with clo-fara did not alter the CL of clo-fara (P> .05). These results will help inform individualized dosing strategies for clo-fara to improve clinical outcomes and limit drug-related adverse events in children undergoing HCT.

[This corrects the article DOI: 10.1371/journal.pbio.2005924.].

Traditional milligram per kilogram (mg/kg) dosing of enoxaparin in neonates frequently fails to achieve target anti‐Xa levels promptly, necessitating repeated laboratory monitoring and dose adjustments. This study investigated whether a personalized dosing strategy based on predicted individual clearance and volume of distribution could improve outcomes, comparing standard‐of‐care (SOC) mg/kg dosing to pharmacokinetic (PK) model‐informed precision dosing (MIPD). A retrospective analysis was conducted on hospitalized neonates treated with enoxaparin at less than 44 weeks postmenstrual age from 2019 to 2022. Data on demographics, drug dosing, PK model covariates, and clinical outcomes were extracted from electronic health records and analyzed using the Pumas‐AI Lyv dosing tool. The primary focus was on comparing the initial SOC dose to the MIPD‐recommended dose. The secondary outcome measured was the time required to achieve therapeutic anti‐Xa levels. The study included 168 neonates with a median postnatal age of 15 days (range 1–149) and a median dosing weight of 3.1 kg (range: 0.82–5.2). MIPD‐recommended initial doses were 20%–60% higher than SOC doses in 32% of the cases and over 60% higher in 11% of cases. Neonates who received SOC doses that were much lower than the MIPD recommendation showed the longest delays in reaching therapeutic anti‐Xa levels. The results indicate that PK model‐informed of enoxaparin dosing leads to higher initial dosages than SOC in neonates, potentially reducing the time to therapeutic anti‐Xa levels. These findings are being utilized to define dosing limits for a prospective trial of MIPD in neonatal intensive care settings. [ABSTRACT FROM AUTHOR]

COVID‐19 vaccines, including mRNA‐1273, have been rapidly developed and deployed. Establishing the optimal dose is crucial for developing a safe and effective vaccine. Modeling and simulation have the potential to play a key role in guiding the selection and development of the vaccine dose. In this context, we have developed an immunostimulatory/immunodynamic (IS/ID) model to quantitatively characterize the neutralizing antibody titers elicited by mRNA‐1273 obtained from three clinical studies. The developed model was used to predict the optimal vaccine dose for future pediatric trials. A 25‐μg primary vaccine series was predicted to meet non‐inferiority criteria in young children (aged 2–5 years) and infants (aged 6–23 months). The geometric mean titers and geometric mean ratios for this dose level predicted using the IS/ID model a priori matched those observed in the pediatric clinical study. These findings demonstrate that IS/ID models represent a novel approach to guide data‐driven clinical dose selection of vaccines. [ABSTRACT FROM AUTHOR]

The heart exhibits the highest basal oxygen (O2) consumption per tissue mass of any organ in the body and is uniquely dependent on aerobic metabolism to sustain contractile function. During acute hypoxic states, the body responds with a compensatory increase in cardiac output that further increases myocardial O2 demand, predisposing the heart to ischemic stress and myocardial dysfunction. Here, we test the utility of a novel engineered protein derived from the heme-based nitric oxide (NO)/oxygen (H-NOX) family of bacterial proteins as an O2 delivery biotherapeutic (Omniox-cardiovascular [OMX-CV]) for the hypoxic myocardium. Because of their unique binding characteristics, H-NOX-based variants effectively deliver O2 to hypoxic tissues, but not those at physiologic O2 tension. Additionally, H-NOX-based variants exhibit tunable binding that is specific for O2 with subphysiologic reactivity towards NO, circumventing a significant toxicity exhibited by hemoglobin (Hb)-based O2 carriers (HBOCs). Juvenile lambs were sedated, mechanically ventilated, and instrumented to measure cardiovascular parameters. Biventricular admittance catheters were inserted to perform pressure-volume (PV) analyses. Systemic hypoxia was induced by ventilation with 10% O2. Following 15 minutes of hypoxia, the lambs were treated with OMX-CV (200 mg/kg IV) or vehicle. Acute hypoxia induced significant increases in heart rate (HR), pulmonary blood flow (PBF), and pulmonary vascular resistance (PVR) (p < 0.05). At 1 hour, vehicle-treated lambs exhibited severe hypoxia and a significant decrease in biventricular contractile function. However, in OMX-CV-treated animals, myocardial oxygenation was improved without negatively impacting systemic or PVR, and both right ventricle (RV) and left ventricle (LV) contractile function were maintained at pre-hypoxic baseline levels. These data suggest that OMX-CV is a promising and safe O2 delivery biotherapeutic for the preservation of myocardial contractility in the setting of acute hypoxia.

A prospective multicenter study was conducted to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of fludarabine plasma (f-ara-a) and intracellular triphosphate (f-ara-ATP) in children undergoing hematopoietic cell transplantation (HCT) and receiving fludarabine with conditioning. Plasma and peripheral blood mononuclear cells (PBMCs) were collected over the course of therapy for quantitation of f-ara-a and f-ara-ATP. Nonlinear mixed-effects modeling was used to develop the PK model, including identification of covariates impacting drug disposition. Data from a total of 133 children (median age, 5 years; range, .2 to 17.9) undergoing HCT for a variety of malignant and nonmalignant disorders were available for PK-PD modeling. The implementation of allometric scaling of PK parameters alone was insufficient to describe drug clearance, particularly in very young children. Renal impairment was predicted to increase drug exposure across all ages. The rate of f-ara-a entry into PBMCs (expressed in pmoles per million cells) decreased over the course of therapy, resulting in 78% lower f-ara-ATP after the fourth dose (1.7 pmoles/million cells [range, .2 to 7.2]) compared with first dose (7.9 pmoles/million cells [range, .7 to 18.2]). The overall incidence of treatment-related mortality (TRM) was low at 3% and 8% at days 60 and 360, respectively, and no association with f-ara-a exposure and TRM was found. In the setting of malignancy, disease-free survival was highest at 1 year after HCT in subjects achieving a systemic f-ara-a cumulative area under the curve (cAUC) greater than 15 mg*hour/L compared to patients with a cAUC less than 15 mg*hour/L (82.6% versus 52.8% P = .04). These results suggest that individualized model-based dosing of fludarabine in infants and young children may reduce morbidity and mortality through improved rates of disease-free survival and limiting drug-related toxicity. ClinicalTrials.gov Identifier: NCT01316549.

Regulatory T cells (Tregs) are essential for maintaining immune homeostasis by serving as negative regulators of adaptive immune system effector cell responses. Reduced production or function of Tregs has been implicated in several human autoimmune diseases. The cytokine interleukin 2 plays a central role in promoting Treg differentiation, survival, and function in vivo and may therefore have therapeutic benefits for autoimmune diseases. mRNA‐6231 is an investigational, lipid nanoparticle‐encapsulated, mRNA‐based therapy that encodes a modified human interleukin 2 mutein fused to human serum albumin (HSA‐IL2m). Herein, we report the development of a semi‐mechanistic kinetic‐pharmacodynamic model to quantify the relationship between subcutaneous dose(s) of mRNA‐6231, HSA‐IL2m protein expression, and Treg expansion in nonhuman primates. The nonclinical kinetic‐pharmacodynamic model was extrapolated to humans using allometric scaling principles and the physiological basis of pharmacological mechanisms to predict the clinical response to therapy a priori. Model‐based simulations were used to inform the dose selection and design of the first‐in‐human clinical study (NCT04916431). The modeling approach used to predict human responses was validated when data became available from the phase I clinical study. This validation indicates that the approach is valuable in informing clinical decision‐making. [ABSTRACT FROM AUTHOR]

Optimal pediatric dosing of unfractionated heparin (UFH) is challenging because of the paucity of clinical outcome and pharmacokinetic–pharmacodynamic (PK/PD) studies in pediatrics. This study aimed to: (i) develop a PK/PD model for UFH, quantified by anti‐factor Xa assay, and the UFH effect, measured by activated partial thromboplastin time (aPTT); and (ii) use simulations to evaluate pediatric UFH infusions for achieving the anti‐factor Xa (0.3–0.7 IU/mL) therapeutic target. Electronic health record data were retrospectively collected from 633 patients aged <19 years admitted to Texas Children's Hospital. The PK/PD model was developed using a 70% (training)/30% (testing) split‐sample approach. A 1‐compartment PK model with linear elimination adequately described the UFH PK. An allometrically scaled body weight on clearance (CL) and volume of distribution (Vd) with an age‐dependent maturation function of extracellular water on Vd were the covariates identified. Comparable with literature, the typical values for CL and Vd were 3.28 L/(h·50 kg) and 8.83 L/50 kg, respectively. A linear model adequately described the UFH–aPTT relationship with an estimated slope of 150 seconds/(IU/mL). Simulations of the currently recommended starting infusions (28 IU/h/kg for pediatrics <1 year old or 20 IU/h/kg for pediatrics >1 year old) showed that the anti‐factor Xa therapeutic target was achieved only in 15.3%, 14.6%, 36.9%, and 45.11% of subjects in the age groups of <1 year, 1–6 years, 6–12 years, and 12–19 years, respectively. In conclusion, the UFH anti‐factor Xa target is not achieved initially, especially in young pediatrics, suggesting the need to optimize UFH dosing to achieve higher therapeutic success. [ABSTRACT FROM AUTHOR]

Aim: The study objective was to develop a population pharmacokinetic model for busulfan to comprehensively examine drug–drug interactions in paediatric patients undergoing haematopoietic stem cell transplantation. Currently, there is limited evidence to substantiate potential drug–drug interactions with busulfan. Methods: This retrospective study population was comprised of 250 patients receiving, on average, 0.8 mg/kg intravenous busulfan as pretreatment. All model analyses were conducted using nonlinear mixed effects modelling in Pumas v2.0. The metabolic pathways of primary interest were glutathione conjugation and cytochrome P450 (CYP) activity. Concomitant medications were categorized as CYP inhibitors, inducers or glutathione S‐transferase depleters, and included in the model as conditional covariates. A bootstrap simulation and visual predictive check were conducted to qualify the final model. Results: The final 1‐compartment model incorporates covariates of weight and age in relation to their effects on both total body clearance and volume of distribution. The estimated typical values of clearance and volume were 1.138 L/h (CI: 1.095–1.179 L/h) and 3.527 L (CI: 3.418–3.621 L), respectively. No significant changes in clearance were observed when medications that alter proposed hepatic and metabolic pathways of busulfan were coadministered. Conclusion: To the best of our knowledge, this is the largest single centre study of busulfan in children and the first to quantify the maturation effect of both clearance and volume. This study could not demonstrate a difference in busulfan clearance when comparing patients who received medications that alter the glutathione S‐transferase, CYP3A4 or CYP2C9 pathway to those who did not. [ABSTRACT FROM AUTHOR]