Impact of Delayed Cord Clamping on Red Blood Cell Transfusion and Related Outcomes in Very Low Birth Weight Infants.

OBJECTIVE: Delayed cord clamping (DCC) for 30 to 60 seconds after birth facilitates placental transfusion, increases blood volume, and decreases red blood cell (RBC) transfusion in preterm infants. Study objective was to determine (1) RBC transfusion burden over a 5-year period, (2) impact of DCC practice on RBC transfusions, and (3) association of RBC transfusion on outcomes in very low birthweight (VLBW) preterm infants. STUDY DESIGN: A retrospective medical chart review was performed in 787 VLBW infants between 2016 and 2020. Demographic factors, DCC status, number of RBC transfusions, and neonatal outcomes were determined in eligible infants. Adjusted association between DCC, RBC transfusion, and outcomes were determined using logistic and linear regression methods. RESULTS: Of the 538 eligible VLBW infants, 62% (N = 332) received RBC transfusions. Proportion receiving RBC transfusion were significantly higher for infants <1,000 g (N = 217, 65.4%) and gestational age (GA) <29 weeks (N = 256, 77.1%) than larger (1,001-1,250 g, N = 77, 23.2% and 1,251-1,500 g, N = 38, 11.4%) and older GA ≥ 29 weeks' infants (N = 76, 22.9%, p < 0.05). Of the 81/538 (15.1%) who received DCC, 48 (59.2%) received no RBC transfusion (p < 0.001). In multivariable logistic regression analysis, preterm infants with DCC were 55% less likely to receive RBC transfusions as compared with infants with no DCC. At any given GA, the number of RBC transfusions in preterm infants with DCC was 25% lower as compared with infants without DCC (p < 0.05). Transfusion was associated with 8-fold increased odds for bronchopulmonary dysplasia and 4-fold increased odds for medical and surgically treated patent ductus arteriosus compared with no transfusion. There was no significant association of transfusion with neonatal sepsis, laser treated retinopathy of prematurity, necrotizing enterocolitis, and intraventricular hemorrhage. CONCLUSION: DCC was significantly associated with reduced RBC transfusion, but fewer preterm infants received DCC. Further research is needed to explore the feasibility of providing neonatal resuscitation during DCC in preterm infants. KEY POINTS: · Delayed cord clamping significantly reduced the need for RBC transfusions.. · Fewer very preterm infants received DCC.. · Future research is needed to explore feasibility of neonatal resuscitation during DCC..

Development and Use of an Ex-Vivo In-Vivo Correlation to Predict Antiepileptic Drug Clearance in Patients Undergoing Continuous Renal Replacement Therapy.

OBJECTIVES: Results from previous ex-vivo continuous renal replacement therapy (CRRT) models have successfully demonstrated similar extraction coefficients (EC) identified from in-vivo clinical trials. The objectives of this study are to develop an ex-vivo in-vivo correlation (EVIVC) model to predict drug clearance for commonly used antiepileptics and to evaluate similarity in drug extraction across different CRRT modalities to extrapolate dosing recommendations. METHODS: Levetiracetam, lacosamide, and phenytoin CRRT clearance was evaluated using the Prismaflex CRRT system and M150 hemodiafilters using an albumin containing normal saline (ALB-NS) vehicle with 3 different albumin concentrations (2 g/dL, 3 g/dL, and 4 g/dL) and a human plasma vehicle at 3 different effluent flow rates (1 L/hr, 2 L/hr, and 3 L/hr). Blood and effluent/dialysate concentrations were collected after circuit priming. ECs were calculated for each drug, modality, vehicle, and experimental arm combination. RESULTS: The calculated average EC for levetiracetam and lacosamide was approximated to the fraction unbound from plasma protein. Human plasma and ALB-NS vehicles demonstrated adequate prediction of in-vivo CRRT clearance. Geometric mean ratios indicated similarity in extraction coefficients when comparing between hemofiltration and hemodiafiltration modalities and between filtration and dialysis modalities at effluent flow rates ≤ 2L/hr. Evaluation of phenytoin provided inconsistent findings with regards to extraction coefficient similarity across different CRRT modalities. CONCLUSION: The findings indicate that an ex-vivo study can be used as a surrogate to predict in-vivo levetiracetam and lacosamide clearance in patients receiving CRRT.

Effect of maternal adverse childhood experiences (ACE) and cannabis use on pregnancy outcomes.

This study aimed to characterize the relationship between cannabis use, ACE score, and pregnancy outcomes. Pregnant patients in Baltimore, MD, completed the 17-point ACE checklist. Charts of the birth parent and neonate were reviewed for urine toxicology testing at initiation of care and delivery, prenatal care metrics, and birth statistics. Multivariable logistic regression analysis was performed to assess the relationship between ACE score, cannabis use, and pregnancy outcomes. Of 256 birth parents, 87 (34.0%) tested positive for cannabis at initial visit and 39 (15.2%) tested positive for cannabis at delivery. Testing positive for cannabis at initial visit or delivery was associated with higher ACE score (15.1 vs 13.7, p = 0.04; 16.2 vs 13.8, p = 0.01). Of those who tested positive for cannabis at initial visit, 39/87 (45.0%) tested positive at delivery. Continued cannabis use at delivery was associated with lower maternal weight gain (7.9 kg vs 13.3 kg, p = 0.003), fewer prenatal visits (7 vs 8, p = 0.010), and numerically higher mean ACE score. Cannabis use at delivery was associated with 10% lower birthweight (2665 g vs 3014 g p < 0.05) but not with pre-term birth. Total ACE score was not significantly associated with any birth outcome. Worse pregnancy outcomes were associated with cannabis use throughout pregnancy but not with cannabis use at prenatal care initiation. The interplay of ACE and continued cannabis use during pregnancy warrants further research on the physiologic effects of cannabis and interventions to decrease substance use during pregnancy.

Evaluation of an ex-vivo neonatal extracorporeal membrane oxygenation circuit on antiepileptic drug sequestration.

Antiepileptic dosing information used to manage neonatal patients receiving extracorporeal membrane oxygenation (ECMO) is limited. The objective of this study is to quantify the extent of sequestration of various antiepileptic drugs using an ex-vivo neonatal ECMO circuit. Two neonatal closed-loop ECMO circuits were prepared using a Rotaflow centrifugal pump, custom polyvinylchloride tubing and a Quadrox-i Neonatal membrane oxygenator. After 5 minutes of circuit priming and stabilization with normal saline/albumin or expired human whole blood, single boluses of levetiracetam (200 mg), lacosamide (20 mg), and phenytoin (200 mg) were injected into the circuit. To account for spontaneous drug degradation, two polyvinylchloride beakers were filled with normal saline/albumin or expired human whole blood and equivalent antiepileptic drug doses were prepared. Simultaneous pharmacokinetic samples were collected from the control solution and the pre-centrifugal pump, pre-oxygenator, and post-oxygenator sampling ports from each circuit. Similar drug recovery profiles were observed among the three sampling sites investigated. Percent drug sequestration after a 24-hour circuit flow period was relatively similar between the two different circuits and ranged between 5.5%-13.2% for levetiracetam, 18.4%-22.3% for lacosamide, and 24.5%-30.2% for phenytoin. A comparison at 12 and 24 hours demonstrated similar percent drug sequestration across all three drugs in each circuit. Percent drug sequestrations for levetiracetam and lacosamide were less than 20% and for phenytoin were as high as 30% based on the sampling following single bolus dose administration into a neonatal ECMO circuit. Careful consideration of patient clinical status should be taken in consideration when optimizing antiepileptic therapy in neonates receiving ECMO.

Evaluation of Linezolid Pharmacokinetics in Critically Ill Obese Patients with Severe Skin and Soft Tissue Infections.

Linezolid standard dosing is fixed at 600 mg every 12 h (q12h) for adults. Literature suggests critically ill, obese patients require higher doses. The study aim is 2-fold: (i) to describe linezolid pharmacokinetics (PK), and (ii) to evaluate if PK/pharmacodynamic (PD) target attainment is achieved with standard dosing in critically ill, obese patients with severe skin and soft tissue infections (SSTIs). Adult patients with a body mass index (BMI) of ≥30 kg/m2 and receiving intravenous (i.v.) linezolid from August 2018 to April 2019 were eligible for consent in this prospective study. Severe SSTIs were defined as necrotizing fasciitis, myonecrosis, or SSTI with sepsis syndrome. Four blood samples were collected at steady state at 1, 3, 5 h postinfusion and as a trough. Target attainment was defined as achieving area under the concentration-time curve from 0 to 24 h to MIC (AUC0-24h/MIC) of ≥100 h*mg/liter. Monte Carlo simulations were used to determine the probability of target attainment (PTA). Eleven patients were included in the study. The median BMI was 45.7 kg/m2, and median total body weight (TBW) was 136.0 kg. Seven patients received standard linezolid doses, and four received 600 mg q8h. A one-compartment model described linezolid PK. Based on AUC0-24h/MIC targets, for noncirrhotic patients at 140 kg, the PTA with standard linezolid doses was 100%, 98.8%, 34.1%, and 0% for MICs of 0.5, 1, 2, and 4 mg/liter, respectively. In conclusion, target attainment of ≥90% is not achieved with standard linezolid doses for noncirrhotic patients ≥140 kg with MICs of ≥2 mg/liter. This study adds to accumulating evidence that standard linezolid doses may not be adequate for all patients.

A prospective, real-world, clinical pharmacokinetic study to inform lacosamide dosing in critically ill patients undergoing continuous venovenous haemofiltration (PADRE-02).

AIMS: Although the use of continuous renal replacement therapy (CRRT) has increased, limited dosing information exists on the effect of CRRT on antiepileptic drug pharmacokinetics. The objectives of this practice-based study are to evaluate the pharmacokinetics of lacosamide and recommend individualized dosing recommendations in critically ill patients receiving continuous venovenous haemofiltration (CVVH). METHODS: Seven patients receiving lacosamide and CVVH in a neurocritical care unit were enrolled. Pre-filter, post-filter and ultrafiltrate samples were obtained at baseline, right after the completion of the infusion, and up to six additional sampling time points post-administration. Patient-specific flow rates and clinical measures were also collected simultaneously at the time of sampling. Plasma concentrations were measured using a validated high-performance liquid chromatography with ultraviolet radiation detection (HPLC-UV) bioanalytical method. Non-compartmental analysis was utilized to characterize the pharmacokinetics of lacosamide. RESULTS: The observed mean sieving coefficient for lacosamide was 0.80 ± 0.10, suggesting high removal of lacosamide. Concentrations measured in six out of seven patients were observed to be outside the therapeutic range (5-12 mg/L). The estimated average volume of distribution was found to be similar to healthy patients (0.58 L/kg). The mean bias and precision of the estimated total clearance was -2.53% and 14.9%, respectively. Simulations of various doses suggest that effluent flow rate-based dosing regimens could be used to individualize lacosamide therapeutics. CONCLUSIONS: CVVH clearance contributed a major fraction of the total lacosamide clearance in neurocritically ill patients. Given that drug clearance increases with higher effluent flow rates, lacosamide dosing regimens should be increased to match exposures observed in patients with normal renal function.

A novel approach for personalized response model: deep learning with individual dropout feature ranking.

Deep learning is the fastest growing field in artificial intelligence and has led to many transformative innovations in various domains. However, lack of interpretability sometimes hinders its application in hypothesis-driven domains such as biology and healthcare. In this paper, we propose a novel deep learning model with individual feature ranking. Several simulated datasets with the scenarios that contributing features are correlated and buried among non-contributing features were used to characterize the novel analysis approach. A publicly available clinical dataset was also applied. The performance of the individual level dropout feature ranking model was compared with commonly used artificial neural network model, random forest model, and population level dropout feature ranking model. The individual level dropout feature ranking model provides a reasonable prediction of the outcomes. Unlike the random forest model and population level dropout feature ranking model, which can only identify global-wise contributing features (i.e., at population level), the individual level dropout feature ranking model allows further identification of impactful features on response at individual level. Therefore, it provides a basis for clustering patients into subgroups. This may provide a new tool for enriching patients in clinical drug development and developing personalized or individualized medicine.

A Population Pharmacokinetics and Pharmacodynamic Approach To Optimize Tazobactam Activity in Critically Ill Patients.

The percentage of the time that the free drug concentration remains above a concentration threshold (%fT > concentration threshold) has frequently been identified to be the optimal pharmacokinetic (PK)-pharmacodynamic (PD) target of interest for tazobactam using in vitro infection models. Similar in vitro models suggested that an 85% fT > concentration threshold of 2 µg/ml for tazobactam is required to demonstrate a 2-log10-unit decrease in the number of CFU per milliliter from that at the baseline at 24 h for high-level ß-lactamase-producing Escherichia coli strains. The objective of this study was to characterize the tazobactam concentrations in a cohort of critically ill patients with Gram-negative bacterial infections, determine if traditional dosing regimens achieve a prespecified PK/PD target of an 80% fT > concentration threshold of 2 µg/ml, and propose alternative dosing regimens. Hospitalized critically ill adult patients receiving piperacillin-tazobactam (TZP) for a culture-positive Gram-negative bacterial infection were eligible to consent for study inclusion. Two blood samples were drawn, one during the midpoint of the dosing interval and one at the time of the trough concentration once the patient achieved PK steady state. A population PK model was developed using Phoenix NLME (v8.1) software to characterize the observed concentration-time profile of tazobactam, explore potential covariates to explain the variability in the clearance and volume parameters, and to simulate potential dosing regimens that would achieve the PK/PD target. The PK of tazobactam were adequately described by a one-compartment model with first-order elimination in 18 patients who provided consent. The final model incorporated creatinine clearance as a covariate on clearance. Simulations demonstrated target attainments of less than 50% for tazobactam using traditional dosing regimens (4/0.5 g over 30 min every 6 h). Target attainments of greater than 75% were achieved when using extended infusion times of 4 to 6 h or when administering TZP as a continuous infusion (16/2 g over 24 h). Traditional tazobactam dosing regimens fail to achieve conservative PK/PD targets in critically ill patients. Increases in the tazobactam dose or prolongation of the infusion rate may be warranted to achieve activity against ß-lactamase-producing Gram-negative bacteria.

Development and validation of a HPLC-UV assay for quantification of levetiracetam concentrations in critically ill patients undergoing continuous renal replacement therapy.

Limited clinical data exists on the effects of continuous renal replacement therapy (CRRT) on drug pharmacokinetics. A high-performance liquid chromatography with ultraviolet detection method was developed and validated to determine levetiracetam concentrations in human plasma and CRRT effluent samples. Five hundred microliters of human plasma and 250 µL effluent samples were used to quantify levetiracetam. Plasma samples were purified by protein precipitation, evaporated under nitrogen gas at room temperature and reconstituted in 50 mm potassium dihydrogen phosphate buffer (pH of 4.5). Reverse-phase chromatographic separation was achieved within 20 min using a mobile phase eluting gradient of 50 mm potassium dihydrogen phosphate and acetonitrile. UV detection was set at 195 nm. The calibration curve was found to be linear over the range of 2-80µg/mL. Inter- and intra-day precisions were < 8% for both plasma and effluent samples. The accuracy was determined to be within -12-10% of nominal concentrations. The method was selective and sensitive with a lower limit of quantification of 2 µg/mL. Overall recovery of levetiracetam from plasma was ~100%. The validated assay was successfully applied in a pharmacokinetic study to determine potential dose adjustments in patients undergoing CRRT and receiving levetiracetam.

Exposure-response analysis after subcutaneous administration of RBP-7000, a once-a-month long-acting Atrigel formulation of risperidone.

AIMS: A new, long-acting, subcutaneous (SC) formulation of risperidone (RBP-7000) has been developed for the treatment of schizophrenia to address issues of non-adherence associated with oral risperidone treatment. The objective of this work was to establish an exposure-response relationship between total active moiety (AM) plasma exposure (risperidone + 9-hydroxy-risperidone) and Positive and Negative Syndrome Scale (PANSS) or Clinical Global Impression severity (CGI-S) scores using data from a registration trial. METHODS: This was a Phase 3 randomized, double-blind, placebo-controlled, multicenter study in 354 patients to evaluate the efficacy, safety and tolerability of RBP-7000 (90 mg and 120 mg). Non-linear mixed effects modelling was used to develop an integrated population pharmacokinetic/pharmacodynamic (PK/PD) model that included a joint PK model for risperidone and 9-hydroxy-risperidone with placebo and drug-effect models to establish the relation between total AM exposure and PANSS or CGI-S scores. RESULTS: CYP2D6 poor and intermediate metabolizers had lower formation rates of 9-hydroxy-risperidone (94% and 76% lower, respectively) compared to the extensive CYP2D6 metabolizers. The maximum placebo-corrected relative decrease in PANSS score from baseline following RBP-7000 treatment was 5.4%, half of which could be achieved at plasma concentrations of 4.6 ng ml-1 of the total AM. A proportional odds model for the CGI-S score related the total AM plasma concentration to the probability of improving/worsening scores over time. CONCLUSIONS: Exposure-response analysis was established between total AM concentrations and PANSS and CGI-S scores, with good precision in parameter estimates. CYP2D6 phenotype on risperidone metabolism was the only identified covariate.

Population pharmacokinetics and site of action exposures of veliparib with topotecan plus carboplatin in patients with haematological malignancies.

AIMS: Veliparib is a potent inhibitor of poly(ADP-ribose) polymerase (PARP) enzyme. The objectives of the analysis were to evaluate the effect of baseline covariates and co-administration of topotecan plus carboplatin (T + C) on pharmacokinetics of veliparib in patients with refractory acute leukaemia, and compare veliparib concentration in various biological matrices. METHODS: A population pharmacokinetic model was developed and effect of age, body size indices, sex, creatinine clearance (CrCL) and co-administration of T + C on the pharmacokinetics of veliparib were evaluated. The final model was qualified using bootstrap and quantitative predictive check. Linear regression was conducted to correlate concentrations of veliparib in various biological matrices. RESULTS: A two compartment model with first-order absorption with Tlag described veliparib pharmacokinetics. The apparent clearance (CL/F) and volume (Vc /F) were 16.5 l h-1 and 122.7 l, respectively. The concomitant administration of T + C was not found to affect veliparib CL/F. CrCL and lean body mass (LBM) were significant covariates on CL/F and Vc/F, respectively. While a strong positive relationship was observed between veliparib concentrations in plasma and bone marrow supernatant, no correlation was observed between plasma and peripheral blood or bone marrow blasts. CONCLUSIONS: Consistent with veliparib's physiochemical properties and its elimination mechanism, LBM and CrCL were found to affect pharmacokinetics of veliparib while concomitant administration of T + C did not affect veliparib's CL/F. Plasma concentrations were found to be a reasonable surrogate for veliparib concentrations in peripheral blood and bone marrow supernatant but not blasts. The current model will be utilized to conduct exposure-response analysis to support dosing recommendations.

Statistical modeling for Bayesian extrapolation of adult clinical trial information in pediatric drug evaluation.

Children represent a large underserved population of "therapeutic orphans," as an estimated 80% of children are treated off-label. However, pediatric drug development often faces substantial challenges, including economic, logistical, technical, and ethical barriers, among others. Among many efforts trying to remove these barriers, increased recent attention has been paid to extrapolation; that is, the leveraging of available data from adults or older age groups to draw conclusions for the pediatric population. The Bayesian statistical paradigm is natural in this setting, as it permits the combining (or "borrowing") of information across disparate sources, such as the adult and pediatric data. In this paper, authored by the pediatric subteam of the Drug Information Association Bayesian Scientific Working Group and Adaptive Design Working Group, we develop, illustrate, and provide suggestions on Bayesian statistical methods that could be used to design improved pediatric development programs that use all available information in the most efficient manner. A variety of relevant Bayesian approaches are described, several of which are illustrated through 2 case studies: extrapolating adult efficacy data to expand the labeling for Remicade to include pediatric ulcerative colitis and extrapolating adult exposure-response information for antiepileptic drugs to pediatrics.

Project Optimus Elicits the "Holistic" Benefits of PK/PD Modeling of Immunotherapy.

Leveraging a heterogeneous dataset, a recent article demonstrated the application of pharmacometric modeling to inform the dosing of nivolumab-relatlimab fixed-dose combination in special populations, including adolescents lacking clinical data. The use of model-informed approaches during clinical drug development can be cost-effective, which ensures fast access to drugs and enhances patient outcomes. See related article by Zhao et al., p. 3050.

Exposure-Response Modeling in Adults and Adolescents With Schizophrenia to Support the Extrapolation of Brexpiprazole Efficacy to Adolescents.

In order to accelerate drug development and avoid unnecessary drug trials in vulnerable pediatric populations, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the effectiveness of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to adolescents. Extrapolation is based on the evidence-based assumptions that (1) disease characteristics and (2) response to therapy, are similar in adults and adolescents. Whereas the FDA validated the extrapolation approach using data from multiple drug development programs, aripiprazole data are the most relevant to confirm the validity of the extrapolation approach for brexpiprazole, since aripiprazole and brexpiprazole both modulate dopaminergic and serotonergic signaling in the brain. The aims of this analysis were (1) to quantitatively assess the aripiprazole exposure (average steady-state concentration)-response (Positive and Negative Syndrome Scale total score change from baseline) similarity between adults and adolescents with schizophrenia, (2) to extend the aripiprazole exposure-response modeling to brexpiprazole using adult data, and (3) to use the brexpiprazole model to predict schizophrenia symptom response in adolescents. Disease-drug-dropout models were developed using patient-level data from clinical studies of aripiprazole (1007 adults, 294 adolescents) and brexpiprazole (1235 adults) in schizophrenia. The aripiprazole model demonstrated similar exposure-response between adults and adolescents with schizophrenia, validating the extrapolation approach. Extrapolation of the brexpiprazole adult exposure-response model to adolescents predicted the efficacy of brexpiprazole in adolescents aged 13-17 years with schizophrenia.

Pharmacokinetic Modeling Using Real-World Data to Optimize Unfractionated Heparin Dosing in Pediatric Patients on Extracorporeal Membrane Oxygenation and Evaluate Target Achievement-Clinical Outcomes Relationship.

Unfractionated heparin (UFH) is a commonly used anticoagulant for pediatric patients undergoing extracorporeal membrane oxygenation (ECMO), but evidence is lacking on the ideal dosing. We aimed to (1) develop a population pharmacokinetic (PK) model for UFH, measured through anti-factor Xa assay; (2) optimize UFH starting infusions and dose titrations through simulations; and (3) explore UFH exposure-clinical outcomes relationship. Data from 218 patients admitted to Utah's Primary Children's Hospital were retrospectively collected. A 1-compartment PK model with time-varying clearance (CL) adequately described UFH PK. Weight on CL and volume of distribution and ECMO circuit change on CL were significant covariates. The typical estimates for initial CL and first-order rate constant to reach steady-state CL were 0.57 L/(h·10 kg) and 0.02/h. Comparable to non-ECMO patients, the typical steady-state CL was 0.81 L/(h·10 kg). Simulations showed that a 75 IU/kg UFH bolus dose followed by starting infusions of 25 and 20 IU/h/kg for patients aged younger than 6 years and 6 years or older, respectively, achieved the therapeutic target in 56.6% of all patients, whereas only 3.1% exceeded the target. The proposed UFH titration schemes achieved the target in more than 90% of patients while less than 0.63% were above the target after 24 and 48 hours of treatment. The median intensive care unit survival time in patients within and below the target at 24 hours was 136 and 66 hours, respectively. In conclusion, PK model of UFH was developed for pediatric patients on ECMO. The proposed UFH dosing scheme attained the anti-factor Xa target rapidly and safely.

Pharmacokinetics and Biodistribution of 16,16 dimethyl Prostaglandin E2 in Non-Irradiated and Irradiated Mice and Non-Irradiated Non-Human Primates.

Exposure to high-dose ionizing radiation can lead to life-threatening injuries and mortality. Bone marrow is the most sensitive organ to radiation damage, resulting in the hematopoietic acute radiation syndrome (H-ARS) with the potential sequelae of infection, hemorrhage, anemia, and death if untreated. The development of medical countermeasures (MCMs) to protect or mitigate radiation injury is a medical necessity. In our well-established murine model of H-ARS we have demonstrated that the prostaglandin E2 (PGE2) analog 16,16 dimethyl-PGE2 (dmPGE2) has survival efficacy as both a radioprotectant and radiomitigator. The purpose of this study was to investigate the pharmacokinetics (PK) and biodistribution of dmPGE2 when used as a radioprotector in irradiated and non-irradiated inbred C57BL/6J mice, PK in irradiated and non-irradiated Jackson Diversity Outbred (JDO) mice, and the PK profile of dmPGE2 in non-irradiated non-human primates (NHPs). The C57BL/6J and JDO mice each received a single subcutaneous (SC) dose of 35 ug of dmPGE2 and were randomized to either receive radiation 30 min later or remain non-irradiated. Plasma and tissue PK profiles were established. The NHP were dosed with 0.1 mg/kg by SC administration and the PK profile in plasma was established. The concentration time profiles were analyzed by standard non-compartmental analysis and the metrics of AUC0-Inf, AUC60-480 (AUC from 60-480 min), Cmax, and t1/2 were evaluated. AUC60-480 represents the postirradiation time frame and was used to assess radiation effect. Overall, AUC0-Inf, Cmax, and t1/2 were numerically similar between strains (C57BL/6J and JDO) when combined, regardless of exposure status (AUC0-Inf: 112.50 ng·h/ml and 114.48 ng·h/ml, Cmax: 44.53 ng/ml and 63.96 ng/ml; t1/2: 1.8 h and 1.1 h, respectively). PK metrics were numerically lower in irradiated C57BL/6J mice than in non-irradiated mice [irradiation ratio: irradiated values/non-irradiated values = 0.71 for AUC60-480 (i.e., 29% lower), and 0.6 for t1/2]. In JDO mice, the radiation ratio was 0.53 for AUC60-480 (i.e., 47% lower), and 1.7 h for t1/2. The AUC0-Inf, Cmax, and t1/2 of the NHPs were 29.20 ng·h/ml, 7.68 ng/ml, and 3.26 h, respectively. Despite the numerical differences seen between irradiated and non-irradiated groups in PK parameters, the effect of radiation on PK can be considered minimal based on current data. The biodistribution in C57BL/6J mice showed that dmPGE2 per gram of tissue was highest in the lungs, regardless of exposure status. The radiation ratio for the different tissue AUC60-480 in C57BL/6J mice ranged between 0.5-1.1 (50% lower to 10% higher). Spleen, liver and bone marrow showed close to twice lower exposures after irradiation, whereas heart had a 10% higher exposure. Based on the clearance values from mice and NHP, the estimated allometric scaling coefficient was 0.81 (95% CI: 0.75, 0.86). While slightly higher than the current literature estimates of 0.75, this scaling coefficient can be considered a reasonable estimate and can be used to scale dmPGE2 dosing from animals to humans for future trials.

Intergenerational transmission of sucralose and acesulfame-potassium from mothers to their infants via human milk: a pharmacokinetic study.

BACKGROUND: Low-calorie sweetener (LCS) consumption is prevalent among lactating mothers, yet infants' exposure to LCS in human milk is not well-characterized. OBJECTIVES: Conduct a pharmacokinetic study of sucralose and acesulfame-potassium (ace-K) in mothers' milk and plasma over 72 h and in infants' plasma. METHODS: Following baseline blood and milk collection, mothers (n = 40) consumed 20 oz of diet cranberry juice containing sucralose and ace-K. Blood samples were collected from the mother 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 h after beverage ingestion, and milk was expressed at 1, 2, 3, 4, 6, 8, 12, and 24 h postingestion. One blood sample was collected from each infant, the timing of which was determined using pharmacokinetics model-based simulation. Concentration-time profiles of LCS from the mother's plasma and milk were analyzed using noncompartmental methods. RESULTS: Ace-K rapidly entered human milk with the largest observed concentration of 373.0 (coefficient of variation 69%) ng/mL first detected 4 h following diet beverage ingestion. Sucralose appeared in human milk 1-2 h after diet beverage ingestion with the largest observed concentration of 7.2 (coefficient of variation 63%) ng/mL first detected 7 h postingestion. The mean 24-h milk to plasma ratio of ace-K was 1.75 [standard deviation (SD) 1.37] with a mean relative infant dose of 1.59% (SD 1.72%). Ace-K was detected in all infants' plasma with an mean concentration of 9.2 (SD% 14.8) ng/mL ∼6 h after maternal beverage ingestion. The mean 24-h milk to plasma ratio of sucralose was 0.15 (SD 0.06) with a mean relative infant dose of 0.04% (SD 0.02%). Sucralose was detected in only 15 infants' plasma, and the mean concentration was 5.0 (SD% 7.1) ng/mL ∼5 h after diet beverage ingestion. CONCLUSIONS: Ace-K rapidly transfers from human milk into infants' circulation whereas sucralose was detected at much lower concentrations and in some but not all infants. Future research should investigate the effects of early-life sucralose and ace-K exposure via human milk on infants' health. This trial was registered at clinicaltrials.gov as NCT05379270.

DON in pediatric cerebral malaria, a phase I/IIA dose-escalation safety study: study protocol for a clinical trial.

BACKGROUND: Despite treatment with highly effective antimalarial drugs, malaria annually claims the lives of over half a million children under 5-years of age in sub-Saharan Africa. Cerebral malaria (CM), defined as Plasmodium falciparum infection with coma, is the severe malaria syndrome with the highest mortality. Studies in the CM mouse model suggest that a T cell-mediated response underlies CM pathology, opening a new target for therapy in humans. This trial aims to establish the preliminary safety of one such novel therapy, the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON). METHODS: In this phase I/IIa dose-escalation clinical trial, a single dose of intravenous (IV) DON is administered to three participants groups-healthy adults and adults with uncomplicated malaria, then pediatric participants with CM-to primarily assess safety. The secondary objective of this trial is to assess pharmacokinetics of DON over a range of doses. The open-label adult portion of the trial enrolls 40 healthy adults concurrently with 40 adults with uncomplicated malaria. Cohorts of 10 participants receive a single IV dose of DON with doses escalating between cohorts from 0.1 mg/kg, 1.0 mg/kg, 5.0 mg/kg, to 10 mg/kg. Following subsequent safety review, a randomized, double-blind, and placebo-controlled pediatric study enrolls 72 participants aged 6 months to 14 years with CM. The pediatric portion of the study minimally spans three malaria seasons including a planned interim analysis after 50% of pediatric enrollments. The first half of pediatric participants receive DON 0.1 mg/kg, 1.0 mg/kg, or placebo. Dosing for the second half of pediatric participants is informed by the safety and preliminary efficacy results of those previously enrolled. The pediatric portion of the study has an exploratory outcome evaluating the preliminary efficacy of DON. Efficacy is assessed by diagnostics predictive of CM outcome: electroencephalography (EEG), magnetic resonance imaging (MRI), and transcranial doppler (TCD), measured before and after DON administration. All participants with malaria receive standard of care antimalarials in accordance with local guidelines, regardless of study drug dose group. DISCUSSION: This preliminary safety and efficacy study evaluates DON, a candidate adjunctive therapy for pediatric CM. If results support DON preliminary safety and efficacy, follow-up phase II and III clinical trials will be indicated. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov on 28 July 2022 (NCT05478720).

Predicting Maternal and Infant Tetrahydrocannabinol Exposure in Lactating Cannabis Users: A Physiologically Based Pharmacokinetic Modeling Approach.

A knowledge gap exists in infant tetrahydrocannabinol (THC) data to guide breastfeeding recommendations for mothers who use cannabis. In the present study, a paired lactation and infant physiologically based pharmacokinetic (PBPK) model was developed and verified. The verified model was used to simulate one hundred virtual lactating mothers (mean age: 28 years, body weight: 78 kg) who smoked 0.32 g of cannabis containing 14.14% THC, either once or multiple times. The simulated breastfeeding conditions included one-hour post smoking and subsequently every three hours. The mean peak concentration (Cmax) and area under the concentration-time curve (AUC(0-24 h)) for breastmilk were higher than in plasma (Cmax: 155 vs. 69.9 ng/mL; AUC(0-24 h): 924.9 vs. 273.4 ng·hr/mL) with a milk-to-plasma AUC ratio of 3.3. The predicted relative infant dose ranged from 0.34% to 0.88% for infants consuming THC-containing breastmilk between birth and 12 months. However, the mother-to-infant plasma AUC(0-24 h) ratio increased up to three-fold (3.4-3.6) with increased maternal cannabis smoking up to six times. Our study demonstrated the successful development and application of a lactation and infant PBPK model for exploring THC exposure in infants, and the results can potentially inform breastfeeding recommendations.