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Article ; Online: How to Rapidly Determine First-in-Children Dosing for COVID-19 Therapeutics.

Watt, Kevin M

2020 Volume 174, Issue 10, Page(s) e202435

MeSH term(s)	Betacoronavirus ; COVID-19 ; Child ; Coronavirus ; Coronavirus Infections ; Humans ; Pandemics ; Pneumonia, Viral ; SARS-CoV-2 ; Therapies, Investigational
Keywords	covid19
Language	English
Publishing date	2020-10-05
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	2701223-2
ISSN	2168-6211 ; 2168-6203
ISSN (online)	2168-6211
ISSN	2168-6203
DOI	10.1001/jamapediatrics.2020.2435
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Article: How to Rapidly Determine First-in-Children Dosing for COVID-19 Therapeutics

Watt, Kevin M

JAMA Pediatr

Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #32501513
Database	COVID19

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Article ; Online: How to Rapidly Determine First-in-Children Dosing for COVID-19 Therapeutics

Watt, Kevin M.

JAMA Pediatrics

2020 Volume 174, Issue 10, Page(s) e202435

Keywords	Pediatrics, Perinatology, and Child Health ; covid19
Language	English
Publisher	American Medical Association (AMA)
Publishing country	us
Document type	Article ; Online
ZDB-ID	2701223-2
ISSN	2168-6211 ; 2168-6203
ISSN (online)	2168-6211
ISSN	2168-6203
DOI	10.1001/jamapediatrics.2020.2435
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Medication patterns and dosing guidance in pediatric patients supported with intermittent hemodialysis or continuous kidney replacement therapy.

McKnite, Autumn M / Green, Danielle J / Nelson, Raoul / Brewer, Simon C / Watt, Kevin M

Pediatric nephrology (Berlin, Germany)

2023 Volume 39, Issue 5, Page(s) 1521–1532

Abstract: Background: Hemodialysis is a life-saving technology used during periods of acute or chronic kidney failure to remove toxins, and maintain fluid, electrolyte and metabolic balance. While this technology plays an important role for pediatric patients ... ...

Abstract	Background: Hemodialysis is a life-saving technology used during periods of acute or chronic kidney failure to remove toxins, and maintain fluid, electrolyte and metabolic balance. While this technology plays an important role for pediatric patients with kidney dysfunction, it can alter the pharmacokinetic behavior of medications placing patients at risk for suboptimal dosing and drug toxicity. The ability to directly translate pharmacokinetic alterations into dosing recommendations has thus far been limited and dosing guidance specific to pediatric hemodialysis patients is rare. Despite differences in dialysis prescription and patient populations, intermittent (iHD) and continuous kidney replacement therapy (CKRT) patients are often pooled together. In order to develop evidence-based dosing guidelines, it is important to first prioritize drugs for study in each modality. Methods: Here we aim to identify priority drugs in two hemodialysis modalities, through: 1) Identification of hospitalized, pediatric patients who received CKRT or intermittent hemodialysis (iHD) using a machine learning-based predictive model based on medications; 2) Identification of medication administration patterns in these patient cohorts; and 3) Identification of the most commonly prescribed drugs that lack published dosing guidance. Results: Notable differences were found in the pattern of medications and drug dosing guidance between iHD and CKRT patients. Antibiotics, diuretics and sedatives were more common in CKRT patients. Out of the 50 most commonly administered medications in the two modalities, only 34% and 28% had dosing guidance present for iHD and CKRT, respectively. Conclusions: Our results add to the understanding of the differences between iHD and CKRT patient populations by identifying commonly used medications that lack dosing guidance for each hemodialysis modality, helping to pinpoint priority medications for further study. Overall, this study provides an overview of the current limitations in medication use in this at-risk population, and provides a framework for future studies by identifying commonly used medications in pediatric CKRT and iHD patients.
MeSH term(s)	Child ; Humans ; Acute Kidney Injury/epidemiology ; Anti-Bacterial Agents/therapeutic use ; Continuous Renal Replacement Therapy ; Kidney Failure, Chronic/therapy ; Kidney Failure, Chronic/metabolism ; Pharmaceutical Preparations ; Renal Dialysis/methods ; Renal Replacement Therapy
Chemical Substances	Anti-Bacterial Agents ; Pharmaceutical Preparations
Language	English
Publishing date	2023-12-05
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	631932-4
ISSN	1432-198X ; 0931-041X
ISSN (online)	1432-198X
ISSN	0931-041X
DOI	10.1007/s00467-023-06199-z
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Article: Streamlining the Detection of Human Thyroid Receptor Ligand Interactions with XL1-Blue Cell-Free Protein Synthesis and Beta-Galactosidase Fusion Protein Biosensors.

Hunt, J Porter / Free, Tyler J / Galiardi, Jackelyn / Watt, Kevin M / Wood, David W / Bundy, Bradley C

Life (Basel, Switzerland)

2023 Volume 13, Issue 10

Abstract: Thyroid receptor signaling controls major physiological processes and disrupted signaling can cause severe disorders that negatively impact human life. Consequently, methods to detect thyroid receptor ligands are of great toxicologic and pharmacologic ... ...

Abstract	Thyroid receptor signaling controls major physiological processes and disrupted signaling can cause severe disorders that negatively impact human life. Consequently, methods to detect thyroid receptor ligands are of great toxicologic and pharmacologic importance. Previously, we reported thyroid receptor ligand detection with cell-free protein synthesis of a chimeric fusion protein composed of the human thyroid receptor beta (hTRβ) receptor activator and a β-lactamase reporter. Here, we report a 60% reduction in sensing cost by reengineering the chimeric fusion protein biosensor to include a reporter system composed of either the full-length beta galactosidase (β-gal), the alpha fragment of β-gal (β-gal-α), or a split alpha fragment of the β-gal (split β-gal-α). These biosensor constructs are deployed using
Language	English
Publishing date	2023-09-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662250-6
ISSN	2075-1729
ISSN	2075-1729
DOI	10.3390/life13101972
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Article: Cefepime Extraction by Extracorporeal Life Support Circuits.

Green, Danielle J / Watt, Kevin M / Fish, Douglas N / McKnite, Autumn / Kelley, Walter / Bensimhon, Adam R

The journal of extra-corporeal technology

2023 Volume 54, Issue 3, Page(s) 212–222

Abstract: Extracorporeal life support (ECLS) devices are lifesaving for critically ill patients with multi-organ dysfunction. Despite this, patients supported with ECLS are at high risk for ECLS-related complications, including nosocomial infections, and mortality ...

Abstract	Extracorporeal life support (ECLS) devices are lifesaving for critically ill patients with multi-organ dysfunction. Despite this, patients supported with ECLS are at high risk for ECLS-related complications, including nosocomial infections, and mortality rates are high in this patient population. The high mortality rates are suspected to be, in part, a result of significantly altered drug disposition by the ECLS circuit, resulting in suboptimal antimicrobial dosing. Cefepime is commonly used in critically ill patients with serious infections. Cefepime dosing is not routinely guided by therapeutic drug monitoring and treatment success is dependent upon the percentage of time of the dosing interval that the drug concentration remains above the minimum inhibitory concentration of the organism. This
MeSH term(s)	Humans ; Cefepime ; Extracorporeal Membrane Oxygenation/methods ; Critical Illness/therapy ; Renal Dialysis ; Hemofiltration
Chemical Substances	Cefepime (807PW4VQE3)
Language	English
Publishing date	2023-01-19
Publishing country	France
Document type	Journal Article
ZDB-ID	390977-3
ISSN	0022-1058
ISSN	0022-1058
DOI	10.1182/ject-212-222
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Article ; Online: Interaction of ceftazidime and clindamycin with extracorporeal life support.

Hunt, J Porter / McKnite, Autumn M / Green, Danielle J / Whelan, Aviva J / Imburgia, Carina E / Watt, Kevin M

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy

2023 Volume 29, Issue 12, Page(s) 1119–1125

Abstract: Background: Ceftazidime and clindamycin are commonly prescribed to critically ill patients who require extracorporeal life support such as ECMO and CRRT. The effect of ECMO and CRRT on the disposition of ceftazidime and clindamycin is currently unknown.! ...

Abstract	Background: Ceftazidime and clindamycin are commonly prescribed to critically ill patients who require extracorporeal life support such as ECMO and CRRT. The effect of ECMO and CRRT on the disposition of ceftazidime and clindamycin is currently unknown. Methods: Ceftazidime and clindamycin extraction were studied with ex vivo ECMO and CRRT circuits primed with human blood. The percent recovery of these drugs over time was calculated to determine the degree of interaction between these drugs and circuit components. Results: Neither ceftazidime nor clindamycin exhibited measurable interactions with the ECMO circuit. In contrast, CRRT cleared 100% of ceftazidime from the experimental circuit within the first 2 h. Clearance of clindamycin from the CRRT circuit was slower, with about 20% removed after 6 h. Conclusion: Clindamycin and ceftazidime dosing adjustments are likely required in patients who are supported with CRRT, and future studies to quantify these adjustments should consider the pathophysiology of the patient in combination with the clearance due to CRRT. Dosing adjustments to account for adsorption to ECMO circuit components are likely unnecessary and should focus instead on the pathophysiology of the patient and changes in volume of distribution. These results will help improve the safety and efficacy of ceftazidime and clindamycin in patients requiring ECMO and CRRT.
MeSH term(s)	Humans ; Renal Replacement Therapy/methods ; Extracorporeal Membrane Oxygenation/methods ; Ceftazidime/therapeutic use ; Clindamycin/therapeutic use ; Critical Illness
Chemical Substances	Ceftazidime (9M416Z9QNR) ; Clindamycin (3U02EL437C)
Language	English
Publishing date	2023-08-10
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1355399-9
ISSN	1437-7780 ; 1341-321X
ISSN (online)	1437-7780
ISSN	1341-321X
DOI	10.1016/j.jiac.2023.08.007
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Zs.A 5236: Show issues

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Article ; Online: Maximum likelihood estimation of renal transporter ontogeny profiles for pediatric PBPK modeling.

Hunt, J Porter / Dubinsky, Samuel / McKnite, Autumn M / Cheung, Kit Wun Kathy / van Groen, Bianca D / Giacomini, Kathleen M / de Wildt, Saskia N / Edginton, Andrea N / Watt, Kevin M

CPT: pharmacometrics & systems pharmacology

2024 Volume 13, Issue 4, Page(s) 576–588

Abstract: Optimal treatment of infants with many renally cleared drugs must account for maturational differences in renal transporter (RT) activity. Pediatric physiologically-based pharmacokinetic (PBPK) models may incorporate RT activity, but this requires ... ...

Abstract	Optimal treatment of infants with many renally cleared drugs must account for maturational differences in renal transporter (RT) activity. Pediatric physiologically-based pharmacokinetic (PBPK) models may incorporate RT activity, but this requires ontogeny profiles for RT activity in children, especially neonates, to predict drug disposition. Therefore, RT expression measurements from human kidney postmortem cortical tissue samples were normalized to represent a fraction of mature RT activity. Using these data, maximum likelihood estimated the distributions of RT activity across the pediatric age spectrum, including preterm and term neonates. PBPK models of four RT substrates (acyclovir, ciprofloxacin, furosemide, and meropenem) were evaluated with and without ontogeny profiles using average fold error (AFE), absolute average fold error (AAFE), and proportion of observations within the 5-95% prediction interval. Novel maximum likelihood profiles estimated ontogeny distributions for the following RT: OAT1, OAT3, OCT2, P-gp, URAT1, BCRP, MATE1, MRP2, MRP4, and MATE-2 K. Profiles for OAT3, P-gp, and MATE1 improved infant furosemide and neonate meropenem PBPK model AFE from 0.08 to 0.70 and 0.53 to 1.34 and model AAFE from 12.08 to 1.44 and 2.09 to 1.36, respectively, and improved the percent of data within the 5-95% prediction interval from 48% to 98% for neonatal ciprofloxacin simulations, respectively. Even after accounting for other critical population-specific maturational differences, novel RT ontogeny profiles substantially improved neonatal PBPK model performance, providing validated estimates of maturational differences in RT activity for optimal dosing in children.
MeSH term(s)	Infant ; Infant, Newborn ; Child ; Humans ; Likelihood Functions ; Meropenem ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Furosemide ; Neoplasm Proteins ; Models, Biological ; Ciprofloxacin
Chemical Substances	Meropenem (FV9J3JU8B1) ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Furosemide (7LXU5N7ZO5) ; Neoplasm Proteins ; Ciprofloxacin (5E8K9I0O4U)
Language	English
Publishing date	2024-01-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.13102
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Article ; Online: Anakinra Removal by Continuous Renal Replacement Therapy: An Ex Vivo Analysis.

Dubinsky, Samuel D J / Watt, Kevin M / Imburgia, Carina E / Mcknite, Autumn M / Hunt, J Porter / Rice, Cassandra / Rower, Joseph E / Edginton, Andrea N

Critical care explorations

2023 Volume 5, Issue 12, Page(s) e1010

Abstract: Objectives: Patients with sepsis are at significant risk for multiple organ dysfunction, including the lungs and kidneys. To manage the morbidity associated with kidney impairment, continuous renal replacement therapy (CRRT) may be required. The extent ... ...

Abstract	Objectives: Patients with sepsis are at significant risk for multiple organ dysfunction, including the lungs and kidneys. To manage the morbidity associated with kidney impairment, continuous renal replacement therapy (CRRT) may be required. The extent of anakinra pharmacokinetics in CRRT remains unknown. The objectives of this study were to investigate the anakinra-circuit interaction and quantify the rate of removal from plasma. Design: The anakinra-circuit interaction was evaluated using a closed-loop ex vivo CRRT circuit. CRRT was performed in three phases based on the method of solute removal: 1) hemofiltration, 2) hemodialysis, and 3) hemodiafiltration. Standard control samples of anakinra were included to assess drug degradation. Setting: University research laboratory. Patients: None. Interventions: Anakinra was administered to the CRRT circuit and serial prefilter blood samples were collected along with time-matched control and hemofiltrate samples. Each circuit was run in triplicate to assess inter-run variability. Concentrations of anakinra in each reference fluid were measured by enzyme-linked immunosorbent assay. Transmembrane filter clearance was estimated by the product of the sieving coefficient/dialysate saturation constant and circuit flow rates. Measurements and main results: Removal of anakinra from plasma occurred within minutes for each CRRT modality. Average drug remaining (%) in plasma following anakinra administration was lowest with hemodiafiltration (34.9%). The average sieving coefficient was 0.34, 0.37, and 0.41 for hemodiafiltration, hemofiltration, and hemodialysis, respectively. Transmembrane clearance was fairly consistent across each modality with the highest during hemodialysis (5.53 mL/min), followed by hemodiafiltration (4.99 mL/min), and hemofiltration (3.94 mL/min). Percent drug remaining within the control samples (93.1%) remained consistent across each experiment, indicating negligible degradation within the blood. Conclusions: The results of this analysis are the first to demonstrate that large molecule therapeutic proteins such as anakinra, are removed from plasma with modern CRRT technology. Current dosing recommendations for patients with severe renal impairment may result in subtherapeutic anakinra concentrations in those receiving CRRT.
Language	English
Publishing date	2023-12-14
Publishing country	United States
Document type	Journal Article
ISSN	2639-8028
ISSN (online)	2639-8028
DOI	10.1097/CCE.0000000000001010
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Article: The Design of Nested Adaptive Clinical Trials of Multiple Organ Dysfunction Syndrome Children in a Single Study.

VanBuren, John M / Hall, Mark / Zuppa, Athena F / Mourani, Peter M / Carcillo, Joseph / Dean, J Michael / Watt, Kevin / Holubkov, Richard

Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

2023 Volume 24, Issue 12, Page(s) e635–e646

Abstract: Objectives: Describe the statistical design of the Personalized Immunomodulation in Sepsis-induced Multiple Organ Dysfunction Syndrome (MODS) (PRECISE) study.: Design: Children with sepsis-induced MODS undergo real-time immune testing followed by ... ...

Abstract	Objectives: Describe the statistical design of the Personalized Immunomodulation in Sepsis-induced Multiple Organ Dysfunction Syndrome (MODS) (PRECISE) study. Design: Children with sepsis-induced MODS undergo real-time immune testing followed by assignment to an immunophenotype-specific study cohort. Interventional cohorts include the granulocyte macrophage-colony stimulating factor (GM-CSF) for the Reversal of Immunoparalysis in Pediatric Sepsis-induced MODS (GRACE)-2 trial, which uses the drug GM-CSF (or placebo) to reverse immunoparalysis; and the Targeted Reversal of Inflammation in Pediatric Sepsis-induced MODS (TRIPS) trial, which uses the drug anakinra (or placebo) to reverse systemic inflammation. Both trials have adaptive components and use a statistical framework in which frequent data monitoring assesses futility and efficacy, allowing potentially earlier stopping than traditional approaches. Prespecified simulation-based stopping boundaries are customized to each trial to preserve an overall one-sided type I error rate. The TRIPS trial also uses response-adaptive randomization, updating randomization allocation proportions to favor active arms that appear more efficacious based on accumulating data. Setting: Twenty-four U.S. academic PICUs. Patients: Septic children with specific immunologic derangements during ongoing dysfunction of at least two organs. Interventions: The GRACE-2 trial compares GM-CSF and placebo in children with immunoparalysis. The TRIPS trial compares four different doses of anakinra to placebo in children with moderate to severe systemic inflammation. Measurements and main results: Both trials assess primary efficacy using the sum of the daily pediatric logistic organ dysfunction-2 score over 28 days. Ranked summed scores, with mortality assigned the worst possible value, are compared between arms using the Wilcoxon Rank Sum test (GRACE-2) and a dose-response curve (TRIPS). We present simulation-based operating characteristics under several scenarios to demonstrate the behavior of the adaptive design. Conclusions: The adaptive design incorporates innovative statistical features that allow for multiple active arms to be compared with placebo based on a child's personal immunophenotype. The design increases power and provides optimal operating characteristics compared with traditional conservative methods.
MeSH term(s)	Humans ; Child ; Multiple Organ Failure/etiology ; Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use ; Interleukin 1 Receptor Antagonist Protein/therapeutic use ; Sepsis/complications ; Sepsis/drug therapy ; Inflammation
Chemical Substances	Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1) ; Interleukin 1 Receptor Antagonist Protein
Language	English
Publishing date	2023-07-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2052349-X
ISSN	1947-3893 ; 1529-7535
ISSN (online)	1947-3893
ISSN	1529-7535
DOI	10.1097/PCC.0000000000003332
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