Pharmacokinetics during therapeutic hypothermia in neonates: from pathophysiology to translational knowledge and physiologically-based pharmacokinetic (PBPK) modeling

Leys, Karen; Stroe, Marina-Stefania; Annaert, Pieter; Van Cruchten, Steven; Carpentier, Sebastien; Allegaert, Karel; Smits, Anne

doi:10.1080/17425255.2023.2237412

Cited by 4 publications

(5 citation statements)

References 144 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The similarities between pigs and humans in anatomy and physiology, including drug metabolising enzymes, suggest pigs are well suited to predicting the PK profile in humans. 36 Melatonin is metabolised by the hepatic CYP450 system 37 and renally cleared, 38 processes which may be affected by the systemic HI injury. The volume of drug distribution in this term-equivalent piglet study was similar to that in a study of intravenous melatonin administration to preterm infants by Merchant et al, 39 although the half-life in piglets (10.2 h) was shorter than preterm babies (16.9 h).…”

Section: Discussionmentioning

confidence: 99%

“…The population‐PK parameters following intravenous melatonin administration are not well characterised in the target population of term infants with NE. The similarities between pigs and humans in anatomy and physiology, including drug metabolising enzymes, suggest pigs are well suited to predicting the PK profile in humans 36 . Melatonin is metabolised by the hepatic CYP450 system 37 and renally cleared, 38 processes which may be affected by the systemic HI injury.…”

Section: Discussionmentioning

confidence: 99%

“…Melatonin, ethanol and acetaldehyde concentrations were measured on serum and brain tissue samples by NovoLytiX GmbH (see Supporting Information). For melatonin and ethanol pharmacokinetic analysis, serum blood samples were taken at 1, 1.5, 2, 3, 7, 13,24,25,26,30,36,48,49,50,54,60,62 and 65 h after HI.…”

Section: Biochemical Assaysmentioning

confidence: 99%

See 2 more Smart Citations

Melatonin reduces brain injury following inflammation‐amplified hypoxia–ischemia in a translational newborn piglet study of neonatal encephalopathy

Pang,

Meehan,

Maple

et al. 2024

Journal of Pineal Research

View full text Add to dashboard Cite

There is a need to develop therapies for neonatal encephalopathy (NE) in low‐ and middle‐income countries (LMICs) where the burden of disease is greatest and therapeutic hypothermia (HT) is not effective. We aimed to assess the efficacy of melatonin following inflammation‐amplified hypoxia–ischaemia (IA‐HI) in the newborn piglet. The IA‐HI model accounts for the contribution of infection/inflammation in this setting and HT is not cytoprotective. We hypothesised that intravenous melatonin (5% ethanol, at 20 mg/kg over 2 h at 1 h after HI + 10 mg/kg/12 h between 24 and 60 h) is safe and associated with: (i) reduction in magnetic resonance spectroscopy lactate/N‐acetylaspartate (MRS Lac/sNAA); (ii) preservation of phosphorus MRS phosphocreatine/phosphate exchange pool (PCr/Epp); (iii) improved aEEG/EEG recovery and (iv) cytoprotection on immunohistochemistry. Male and female piglets underwent IA‐HI by carotid artery occlusion and reduction in FiO2 to 6% at 4 h into Escherichia coli lipopolysaccharide sensitisation (2 μg/kg bolus + 1 μg/kg/h over 12 h). At 1 h after IA‐HI, piglets were randomised to HI‐saline (n = 12) or melatonin (n = 11). There were no differences in insult severity between groups. Target melatonin levels (15–30 mg/L) were achieved within 3 h and blood ethanol levels were <0.25 g/L. At 60 h, compared to HI‐saline, melatonin was associated with a reduction of 0.197 log10 units (95% CrI [−0.366, −0.028], Pr(sup) 98.8%) in basal‐ganglia and thalamic Lac/NAA, and 0.257 (95% CrI [−0.676, 0.164], Pr(sup) 89.3%) in white matter Lac/NAA. PCr/Epp was higher in melatonin versus HI‐saline (Pr(sup) 97.6%). Melatonin was associated with earlier aEEG/EEG recovery from 19 to 24 h (Pr(sup) 95.4%). Compared to HI‐saline, melatonin was associated with increased NeuN+ cell density (Pr(sup) 99.3%) across five of eight regions and reduction in TUNEL‐positive cell death (Pr(sup) 89.7%). This study supports the translation of melatonin to early‐phase clinical trials. Melatonin is protective following IA‐HI where HT is not effective. These data guide the design of future dose‐escalation studies in the next phase of the translational pipeline.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Melatonin reduces brain injury following inflammation‐amplified hypoxia–ischemia in a translational newborn piglet study of neonatal encephalopathy

Pang,

Meehan,

Maple

et al. 2024

Journal of Pineal Research

View full text Add to dashboard Cite

show abstract

“…In this context and considering all the different variables, every effort should be made to design optimal therapeutic protocols for all diseases, which could be individualised for each patient within the context of personalised medicine. In particular, this approach should be considered where variations in drug response are measurable, such as, for example, drug absorption, distribution, metabolism and elimination (ADME) parameters [26][27][28][29] and also for toxicity such as drug allergy or other drug reactions or interactions [29][30][31][32][33][34]. Furthermore, the availability of alternative drugs should also be an option for patients with low response and/or toxicity to a particular leading drug for a specific disease [35][36][37][38][39][40].…”

Section: Introductionmentioning

confidence: 99%

Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs

Kontoghiorghes

2023

IJMS

View full text Add to dashboard Cite

The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols could ideally be designed in all diseases including for millions of patients affected by excess iron deposition (EID) toxicity based on personalised medicine parameters, as well as many variations and limitations. EID is an adverse prognostic factor for all diseases and especially for millions of chronically red-blood-cell-transfused patients. Differences in iron chelation therapy posology cause disappointing results in neurodegenerative diseases at low doses, but lifesaving outcomes in thalassemia major (TM) when using higher doses. In particular, the transformation of TM from a fatal to a chronic disease has been achieved using effective doses of oral deferiprone (L1), which improved compliance and cleared excess toxic iron from the heart associated with increased mortality in TM. Furthermore, effective L1 and L1/deferoxamine combination posology resulted in the complete elimination of EID and the maintenance of normal iron store levels in TM. The selection of effective chelation protocols has been monitored by MRI T2* diagnosis for EID levels in different organs. Millions of other iron-loaded patients with sickle cell anemia, myelodysplasia and haemopoietic stem cell transplantation, or non-iron-loaded categories with EID in different organs could also benefit from such chelation therapy advances. Drawbacks of chelation therapy include drug toxicity in some patients and also the wide use of suboptimal chelation protocols, resulting in ineffective therapies. Drug metabolic effects, and interactions with other metals, drugs and dietary molecules also affected iron chelation therapy. Drug selection and the identification of effective or optimal dose protocols are essential for positive therapeutic outcomes in the use of chelating drugs in TM and other iron-loaded and non-iron-loaded conditions, as well as general iron toxicity.

show abstract

“…Such real-world data (RWD) are relevant to calculate the expected Vd (absolute value, L) and its variability and may assist to develop drug dosing regimens specific to this population and its variability. Similar efforts can be considered for other PK relevant variables, like kidney function, cardiac output and regional blood flow, or blood/plasma composition [ 7 ].…”

mentioning

confidence: 99%

Interdisciplinary Collaboration on Real World Data to Close the Knowledge Gap: A Reflection on “De Sutter et al. Predicting Volume of Distribution in Neonates: Performance of Physiologically Based Pharmacokinetic Modelling”

Allegaert,

Smits,

Annaert

2024

Pharmaceutics

Self Cite

View full text Add to dashboard Cite

This commentary further reflects on the paper of De Sutter et al. on predicting volume of distribution in neonates, and the performance of physiologically based pharmacokinetic models We hereby stressed the add on value to collaborate on real world data to further close this knowledge gap. We illustrated this by weight distribution characteristics in breastfed (physiology) and in asphyxiated (pathophysiology), with additional reflection on their kidney and liver function.

show abstract

Pharmacokinetics during therapeutic hypothermia in neonates: from pathophysiology to translational knowledge and physiologically-based pharmacokinetic (PBPK) modeling

Cited by 4 publications

References 144 publications

Melatonin reduces brain injury following inflammation‐amplified hypoxia–ischemia in a translational newborn piglet study of neonatal encephalopathy

Melatonin reduces brain injury following inflammation‐amplified hypoxia–ischemia in a translational newborn piglet study of neonatal encephalopathy

Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs

Interdisciplinary Collaboration on Real World Data to Close the Knowledge Gap: A Reflection on “De Sutter et al. Predicting Volume of Distribution in Neonates: Performance of Physiologically Based Pharmacokinetic Modelling”

Contact Info

Product

Resources

About