Prediction of Drug Exposure in Critically Ill Encephalopathic Neonates Treated With Therapeutic Hypothermia Based on a Pooled Population Pharmacokinetic Analysis of Seven Drugs and Five Metabolites

Abstract

Drug dosing in encephalopathic neonates treated with therapeutic hypothermia is challenging; exposure is dependent on body size and maturation but can also be influenced by factors related to disease and treatment. A better understanding of underlying pharmacokinetic principles is essential to guide drug dosing in this population. The prospective multicenter cohort study PharmaCool was designed to investigate the pharmacokinetics of commonly used drugs in neonatal encephalopathy. In the present study, all data obtained in the PharmaCool study were combined to study the structural system specific effects of body size, maturation, recovery of organ function, and temperature on drug clearance using nonlinear mixed effects modeling. Data collected during the first 5 days of life from 192 neonates treated with therapeutic hypothermia were included. An integrated population pharmacokinetic model of seven drugs (morphine, midazolam, lidocaine, phenobarbital, amoxicillin, gentamicin, and benzylpenicillin) and five metabolites (morphine‐3‐glucuronide, morphine‐6‐glucuronide, 1‐hydroxymidazolam, hydroxymidazolam glucuronide, and monoethylglycylxylidide) was successfully developed based on previously developed models for the individual drugs. For all compounds, body size was related to clearance using allometric relationships and maturation was described with gestational age in a fixed sigmoidal Hill equation. Organ recovery after birth was incorporated using postnatal age. Clearance increased by 1.23%/hours of life (95% confidence interval (CI) 1.03–1.43) and by 0.54%/hours of life (95% CI 0.371–0.750) for high and intermediate clearance compounds, respectively. Therapeutic hypothermia reduced clearance of intermediate clearance compounds only, by 6.83%/°C (95% CI 5.16%/°C–8.34%/°C). This integrated model can be used to facilitate drug dosing and future pharmacokinetic studies in this population.

Creatinine Trends and Patterns in Neonates Undergoing Whole Body Hypothermia: A Systematic Review

“…Renal elimination was reduced (from −25% up to −40%), as reflected by the reduced gentamicin clearance by 25-35.3% with a progressive trend to normalization after termination of WBH (>72 h after initiation of WBH). A similar pattern of decreased clearance (−40%) has been described for amikacin during WBH, or even up to −60% when these estimates were based on mannitol clearance data [22][23][24][25][26].…”

Glomerular Filtration Rate in Asphyxiated Neonates Under Therapeutic Whole-Body Hypothermia, Quantified by Mannitol Clearance

“…Although the OFV did not drop to a statistically significant extent, the unexplained variability on CL did decrease from 1.41 to 1.27 (16%). Furthermore, various studies have previously shown that TH affects renal CL in neonates [ 16 , 17 ]. Based on these observations, we decided to include TH as a covariate on CL.…”

“…The significance of the covariates was statistically tested using a stepwise covariate method involving testing of covariate relationships in a forward inclusion (reduction of OFV of 6.63; p < 0.01) and backward exclusion (reduction of OFV of 10.8; p < 0.001) [ 15 ]. Furthermore, some covariates (i.e., GA on CL, BW on CL, and TH on CL) were included into the final model based on scientific plausibility and prior knowledge [ 16 – 18 ].…”

Pharmacokinetics of Antibiotics in Pediatric Intensive Care: Fostering Variability to Attain Precision Medicine

“…However, hypoxic ischemic asphyxia and lowering the core body temperature affects PK, up to the level that dosing regimens for this specific setting should be adapted. A significant decrease in CL is observed in neonates during therapeutic hypothermia, be it that the extent differs between routes of elimination and compounds, but is most pronounced for renal elimination [157,158]. Based on a systematic review on SCr trends and patterns in neonates undergoing WBH, the impact on renal elimination is most relevant in the first days of life, so during WBH (used in the first 3 days of postnatal life) [159].…”