Pragmatic pharmacology: population pharmacokinetic analysis of fentanyl using remnant samples from children after cardiac surgery

Abstract

AIMSOne barrier contributing to the lack of pharmacokinetic (PK) data in paediatric populations is the need for serial sampling. Analysis of clinically obtained specimens and data may overcome this barrier. To add evidence for the feasibility of this approach, we sought to determine PK parameters for fentanyl in children after cardiac surgery using specimens and data generated in the course of clinical care, without collecting additional blood samples. METHODSWe measured fentanyl concentrations in plasma from leftover clinically-obtained specimens in 130 paediatric cardiac surgery patients and successfully generated a PK dataset using drug dosing data extracted from electronic medical records. Using a population PK approach, we estimated PK parameters for this population, assessed model goodness-of-fit and internal model validation, and performed subset data analyses. Through simulation studies, we compared predicted fentanyl concentrations using model-driven weight-adjusted per kg vs. fixed per kg fentanyl dosing. RESULTSFentanyl clearance for a 6.4 kg child, the median weight in our cohort, is 5.7 l h -1 (2.2-9.2 l h -1 ), similar to values found in prior formal PK studies. Model assessment and subset analyses indicated the model adequately fit the data. Of the covariates studied, only weight significantly impacted fentanyl kinetics, but substantial inter-individual variability remained. In simulation studies, model-driven weight-adjusted per kg fentanyl dosing led to more consistent therapeutic fentanyl concentrations than fixed per kg dosing. CONCLUSIONSWe show here that population PK modelling using sparse remnant samples and electronic medical records data provides a powerful tool for assessment of drug kinetics and generation of individualized dosing regimens.

Development of a System for Postmarketing Population Pharmacokinetic and Pharmacodynamic Studies Using Real‐World Data From Electronic Health Records

“…After all raw data files were extracted from the Vanderbilt EHRs, the final dataset was generated using the following modules: Pro‐Med‐Str, Pro‐Drug Level, Pro‐Laboratory, Pro‐Demographic, and Build‐PK‐IV. When we conducted the previous study with 130 subjects, it took >1 year to generate the final dataset for the analysis, whereas it took only about 2 weeks to prepare the final dataset with our new system. The major time‐determining step in using the system was data checking by the investigator for potential errors identified by the system.…”

“…dosing patterns. The raw dose data for fentanyl and dexmedetomidine were extracted from Vanderbilt Enterprise Data Warehouse . Additionally, other data required to perform PK/PD studies were obtained from the Vanderbilt EHRs for each cohort.…”

“…Build-PK-IV. When we conducted the previous study with 130 subjects, 11 it took >1 year to generate the final dataset for the analysis, whereas it took only about 2 weeks to prepare the final dataset with our new system. The major time-determining step in using the system was data checking by the investigator for potential errors identified by the system.…”

Correction to: Pharmacokinetics of Fentanyl and Its Derivatives in Children: A Comprehensive Review

“…Therefore, infants were not more prone to ventilatory depression than children or adults [35,36]. An opportunistic sampling strategy was applied in children after cardiac surgery, which proved that this technique is applicable to clinical routine because PK parameters were comparable to prior formal studies [37].…”

Analgesics and Sedatives in Critically Ill Newborns and Infants: The Impact on Long‐Term Neurodevelopment

“…[34][35][36][37] Two studies included only infants and children (range, 1 month to 4.5 years) with weight ranging between 3.7 kg and 17.3 kg. 38,39 Only one study included neonates, infants, children, and adolescents, although the total number of included subjects (n = 17) was limited. 36 Intravenous bolus administration was used in most studies (n = 5) followed by continuous infusion (n = 2), whereas 1 study only applied continuous infusion.…”