Impact of Inaccurate Documentation of Sampling and Infusion Time in Model-Informed Precision Dosing.
caspofungin
documentation
infusion rate
meropenem
precision dosing
sampling time
therapeutic drug monitoring
uncertainty
Journal
Frontiers in pharmacology
ISSN: 1663-9812
Titre abrégé: Front Pharmacol
Pays: Switzerland
ID NLM: 101548923
Informations de publication
Date de publication:
2020
2020
Historique:
received:
15
11
2019
accepted:
07
02
2020
entrez:
21
3
2020
pubmed:
21
3
2020
medline:
21
3
2020
Statut:
epublish
Résumé
Routine clinical TDM data is often used to develop population pharmacokinetic (PK) models, which are applied in turn for model-informed precision dosing. The impact of uncertainty in documented sampling and infusion times in population PK modeling and model-informed precision dosing have not yet been systematically evaluated. The aim of this study was to investigate uncertain documentation of (i) sampling times and (ii) infusion rate exemplified with two anti-infectives. A stochastic simulation and estimation study was performed in NONMEM On the population level, the estimates of the proportional residual error (prop.-err.) and the interindividual variability (IIV) on the central volume of distribution (V1) were most affected by erroneous records in the sampling and infusion time (e.g. rBias of prop.-err.: 75.5% vs. 183% (meropenem) and 10.1% vs. 109% (caspofungin) for ± 5 vs. ± 30 min, respectively). On the individual level, the rBias of the planned scenario for the typical values V1, Q and V2 increased with increasing uncertainty in time, while CL, AUC and elimination half-life were least affected. Meropenem as a short half-life drug (~1 h) was more affected than caspofungin (~ 9-11 h). The misspecified model provided biased PK/PD target information (e.g. falsely overestimated time above MIC (T > MIC) when true T > MIC was <0.4 and thus patients at risk of undertreatment), while the accurate model gave precise estimates of the indices across all simulated patients. Even 5-minute-uncertainties caused bias and significant imprecision of primary population and individual PK parameters. Thus, our results underline the importance of accurate documentation of time.
Sections du résumé
BACKGROUND
BACKGROUND
Routine clinical TDM data is often used to develop population pharmacokinetic (PK) models, which are applied in turn for model-informed precision dosing. The impact of uncertainty in documented sampling and infusion times in population PK modeling and model-informed precision dosing have not yet been systematically evaluated. The aim of this study was to investigate uncertain documentation of (i) sampling times and (ii) infusion rate exemplified with two anti-infectives.
METHODS
METHODS
A stochastic simulation and estimation study was performed in NONMEM
RESULTS
RESULTS
On the population level, the estimates of the proportional residual error (prop.-err.) and the interindividual variability (IIV) on the central volume of distribution (V1) were most affected by erroneous records in the sampling and infusion time (e.g. rBias of prop.-err.: 75.5% vs. 183% (meropenem) and 10.1% vs. 109% (caspofungin) for ± 5 vs. ± 30 min, respectively). On the individual level, the rBias of the planned scenario for the typical values V1, Q and V2 increased with increasing uncertainty in time, while CL, AUC and elimination half-life were least affected. Meropenem as a short half-life drug (~1 h) was more affected than caspofungin (~ 9-11 h). The misspecified model provided biased PK/PD target information (e.g. falsely overestimated time above MIC (T > MIC) when true T > MIC was <0.4 and thus patients at risk of undertreatment), while the accurate model gave precise estimates of the indices across all simulated patients.
CONCLUSIONS
CONCLUSIONS
Even 5-minute-uncertainties caused bias and significant imprecision of primary population and individual PK parameters. Thus, our results underline the importance of accurate documentation of time.
Identifiants
pubmed: 32194411
doi: 10.3389/fphar.2020.00172
pmc: PMC7063976
doi:
Types de publication
Journal Article
Langues
eng
Pagination
172Informations de copyright
Copyright © 2020 Alihodzic, Broeker, Baehr, Kluge, Langebrake and Wicha.
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