The PHARMACOM-EPI framework for integrating pharmacometric modelling into pharmacoepidemiological research using real-world data: application to assess death associated with valproate
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The PHARMACOM-EPI framework for integrating pharmacometric modelling into pharmacoepidemiological research using real-world data : application to assess death associated with valproate. / Soeorg, Hiie; Sverrisdóttir, Eva; Andersen, Morten; Lund, Trine Meldgaard; Sessa, Maurizio.
I: Clinical Pharmacology and Therapeutics, Bind 111, Nr. 4, 2022, s. 840-856.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - The PHARMACOM-EPI framework for integrating pharmacometric modelling into pharmacoepidemiological research using real-world data
T2 - application to assess death associated with valproate
AU - Soeorg, Hiie
AU - Sverrisdóttir, Eva
AU - Andersen, Morten
AU - Lund, Trine Meldgaard
AU - Sessa, Maurizio
N1 - This article is protected by copyright. All rights reserved.
PY - 2022
Y1 - 2022
N2 - In pharmacoepidemiology, it is usually expected that the observed association should be directly or indirectly related to the pharmacological effects of the drug/s under investigation. Pharmacological effects are, in turn, strongly connected to the pharmacokinetic and pharmacodynamic properties of a drug, which can be characterized and investigated using pharmacometric models. Recently, the use of pharmacometrics has been proposed to provide pharmacological substantiation of pharmacoepidemiological findings derived from real-world data. However, validated frameworks suggesting how to combine these two disciplines for the aforementioned purpose are missing. Therefore, we propose PHARMACOM-EPI, a framework that provides a structured approach on how to identify, characterize, and apply pharmacometric models with practical details on how to choose software, format dataset, handle missing covariates/dosing data, how to perform the external evaluation of pharmacometric models in real-world data and how to provide pharmacological substantiation of pharmacoepidemiological findings. PHARMACOM-EPI was tested in a proof-of-concept study to pharmacologically substantiate death associated with valproate use in the Danish population aged ≥ 65 years. Pharmacological substantiation of death during a follow-up period of one year showed that in all individuals who died (n=169) individual predictions were within the subtherapeutic range compared with 52.8% of those who did not die (n=1084). Of individuals who died 66.3% (n=112) had a cause of death possibly related to valproate and 33.7% (n=57) with well-defined cause of death unlikely related to valproate. This proof-of-concept study showed that PHARMACOM-EPI was able to provide pharmacological substantiation for death associated with valproate use in the study population.
AB - In pharmacoepidemiology, it is usually expected that the observed association should be directly or indirectly related to the pharmacological effects of the drug/s under investigation. Pharmacological effects are, in turn, strongly connected to the pharmacokinetic and pharmacodynamic properties of a drug, which can be characterized and investigated using pharmacometric models. Recently, the use of pharmacometrics has been proposed to provide pharmacological substantiation of pharmacoepidemiological findings derived from real-world data. However, validated frameworks suggesting how to combine these two disciplines for the aforementioned purpose are missing. Therefore, we propose PHARMACOM-EPI, a framework that provides a structured approach on how to identify, characterize, and apply pharmacometric models with practical details on how to choose software, format dataset, handle missing covariates/dosing data, how to perform the external evaluation of pharmacometric models in real-world data and how to provide pharmacological substantiation of pharmacoepidemiological findings. PHARMACOM-EPI was tested in a proof-of-concept study to pharmacologically substantiate death associated with valproate use in the Danish population aged ≥ 65 years. Pharmacological substantiation of death during a follow-up period of one year showed that in all individuals who died (n=169) individual predictions were within the subtherapeutic range compared with 52.8% of those who did not die (n=1084). Of individuals who died 66.3% (n=112) had a cause of death possibly related to valproate and 33.7% (n=57) with well-defined cause of death unlikely related to valproate. This proof-of-concept study showed that PHARMACOM-EPI was able to provide pharmacological substantiation for death associated with valproate use in the study population.
U2 - 10.1002/cpt.2502
DO - 10.1002/cpt.2502
M3 - Journal article
C2 - 34860420
VL - 111
SP - 840
EP - 856
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
SN - 0009-9236
IS - 4
ER -
ID: 286848547