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 -