Identification of Cytochrome P450 Polymorphisms in Burn Patients and Impact on Fentanyl Pharmacokinetics: A Pilot Study

Kristin N Grimsrud, Xenia Ivanova, Catherine M. Sherwin, Tina L Palmieri, Nam Tran

Research output: Contribution to journalArticle

Abstract

Pain management is critical for burn care. Unfortunately, interindividual variation in pharmacokinetics (PK) due to burn hypermetabolism and genetic polymorphisms can lead to treatment failures in this at-risk population. Analgesics may be affected by genetic polymorphisms affecting cytochrome P450 (CYP) drug metabolizing enzymes. Fentanyl is a common opiate primarily metabolized by CYP3A4 subtypes. Recent studies demonstrate CYP2D6 variants, affecting fentanyl PK. Functional CYP polymorphisms can significantly alter opiate levels resulting in inadequate analgesia or life-threatening toxicity. The goal of our study was to evaluate fentanyl PK and assess associations with CYP polymorphisms. We obtained samples from the previously banked blood of 13 patients (eight males and five females) with >20% TBSA burns. Mean (SD) patient age was 41.7 (14.5) years, and mean burn size was 25.8 (15.3) %TBSA. Plasma fentanyl was quantified, and CYP genotyping was performed. Pharmacokinetic analysis was performed using Monolix software (Lixsoft, France) with a two-compartment population model best-representing fentanyl profiles. Three CYP slow-metabolizing genotypes were identified, which included CYP2D6*9, CYP2D6*29, and CYP3A4*1B. All three patients with variant polymorphisms had increased serum fentanyl concentrations due to impaired clearance. This pilot study supports the need for further research in this topic, and CYP genotyping of individual patients prior to receiving opiate analgesics to inform precision-guided decisions, improve therapeutic efficacy, and, most importantly, increase patient well-being and safety.

Original languageEnglish (US)
Pages (from-to)91-96
Number of pages6
JournalJournal of burn care & research : official publication of the American Burn Association
Volume40
Issue number1
DOIs
StatePublished - Jan 1 2019

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Fentanyl
Cytochrome P-450 Enzyme System
Opiate Alkaloids
Pharmacokinetics
Cytochrome P-450 CYP2D6
Cytochrome P-450 CYP3A
Genetic Polymorphisms
Analgesics
Pain Management
Critical Care
Treatment Failure
Burns
Analgesia
France
Software
Genotype
Safety
Enzymes
Serum
Research

ASJC Scopus subject areas

  • Surgery
  • Emergency Medicine
  • Rehabilitation

Cite this

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title = "Identification of Cytochrome P450 Polymorphisms in Burn Patients and Impact on Fentanyl Pharmacokinetics: A Pilot Study",
abstract = "Pain management is critical for burn care. Unfortunately, interindividual variation in pharmacokinetics (PK) due to burn hypermetabolism and genetic polymorphisms can lead to treatment failures in this at-risk population. Analgesics may be affected by genetic polymorphisms affecting cytochrome P450 (CYP) drug metabolizing enzymes. Fentanyl is a common opiate primarily metabolized by CYP3A4 subtypes. Recent studies demonstrate CYP2D6 variants, affecting fentanyl PK. Functional CYP polymorphisms can significantly alter opiate levels resulting in inadequate analgesia or life-threatening toxicity. The goal of our study was to evaluate fentanyl PK and assess associations with CYP polymorphisms. We obtained samples from the previously banked blood of 13 patients (eight males and five females) with >20{\%} TBSA burns. Mean (SD) patient age was 41.7 (14.5) years, and mean burn size was 25.8 (15.3) {\%}TBSA. Plasma fentanyl was quantified, and CYP genotyping was performed. Pharmacokinetic analysis was performed using Monolix software (Lixsoft, France) with a two-compartment population model best-representing fentanyl profiles. Three CYP slow-metabolizing genotypes were identified, which included CYP2D6*9, CYP2D6*29, and CYP3A4*1B. All three patients with variant polymorphisms had increased serum fentanyl concentrations due to impaired clearance. This pilot study supports the need for further research in this topic, and CYP genotyping of individual patients prior to receiving opiate analgesics to inform precision-guided decisions, improve therapeutic efficacy, and, most importantly, increase patient well-being and safety.",
author = "Grimsrud, {Kristin N} and Xenia Ivanova and Sherwin, {Catherine M.} and Palmieri, {Tina L} and Nam Tran",
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T1 - Identification of Cytochrome P450 Polymorphisms in Burn Patients and Impact on Fentanyl Pharmacokinetics

T2 - A Pilot Study

AU - Grimsrud, Kristin N

AU - Ivanova, Xenia

AU - Sherwin, Catherine M.

AU - Palmieri, Tina L

AU - Tran, Nam

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Pain management is critical for burn care. Unfortunately, interindividual variation in pharmacokinetics (PK) due to burn hypermetabolism and genetic polymorphisms can lead to treatment failures in this at-risk population. Analgesics may be affected by genetic polymorphisms affecting cytochrome P450 (CYP) drug metabolizing enzymes. Fentanyl is a common opiate primarily metabolized by CYP3A4 subtypes. Recent studies demonstrate CYP2D6 variants, affecting fentanyl PK. Functional CYP polymorphisms can significantly alter opiate levels resulting in inadequate analgesia or life-threatening toxicity. The goal of our study was to evaluate fentanyl PK and assess associations with CYP polymorphisms. We obtained samples from the previously banked blood of 13 patients (eight males and five females) with >20% TBSA burns. Mean (SD) patient age was 41.7 (14.5) years, and mean burn size was 25.8 (15.3) %TBSA. Plasma fentanyl was quantified, and CYP genotyping was performed. Pharmacokinetic analysis was performed using Monolix software (Lixsoft, France) with a two-compartment population model best-representing fentanyl profiles. Three CYP slow-metabolizing genotypes were identified, which included CYP2D6*9, CYP2D6*29, and CYP3A4*1B. All three patients with variant polymorphisms had increased serum fentanyl concentrations due to impaired clearance. This pilot study supports the need for further research in this topic, and CYP genotyping of individual patients prior to receiving opiate analgesics to inform precision-guided decisions, improve therapeutic efficacy, and, most importantly, increase patient well-being and safety.

AB - Pain management is critical for burn care. Unfortunately, interindividual variation in pharmacokinetics (PK) due to burn hypermetabolism and genetic polymorphisms can lead to treatment failures in this at-risk population. Analgesics may be affected by genetic polymorphisms affecting cytochrome P450 (CYP) drug metabolizing enzymes. Fentanyl is a common opiate primarily metabolized by CYP3A4 subtypes. Recent studies demonstrate CYP2D6 variants, affecting fentanyl PK. Functional CYP polymorphisms can significantly alter opiate levels resulting in inadequate analgesia or life-threatening toxicity. The goal of our study was to evaluate fentanyl PK and assess associations with CYP polymorphisms. We obtained samples from the previously banked blood of 13 patients (eight males and five females) with >20% TBSA burns. Mean (SD) patient age was 41.7 (14.5) years, and mean burn size was 25.8 (15.3) %TBSA. Plasma fentanyl was quantified, and CYP genotyping was performed. Pharmacokinetic analysis was performed using Monolix software (Lixsoft, France) with a two-compartment population model best-representing fentanyl profiles. Three CYP slow-metabolizing genotypes were identified, which included CYP2D6*9, CYP2D6*29, and CYP3A4*1B. All three patients with variant polymorphisms had increased serum fentanyl concentrations due to impaired clearance. This pilot study supports the need for further research in this topic, and CYP genotyping of individual patients prior to receiving opiate analgesics to inform precision-guided decisions, improve therapeutic efficacy, and, most importantly, increase patient well-being and safety.

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