Influence of CYP3A5 and ABCB1 polymorphisms on the pharmacokinetics of vincristine in adult patients receiving CHOP therapy

Purpose This study aims to clarify the impact of CYP3A5 and ABCB1 polymorphisms on the pharmacokinetics of vincristine (VCR) in adult patients receiving CHOP therapy. Methods Plasma samples were collected immediately after the end of VCR administration and at 1.5, 2.5, 3.5, 5.5, 9.5, 13.5, and 25.5 ...

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Published inCancer chemotherapy and pharmacology Vol. 92; no. 5; pp. 391 - 398
Main Authors Nakagawa, Junichi, Takahata, Takenori, Chen, Yu, Saito, Kensuke, Kamata, Kosuke, Tachita, Takuto, Yamashita, Satoru, Saito, Keigo, Ueno, Kayo, Sato, Atsushi, Sakuraba, Hirotake, Niioka, Takenori
Format Journal Article
LanguageEnglish
Published Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2023
Springer Nature B.V
Subjects
adults
Cancer Research
Gene polymorphism
genotype
half life
Medicine
Medicine & Public Health
Oncology
Original Article
Pharmacokinetics
Pharmacology/Toxicology
Regression analysis
therapeutics
Vincristine
polymorphism
Pharmacokinetics
Vincristine (VCR)
Adult patients
CHOP therapy
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Abstract Purpose This study aims to clarify the impact of CYP3A5 and ABCB1 polymorphisms on the pharmacokinetics of vincristine (VCR) in adult patients receiving CHOP therapy. Methods Plasma samples were collected immediately after the end of VCR administration and at 1.5, 2.5, 3.5, 5.5, 9.5, 13.5, and 25.5 h after the start of administration. Areas under the plasma concentration–time curves of VCR in the elimination phase (AUC 1.5–25.5 ) were calculated using the linear trapezoidal rule. Half-lives of VCR during the early phase (1.5–5.5 h) and terminal phase (5.5–25.5 h; t 1/2γ ) were determined according to the log-linear regression of the concentration–time data for at least 3 sampling points. Results A total of 41 adult patients were enrolled in this study. The median t 1/2γ and AUC 1.5–25.5 were significantly longer and higher in CYP3A5 non-expressers ( CYP3A5*3 / *3 ) than in CYP3A5 expressers ( CYP3A5*1 / *1 or *1 / *3 ) (21.3 vs 13.8 h, P  = 0.005 and 35.5 vs 30.0 ng･h/mL, P  = 0.006, respectively). Conversely, there were no significant differences in pharmacokinetic parameters among the ABCB1 c.1236C>T, c.2677G>A/T, c.3435C>T genotype groups. A stepwise selection multiple linear regression analysis showed that the dose of VCR administered and CYP3A5 non-expresser status were independent factors influencing the AUC 1.5–25.5 (partial R 2  = 0.212, P  = 0.002 and partial R 2  = 0.143, P  = 0.010, respectively). Conclusion The CYP3A5*3 polymorphism was found to be an indicator for predicting exposure to VCR in adult patients receiving CHOP therapy. This information may be useful for the individualization of VCR dosages.
AbstractList PURPOSE: This study aims to clarify the impact of CYP3A5 and ABCB1 polymorphisms on the pharmacokinetics of vincristine (VCR) in adult patients receiving CHOP therapy. METHODS: Plasma samples were collected immediately after the end of VCR administration and at 1.5, 2.5, 3.5, 5.5, 9.5, 13.5, and 25.5 h after the start of administration. Areas under the plasma concentration–time curves of VCR in the elimination phase (AUC₁.₅–₂₅.₅) were calculated using the linear trapezoidal rule. Half-lives of VCR during the early phase (1.5–5.5 h) and terminal phase (5.5–25.5 h; t₁/₂ᵧ) were determined according to the log-linear regression of the concentration–time data for at least 3 sampling points. RESULTS: A total of 41 adult patients were enrolled in this study. The median t₁/₂ᵧ and AUC₁.₅–₂₅.₅ were significantly longer and higher in CYP3A5 non-expressers (CYP3A5*3/*3) than in CYP3A5 expressers (CYP3A5*1/*1 or *1/*3) (21.3 vs 13.8 h, P = 0.005 and 35.5 vs 30.0 ng･h/mL, P = 0.006, respectively). Conversely, there were no significant differences in pharmacokinetic parameters among the ABCB1 c.1236C>T, c.2677G>A/T, c.3435C>T genotype groups. A stepwise selection multiple linear regression analysis showed that the dose of VCR administered and CYP3A5 non-expresser status were independent factors influencing the AUC₁.₅–₂₅.₅ (partial R² = 0.212, P = 0.002 and partial R² = 0.143, P = 0.010, respectively). CONCLUSION: The CYP3A5*3 polymorphism was found to be an indicator for predicting exposure to VCR in adult patients receiving CHOP therapy. This information may be useful for the individualization of VCR dosages.
Purpose This study aims to clarify the impact of CYP3A5 and ABCB1 polymorphisms on the pharmacokinetics of vincristine (VCR) in adult patients receiving CHOP therapy. Methods Plasma samples were collected immediately after the end of VCR administration and at 1.5, 2.5, 3.5, 5.5, 9.5, 13.5, and 25.5 h after the start of administration. Areas under the plasma concentration–time curves of VCR in the elimination phase (AUC 1.5–25.5 ) were calculated using the linear trapezoidal rule. Half-lives of VCR during the early phase (1.5–5.5 h) and terminal phase (5.5–25.5 h; t 1/2γ ) were determined according to the log-linear regression of the concentration–time data for at least 3 sampling points. Results A total of 41 adult patients were enrolled in this study. The median t 1/2γ and AUC 1.5–25.5 were significantly longer and higher in CYP3A5 non-expressers ( CYP3A5*3 / *3 ) than in CYP3A5 expressers ( CYP3A5*1 / *1 or *1 / *3 ) (21.3 vs 13.8 h, P  = 0.005 and 35.5 vs 30.0 ng･h/mL, P  = 0.006, respectively). Conversely, there were no significant differences in pharmacokinetic parameters among the ABCB1 c.1236C>T, c.2677G>A/T, c.3435C>T genotype groups. A stepwise selection multiple linear regression analysis showed that the dose of VCR administered and CYP3A5 non-expresser status were independent factors influencing the AUC 1.5–25.5 (partial R 2  = 0.212, P  = 0.002 and partial R 2  = 0.143, P  = 0.010, respectively). Conclusion The CYP3A5*3 polymorphism was found to be an indicator for predicting exposure to VCR in adult patients receiving CHOP therapy. This information may be useful for the individualization of VCR dosages.
PurposeThis study aims to clarify the impact of CYP3A5 and ABCB1 polymorphisms on the pharmacokinetics of vincristine (VCR) in adult patients receiving CHOP therapy.MethodsPlasma samples were collected immediately after the end of VCR administration and at 1.5, 2.5, 3.5, 5.5, 9.5, 13.5, and 25.5 h after the start of administration. Areas under the plasma concentration–time curves of VCR in the elimination phase (AUC1.5–25.5) were calculated using the linear trapezoidal rule. Half-lives of VCR during the early phase (1.5–5.5 h) and terminal phase (5.5–25.5 h; t1/2γ) were determined according to the log-linear regression of the concentration–time data for at least 3 sampling points.ResultsA total of 41 adult patients were enrolled in this study. The median t1/2γ and AUC1.5–25.5 were significantly longer and higher in CYP3A5 non-expressers (CYP3A5*3/*3) than in CYP3A5 expressers (CYP3A5*1/*1 or *1/*3) (21.3 vs 13.8 h, P = 0.005 and 35.5 vs 30.0 ng･h/mL, P = 0.006, respectively). Conversely, there were no significant differences in pharmacokinetic parameters among the ABCB1 c.1236C>T, c.2677G>A/T, c.3435C>T genotype groups. A stepwise selection multiple linear regression analysis showed that the dose of VCR administered and CYP3A5 non-expresser status were independent factors influencing the AUC1.5–25.5 (partial R2 = 0.212, P = 0.002 and partial R2 = 0.143, P = 0.010, respectively).ConclusionThe CYP3A5*3 polymorphism was found to be an indicator for predicting exposure to VCR in adult patients receiving CHOP therapy. This information may be useful for the individualization of VCR dosages.
This study aims to clarify the impact of CYP3A5 and ABCB1 polymorphisms on the pharmacokinetics of vincristine (VCR) in adult patients receiving CHOP therapy.PURPOSEThis study aims to clarify the impact of CYP3A5 and ABCB1 polymorphisms on the pharmacokinetics of vincristine (VCR) in adult patients receiving CHOP therapy.Plasma samples were collected immediately after the end of VCR administration and at 1.5, 2.5, 3.5, 5.5, 9.5, 13.5, and 25.5 h after the start of administration. Areas under the plasma concentration-time curves of VCR in the elimination phase (AUC1.5-25.5) were calculated using the linear trapezoidal rule. Half-lives of VCR during the early phase (1.5-5.5 h) and terminal phase (5.5-25.5 h; t1/2γ) were determined according to the log-linear regression of the concentration-time data for at least 3 sampling points.METHODSPlasma samples were collected immediately after the end of VCR administration and at 1.5, 2.5, 3.5, 5.5, 9.5, 13.5, and 25.5 h after the start of administration. Areas under the plasma concentration-time curves of VCR in the elimination phase (AUC1.5-25.5) were calculated using the linear trapezoidal rule. Half-lives of VCR during the early phase (1.5-5.5 h) and terminal phase (5.5-25.5 h; t1/2γ) were determined according to the log-linear regression of the concentration-time data for at least 3 sampling points.A total of 41 adult patients were enrolled in this study. The median t1/2γ and AUC1.5-25.5 were significantly longer and higher in CYP3A5 non-expressers (CYP3A5*3/*3) than in CYP3A5 expressers (CYP3A5*1/*1 or *1/*3) (21.3 vs 13.8 h, P = 0.005 and 35.5 vs 30.0 ng･h/mL, P = 0.006, respectively). Conversely, there were no significant differences in pharmacokinetic parameters among the ABCB1 c.1236C>T, c.2677G>A/T, c.3435C>T genotype groups. A stepwise selection multiple linear regression analysis showed that the dose of VCR administered and CYP3A5 non-expresser status were independent factors influencing the AUC1.5-25.5 (partial R2 = 0.212, P = 0.002 and partial R2 = 0.143, P = 0.010, respectively).RESULTSA total of 41 adult patients were enrolled in this study. The median t1/2γ and AUC1.5-25.5 were significantly longer and higher in CYP3A5 non-expressers (CYP3A5*3/*3) than in CYP3A5 expressers (CYP3A5*1/*1 or *1/*3) (21.3 vs 13.8 h, P = 0.005 and 35.5 vs 30.0 ng･h/mL, P = 0.006, respectively). Conversely, there were no significant differences in pharmacokinetic parameters among the ABCB1 c.1236C>T, c.2677G>A/T, c.3435C>T genotype groups. A stepwise selection multiple linear regression analysis showed that the dose of VCR administered and CYP3A5 non-expresser status were independent factors influencing the AUC1.5-25.5 (partial R2 = 0.212, P = 0.002 and partial R2 = 0.143, P = 0.010, respectively).The CYP3A5*3 polymorphism was found to be an indicator for predicting exposure to VCR in adult patients receiving CHOP therapy. This information may be useful for the individualization of VCR dosages.CONCLUSIONThe CYP3A5*3 polymorphism was found to be an indicator for predicting exposure to VCR in adult patients receiving CHOP therapy. This information may be useful for the individualization of VCR dosages.
Author Ueno, Kayo
Kamata, Kosuke
Nakagawa, Junichi
Tachita, Takuto
Yamashita, Satoru
Sakuraba, Hirotake
Saito, Kensuke
Chen, Yu
Sato, Atsushi
Takahata, Takenori
Saito, Keigo
Niioka, Takenori
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  organization: Department of Medical Oncology, Hirosaki University Graduate School of Medicine
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Issue 5
Keywords polymorphism
Pharmacokinetics
Vincristine (VCR)
Adult patients
CHOP therapy
Language English
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Springer Nature B.V
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Snippet Purpose This study aims to clarify the impact of CYP3A5 and ABCB1 polymorphisms on the pharmacokinetics of vincristine (VCR) in adult patients receiving CHOP...
PurposeThis study aims to clarify the impact of CYP3A5 and ABCB1 polymorphisms on the pharmacokinetics of vincristine (VCR) in adult patients receiving CHOP...
This study aims to clarify the impact of CYP3A5 and ABCB1 polymorphisms on the pharmacokinetics of vincristine (VCR) in adult patients receiving CHOP...
PURPOSE: This study aims to clarify the impact of CYP3A5 and ABCB1 polymorphisms on the pharmacokinetics of vincristine (VCR) in adult patients receiving CHOP...
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SubjectTerms adults
Cancer Research
Gene polymorphism
genotype
half life
Medicine
Medicine & Public Health
Oncology
Original Article
Pharmacokinetics
Pharmacology/Toxicology
Regression analysis
therapeutics
Vincristine
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Title Influence of CYP3A5 and ABCB1 polymorphisms on the pharmacokinetics of vincristine in adult patients receiving CHOP therapy
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