Population pharmacokinetics and pharmacogenetics of once daily tacrolimus formulation in stable liver transplant recipients

D J A R Moes, S A S van der Bent, J J Swen, T van der Straaten, A Inderson, E Olofsen, H W Verspaget, H J Guchelaar, J den Hartigh, B van Hoek

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

PURPOSE: The once daily formulation of tacrolimus is an important immunosuppressive drug. Interpatient variability in metabolism has been related to genetic variation in CYP3A4 and CYP3A5. However, in liver transplantation, both donor and recipient genotypes may affect pharmacokinetics. The primary objective of this study was to investigate the effect of CYP3A4*22 and CYP3A5*3 of both donor and recipient on once daily tacrolimus pharmacokinetics. The secondary objective was to develop a limited sampling model able to accurately predict exposure.

METHODS: Stable liver transplant patients receiving once daily tacrolimus (N = 66) were included. Population pharmacokinetic analysis was performed with patients of whom DNA was available (N = 49), and demographic factors, CYP3A4*22 and CYP3A5*3, were tested as covariates. Moreover, a limited sampling model was developed using data of 66 patients.

RESULTS: Pharmacokinetics was best described by a two-compartment model with delayed absorption. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 carrying liver had an average 1.7-fold higher clearance compared to non-carriers. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 non-carrying liver or vice versa showed an average 1.3-fold higher clearance compared with non-carriers. CYP3A4*22 was not significantly associated with once daily tacrolimus pharmacokinetics. Using 0, 2, and 3 h postdose as limited sampling model resulted in significantly improved prediction of tacrolimus exposure compared with trough concentration.

CONCLUSIONS: Both donor and recipient CYP3A5 genotype significantly influences tacrolimus once daily pharmacokinetics. In contrast, CYP3A4*22 appears not suitable as biomarker. The developed limited sampling model can be used to accurately estimate tacrolimus once daily exposure.

Original languageEnglish
Pages (from-to)163-74
Number of pages12
JournalEuropean Journal of Clinical Pharmacology
Volume72
Issue number2
DOIs
Publication statusPublished - Feb 2016

Cite this

Moes, D J A R ; van der Bent, S A S ; Swen, J J ; van der Straaten, T ; Inderson, A ; Olofsen, E ; Verspaget, H W ; Guchelaar, H J ; den Hartigh, J ; van Hoek, B. / Population pharmacokinetics and pharmacogenetics of once daily tacrolimus formulation in stable liver transplant recipients. In: European Journal of Clinical Pharmacology. 2016 ; Vol. 72, No. 2. pp. 163-74.
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title = "Population pharmacokinetics and pharmacogenetics of once daily tacrolimus formulation in stable liver transplant recipients",
abstract = "PURPOSE: The once daily formulation of tacrolimus is an important immunosuppressive drug. Interpatient variability in metabolism has been related to genetic variation in CYP3A4 and CYP3A5. However, in liver transplantation, both donor and recipient genotypes may affect pharmacokinetics. The primary objective of this study was to investigate the effect of CYP3A4*22 and CYP3A5*3 of both donor and recipient on once daily tacrolimus pharmacokinetics. The secondary objective was to develop a limited sampling model able to accurately predict exposure.METHODS: Stable liver transplant patients receiving once daily tacrolimus (N = 66) were included. Population pharmacokinetic analysis was performed with patients of whom DNA was available (N = 49), and demographic factors, CYP3A4*22 and CYP3A5*3, were tested as covariates. Moreover, a limited sampling model was developed using data of 66 patients.RESULTS: Pharmacokinetics was best described by a two-compartment model with delayed absorption. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 carrying liver had an average 1.7-fold higher clearance compared to non-carriers. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 non-carrying liver or vice versa showed an average 1.3-fold higher clearance compared with non-carriers. CYP3A4*22 was not significantly associated with once daily tacrolimus pharmacokinetics. Using 0, 2, and 3 h postdose as limited sampling model resulted in significantly improved prediction of tacrolimus exposure compared with trough concentration.CONCLUSIONS: Both donor and recipient CYP3A5 genotype significantly influences tacrolimus once daily pharmacokinetics. In contrast, CYP3A4*22 appears not suitable as biomarker. The developed limited sampling model can be used to accurately estimate tacrolimus once daily exposure.",
keywords = "Adult, Aged, Cytochrome P-450 CYP3A, Drug Administration Schedule, Female, Genotype, Humans, Immunosuppressive Agents, Liver Transplantation, Male, Middle Aged, Models, Biological, Tacrolimus, Tissue Donors, Clinical Trial, Journal Article",
author = "Moes, {D J A R} and {van der Bent}, {S A S} and Swen, {J J} and {van der Straaten}, T and A Inderson and E Olofsen and Verspaget, {H W} and Guchelaar, {H J} and {den Hartigh}, J and {van Hoek}, B",
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Moes, DJAR, van der Bent, SAS, Swen, JJ, van der Straaten, T, Inderson, A, Olofsen, E, Verspaget, HW, Guchelaar, HJ, den Hartigh, J & van Hoek, B 2016, 'Population pharmacokinetics and pharmacogenetics of once daily tacrolimus formulation in stable liver transplant recipients' European Journal of Clinical Pharmacology, vol. 72, no. 2, pp. 163-74. https://doi.org/10.1007/s00228-015-1963-3

Population pharmacokinetics and pharmacogenetics of once daily tacrolimus formulation in stable liver transplant recipients. / Moes, D J A R; van der Bent, S A S; Swen, J J; van der Straaten, T; Inderson, A; Olofsen, E; Verspaget, H W; Guchelaar, H J; den Hartigh, J; van Hoek, B.

In: European Journal of Clinical Pharmacology, Vol. 72, No. 2, 02.2016, p. 163-74.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Population pharmacokinetics and pharmacogenetics of once daily tacrolimus formulation in stable liver transplant recipients

AU - Moes, D J A R

AU - van der Bent, S A S

AU - Swen, J J

AU - van der Straaten, T

AU - Inderson, A

AU - Olofsen, E

AU - Verspaget, H W

AU - Guchelaar, H J

AU - den Hartigh, J

AU - van Hoek, B

PY - 2016/2

Y1 - 2016/2

N2 - PURPOSE: The once daily formulation of tacrolimus is an important immunosuppressive drug. Interpatient variability in metabolism has been related to genetic variation in CYP3A4 and CYP3A5. However, in liver transplantation, both donor and recipient genotypes may affect pharmacokinetics. The primary objective of this study was to investigate the effect of CYP3A4*22 and CYP3A5*3 of both donor and recipient on once daily tacrolimus pharmacokinetics. The secondary objective was to develop a limited sampling model able to accurately predict exposure.METHODS: Stable liver transplant patients receiving once daily tacrolimus (N = 66) were included. Population pharmacokinetic analysis was performed with patients of whom DNA was available (N = 49), and demographic factors, CYP3A4*22 and CYP3A5*3, were tested as covariates. Moreover, a limited sampling model was developed using data of 66 patients.RESULTS: Pharmacokinetics was best described by a two-compartment model with delayed absorption. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 carrying liver had an average 1.7-fold higher clearance compared to non-carriers. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 non-carrying liver or vice versa showed an average 1.3-fold higher clearance compared with non-carriers. CYP3A4*22 was not significantly associated with once daily tacrolimus pharmacokinetics. Using 0, 2, and 3 h postdose as limited sampling model resulted in significantly improved prediction of tacrolimus exposure compared with trough concentration.CONCLUSIONS: Both donor and recipient CYP3A5 genotype significantly influences tacrolimus once daily pharmacokinetics. In contrast, CYP3A4*22 appears not suitable as biomarker. The developed limited sampling model can be used to accurately estimate tacrolimus once daily exposure.

AB - PURPOSE: The once daily formulation of tacrolimus is an important immunosuppressive drug. Interpatient variability in metabolism has been related to genetic variation in CYP3A4 and CYP3A5. However, in liver transplantation, both donor and recipient genotypes may affect pharmacokinetics. The primary objective of this study was to investigate the effect of CYP3A4*22 and CYP3A5*3 of both donor and recipient on once daily tacrolimus pharmacokinetics. The secondary objective was to develop a limited sampling model able to accurately predict exposure.METHODS: Stable liver transplant patients receiving once daily tacrolimus (N = 66) were included. Population pharmacokinetic analysis was performed with patients of whom DNA was available (N = 49), and demographic factors, CYP3A4*22 and CYP3A5*3, were tested as covariates. Moreover, a limited sampling model was developed using data of 66 patients.RESULTS: Pharmacokinetics was best described by a two-compartment model with delayed absorption. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 carrying liver had an average 1.7-fold higher clearance compared to non-carriers. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 non-carrying liver or vice versa showed an average 1.3-fold higher clearance compared with non-carriers. CYP3A4*22 was not significantly associated with once daily tacrolimus pharmacokinetics. Using 0, 2, and 3 h postdose as limited sampling model resulted in significantly improved prediction of tacrolimus exposure compared with trough concentration.CONCLUSIONS: Both donor and recipient CYP3A5 genotype significantly influences tacrolimus once daily pharmacokinetics. In contrast, CYP3A4*22 appears not suitable as biomarker. The developed limited sampling model can be used to accurately estimate tacrolimus once daily exposure.

KW - Adult

KW - Aged

KW - Cytochrome P-450 CYP3A

KW - Drug Administration Schedule

KW - Female

KW - Genotype

KW - Humans

KW - Immunosuppressive Agents

KW - Liver Transplantation

KW - Male

KW - Middle Aged

KW - Models, Biological

KW - Tacrolimus

KW - Tissue Donors

KW - Clinical Trial

KW - Journal Article

U2 - 10.1007/s00228-015-1963-3

DO - 10.1007/s00228-015-1963-3

M3 - Article

VL - 72

SP - 163

EP - 174

JO - European Journal of Clinical Pharmacology

JF - European Journal of Clinical Pharmacology

SN - 0031-6970

IS - 2

ER -