AimsTacrolimus is a narrow therapeutic range drug that requires fine dose adjustment, for which pharmacokinetic (PK) models have been amply proposed in renal, but not in liver, transplant recipients. This study aimed to build population PK models and Bayesian estimators (BEs) in adult de novo liver transplant patients receiving either the immediate-release (Prograf, twice daily, TD) or prolonged-release (Advagraf, once daily, OD) forms to help PK-guided dose individualization. MethodsIn total, 160 tacrolimus concentration-time profiles (1654 samples) were collected from 80 patients, at day 7 (D7) and week 6 (W6) post-transplant. Four population PK models were developed using in-parallel parametric and nonparametric approaches for each formulation and period post-transplant. The best limited sampling strategies for estimating the area-under-the-curve (AUC) were selected by comparing predicted values to an independent dataset. Finally, the doses required to reach AUC targets were estimated using each BE and compared to the doses obtained using the trapezoidal AUC. ResultsTacrolimus PK was best described using a 1-compartmental model with first-order elimination and 2 gamma-distributions to describe the absorption. In the validation datasets, Bayesian AUC estimates yielded mean bias/root mean squared prediction error of -5.06%/13.43% (OD D7), 2.25%/8.51% (OD W6), -2.36%/7.27% (TD D7) and 0.87%/9.07% (TD W6) for the in-parallel parametric approach; and 8.95%/17.84% (OD D7), -0.11%/10.13% (OD W6), 3.57%/18.40% (TD D7) and 4.48%/12.59% (TD W6) for the nonparametric approach. ConclusionThe BEs and limited sampling strategies proposed here are able to predict accurately and precisely tacrolimus AUC in liver patients using only 3 plasma concentrations. The dosing methods are available on our ImmunoSuppressive Bayesian dose Adjustment website ().
机构:
CHU Limoges, Limoges, FranceUniv Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
Benkali, Khaled
Rostaing, Lionel
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Univ Hosp, Dept Nephrol Dialysis & Multiorgan Transplantat, Toulouse, France
CHU Purpan, U563, INSERM, Biomed Federat Res Inst Toulouse IFR BMT, Toulouse, FranceUniv Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
Rostaing, Lionel
Premaud, Aurelie
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CHU Limoges, Limoges, FranceUniv Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
Premaud, Aurelie
Woillard, Jean-Baptiste
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CHU Limoges, Limoges, FranceUniv Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
Woillard, Jean-Baptiste
Saint-Marcoux, Franck
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CHU Limoges, Limoges, FranceUniv Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
Saint-Marcoux, Franck
Urien, Saik
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Paris Descartes Univ, INSERM, CIC Mere Enfant Cochin Necker, Hop Tarnier,EA 3620,Unite Rech Clin, Paris, FranceUniv Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
Urien, Saik
Kamar, Nassim
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Univ Hosp, Dept Nephrol Dialysis & Multiorgan Transplantat, Toulouse, France
CHU Rangueil, INSERM, U858, Biomed Federat Res Inst Toulouse IFR BMT, F-31054 Toulouse, FranceUniv Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
Kamar, Nassim
Marquet, Pierre
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CHU Limoges, Limoges, FranceUniv Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
Marquet, Pierre
Rousseau, Annick
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Univ Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
CHU Limoges, Limoges, France
Univ Limoges, Biophys Lab, Fac Pharm, F-87025 Limoges, FranceUniv Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
机构:
CHU Limoges, Limoges, FranceUniv Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
Benkali, Khaled
Rostaing, Lionel
论文数: 0引用数: 0
h-index: 0
机构:
Univ Hosp, Dept Nephrol Dialysis & Multiorgan Transplantat, Toulouse, France
CHU Purpan, U563, INSERM, Biomed Federat Res Inst Toulouse IFR BMT, Toulouse, FranceUniv Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
Rostaing, Lionel
Premaud, Aurelie
论文数: 0引用数: 0
h-index: 0
机构:
CHU Limoges, Limoges, FranceUniv Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
Premaud, Aurelie
Woillard, Jean-Baptiste
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机构:
CHU Limoges, Limoges, FranceUniv Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
Woillard, Jean-Baptiste
Saint-Marcoux, Franck
论文数: 0引用数: 0
h-index: 0
机构:
CHU Limoges, Limoges, FranceUniv Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
Saint-Marcoux, Franck
Urien, Saik
论文数: 0引用数: 0
h-index: 0
机构:
Paris Descartes Univ, INSERM, CIC Mere Enfant Cochin Necker, Hop Tarnier,EA 3620,Unite Rech Clin, Paris, FranceUniv Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
Urien, Saik
Kamar, Nassim
论文数: 0引用数: 0
h-index: 0
机构:
Univ Hosp, Dept Nephrol Dialysis & Multiorgan Transplantat, Toulouse, France
CHU Rangueil, INSERM, U858, Biomed Federat Res Inst Toulouse IFR BMT, F-31054 Toulouse, FranceUniv Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
Kamar, Nassim
Marquet, Pierre
论文数: 0引用数: 0
h-index: 0
机构:
CHU Limoges, Limoges, FranceUniv Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
Marquet, Pierre
Rousseau, Annick
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h-index: 0
机构:
Univ Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France
CHU Limoges, Limoges, France
Univ Limoges, Biophys Lab, Fac Pharm, F-87025 Limoges, FranceUniv Limoges, INSERM, U850, Fac Med, F-87025 Limoges, France