A prospective controlled, randomized clinical trial of kidney transplant recipients developed personalized tacrolimus dosing using model-based Bayesian Prediction
Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved..
For three decades, tacrolimus (Tac) dose adjustment in clinical practice has been calculated empirically according to the manufacturer's labeling based on a patient's body weight. Here, we developed and validated a Population pharmacokinetic (PPK) model including pharmacogenetics (cluster CYP3A4/CYP3A5), age, and hematocrit. Our study aimed to assess the clinical applicability of this PPK model in the achievement of Tac Co (therapeutic trough Tac concentration) compared to the manufacturer's labelling dosage. A prospective two-arm, randomized, clinical trial was conducted to determine Tac starting and subsequent dose adjustments in 90 kidney transplant recipients. Patients were randomized to a control group with Tac adjustment according to the manufacturer's labeling or the PPK group adjusted to reach target Co (6-10 ng/ml) after the first steady state (primary endpoint) using a Bayesian prediction model (NONMEM). A significantly higher percentage of patients from the PPK group (54.8%) compared with the control group (20.8%) achieved the therapeutic target fulfilling 30% of the established superiority margin defined. Patients receiving PPK showed significantly less intra-patient variability compared to the control group, reached the Tac Co target sooner (5 days vs 10 days), and required significantly fewer Tac dose modifications compared to the control group within 90 days following kidney transplant. No statistically significant differences occurred in clinical outcomes. Thus, PPK-based Tac dosing offers significant superiority for starting Tac prescription over classical labeling-based dosing according to the body weight, which may optimize Tac-based therapy in the first days following transplantation.
| Errataetall: |
CommentIn: Kidney Int. 2023 Oct;104(4):652-654. - PMID 37739615 |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:104 |
|---|---|
| Enthalten in: |
Kidney international - 104(2023), 4 vom: 28. Okt., Seite 840-850 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Lloberas, Nuria [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 02.10.2023 Date Revised 02.10.2023 published: Print-Electronic CommentIn: Kidney Int. 2023 Oct;104(4):652-654. - PMID 37739615 Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.kint.2023.06.021 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM358922895 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM358922895 | ||
| 003 | DE-627 | ||
| 005 | 20231226075755.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.kint.2023.06.021 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1196.xml |
| 035 | |a (DE-627)NLM358922895 | ||
| 035 | |a (NLM)37391040 | ||
| 035 | |a (PII)S0085-2538(23)00475-1 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Lloberas, Nuria |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A prospective controlled, randomized clinical trial of kidney transplant recipients developed personalized tacrolimus dosing using model-based Bayesian Prediction |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 02.10.2023 | ||
| 500 | |a Date Revised 02.10.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Kidney Int. 2023 Oct;104(4):652-654. - PMID 37739615 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a For three decades, tacrolimus (Tac) dose adjustment in clinical practice has been calculated empirically according to the manufacturer's labeling based on a patient's body weight. Here, we developed and validated a Population pharmacokinetic (PPK) model including pharmacogenetics (cluster CYP3A4/CYP3A5), age, and hematocrit. Our study aimed to assess the clinical applicability of this PPK model in the achievement of Tac Co (therapeutic trough Tac concentration) compared to the manufacturer's labelling dosage. A prospective two-arm, randomized, clinical trial was conducted to determine Tac starting and subsequent dose adjustments in 90 kidney transplant recipients. Patients were randomized to a control group with Tac adjustment according to the manufacturer's labeling or the PPK group adjusted to reach target Co (6-10 ng/ml) after the first steady state (primary endpoint) using a Bayesian prediction model (NONMEM). A significantly higher percentage of patients from the PPK group (54.8%) compared with the control group (20.8%) achieved the therapeutic target fulfilling 30% of the established superiority margin defined. Patients receiving PPK showed significantly less intra-patient variability compared to the control group, reached the Tac Co target sooner (5 days vs 10 days), and required significantly fewer Tac dose modifications compared to the control group within 90 days following kidney transplant. No statistically significant differences occurred in clinical outcomes. Thus, PPK-based Tac dosing offers significant superiority for starting Tac prescription over classical labeling-based dosing according to the body weight, which may optimize Tac-based therapy in the first days following transplantation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a kidney transplantation | |
| 650 | 4 | |a pharmacogenetics | |
| 650 | 4 | |a pharmacokinetics | |
| 650 | 4 | |a population pharmacokinetics | |
| 650 | 4 | |a tacrolimus | |
| 650 | 7 | |a Immunosuppressive Agents |2 NLM | |
| 650 | 7 | |a Tacrolimus |2 NLM | |
| 650 | 7 | |a WM0HAQ4WNM |2 NLM | |
| 700 | 1 | |a Grinyó, Josep M |e verfasserin |4 aut | |
| 700 | 1 | |a Colom, Helena |e verfasserin |4 aut | |
| 700 | 1 | |a Vidal-Alabró, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Fontova, Pere |e verfasserin |4 aut | |
| 700 | 1 | |a Rigo-Bonnin, Raul |e verfasserin |4 aut | |
| 700 | 1 | |a Padró, Ariadna |e verfasserin |4 aut | |
| 700 | 1 | |a Bestard, Oriol |e verfasserin |4 aut | |
| 700 | 1 | |a Melilli, Edoardo |e verfasserin |4 aut | |
| 700 | 1 | |a Montero, Nuria |e verfasserin |4 aut | |
| 700 | 1 | |a Coloma, Ana |e verfasserin |4 aut | |
| 700 | 1 | |a Manonelles, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Meneghini, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Favà, Alex |e verfasserin |4 aut | |
| 700 | 1 | |a Torras, Joan |e verfasserin |4 aut | |
| 700 | 1 | |a Cruzado, Josep M |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Kidney international |d 1972 |g 104(2023), 4 vom: 28. Okt., Seite 840-850 |w (DE-627)NLM000007188 |x 1523-1755 |7 nnns |
| 773 | 1 | 8 | |g volume:104 |g year:2023 |g number:4 |g day:28 |g month:10 |g pages:840-850 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.kint.2023.06.021 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 104 |j 2023 |e 4 |b 28 |c 10 |h 840-850 | ||