Evaluation of limited-sampling strategies to calculate AUC(0–24) and the role of CYP3A5 in Chilean pediatric kidney recipients using extended-release tacrolimus
Background: Kidney transplantation (KTx) requires immunosuppressive drugs such as Tacrolimus (TAC) which is mainly metabolized by CYP3A5. TAC is routinely monitored by trough levels (C0) although it has not shown to be a reliable marker. The area-under-curve (AUC) is a more realistic measure of drug...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1044050/full |
| _version_ | 1797871359499436032 |
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| author | Carla Galvez Pía Boza Mariluz González Catalina Hormazabal Marlene Encina Manuel Azócar Luis E. Castañeda Angélica Rojo María Luisa Ceballos María Luisa Ceballos Paola Krall Paola Krall |
| author_facet | Carla Galvez Pía Boza Mariluz González Catalina Hormazabal Marlene Encina Manuel Azócar Luis E. Castañeda Angélica Rojo María Luisa Ceballos María Luisa Ceballos Paola Krall Paola Krall |
| author_sort | Carla Galvez |
| collection | DOAJ |
| description | Background: Kidney transplantation (KTx) requires immunosuppressive drugs such as Tacrolimus (TAC) which is mainly metabolized by CYP3A5. TAC is routinely monitored by trough levels (C0) although it has not shown to be a reliable marker. The area-under-curve (AUC) is a more realistic measure of drug exposure, but sampling is challenging in pediatric patients. Limited-sampling strategies (LSS) have been developed to estimate AUC. Herein, we aimed to determine AUC(0–24) and CYP3A5 genotype in Chilean pediatric kidney recipients using extended-release TAC, to evaluate different LSS-AUC(0–24) formulas and dose requirements.Patients and methods: We analyzed pediatric kidney recipients using different extended-release TAC brands to determine their trapezoidal AUC(0–24) and CYP3A5 genotypes (SNP rs776746). Daily TAC dose (TAC-D mg/kg) and AUC(0–24) normalized by dose were compared between CYP3A5 expressors (*1/*1 and *1/*3) and non-expressors (*3/*3). We evaluated the single and combined time-points to identify the best LSS-AUC(0–24) model. We compared the performance of this model with two pediatric LSS-AUC(0–24) equations for clinical validation.Results: Fifty-one pharmacokinetic profiles were obtained from kidney recipients (age 13.1 ± 2.9 years). When normalizing AUC(0–24) by TAC-D significant differences were found between CYP3A5 expressors and non-expressors (1701.9 vs. 2718.1 ng*h/mL/mg/kg, p < 0.05). C0 had a poor fit with AUC(0–24) (r2 = 0.5011). The model which included C0, C1 and C4, showed the best performance to predict LSS-AUC(0–24) (r2 = 0.8765) and yielded the lowest precision error (7.1% ± 6.4%) with the lowest fraction (9.8%) of deviated AUC(0–24), in comparison to other LSS equations.Conclusion: Estimation of LSS-AUC(0–24) with 3 time-points is an advisable and clinically useful option for pediatric kidney recipients using extended-release TAC to provide better guidance of decisions if toxicity or drug inefficacy is suspected. The different CYP3A5 genotypes associated with variable dose requirements reinforce considering genotyping before KTx. Further multi-centric studies with admixed cohorts are needed to determine the short- and long-term clinical benefits. |
| first_indexed | 2024-04-10T00:42:40Z |
| format | Article |
| id | doaj.art-3c096cc401114927a90c3cd4f2278ec3 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-10T00:42:40Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-3c096cc401114927a90c3cd4f2278ec32023-03-14T05:23:47ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-03-011410.3389/fphar.2023.10440501044050Evaluation of limited-sampling strategies to calculate AUC(0–24) and the role of CYP3A5 in Chilean pediatric kidney recipients using extended-release tacrolimusCarla Galvez0Pía Boza1Mariluz González2Catalina Hormazabal3Marlene Encina4Manuel Azócar5Luis E. Castañeda6Angélica Rojo7María Luisa Ceballos8María Luisa Ceballos9Paola Krall10Paola Krall11Unidad de Nefrología, Hospital Luis Calvo Mackenna, Santiago de Chile, ChileLaboratorio Clínico, Hospital Luis Calvo Mackenna, Santiago de Chile, ChileUnidad de Nefrología, Hospital Luis Calvo Mackenna, Santiago de Chile, ChileUnidad de Nefrología, Hospital Luis Calvo Mackenna, Santiago de Chile, ChileLaboratorio Clínico, Hospital Luis Calvo Mackenna, Santiago de Chile, ChileServicio de Farmacia Clínica, Hospital Luis Calvo Mackenna, Santiago de Chile, ChilePrograma de Genética Humana, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile, ChileUnidad de Nefrología, Hospital Luis Calvo Mackenna, Santiago de Chile, ChileUnidad de Nefrología, Hospital Luis Calvo Mackenna, Santiago de Chile, ChileDepartamento de Pediatría y Cirugía Infantil Oriente, Facultad de Medicina, Universidad de Chile, Santiago de Chile, ChileDepartamento de Pediatría y Cirugía Infantil Oriente, Facultad de Medicina, Universidad de Chile, Santiago de Chile, ChileInstituto de Medicina, Facultad de Medicina, Universidad Austral de Chile, Valdivia, ChileBackground: Kidney transplantation (KTx) requires immunosuppressive drugs such as Tacrolimus (TAC) which is mainly metabolized by CYP3A5. TAC is routinely monitored by trough levels (C0) although it has not shown to be a reliable marker. The area-under-curve (AUC) is a more realistic measure of drug exposure, but sampling is challenging in pediatric patients. Limited-sampling strategies (LSS) have been developed to estimate AUC. Herein, we aimed to determine AUC(0–24) and CYP3A5 genotype in Chilean pediatric kidney recipients using extended-release TAC, to evaluate different LSS-AUC(0–24) formulas and dose requirements.Patients and methods: We analyzed pediatric kidney recipients using different extended-release TAC brands to determine their trapezoidal AUC(0–24) and CYP3A5 genotypes (SNP rs776746). Daily TAC dose (TAC-D mg/kg) and AUC(0–24) normalized by dose were compared between CYP3A5 expressors (*1/*1 and *1/*3) and non-expressors (*3/*3). We evaluated the single and combined time-points to identify the best LSS-AUC(0–24) model. We compared the performance of this model with two pediatric LSS-AUC(0–24) equations for clinical validation.Results: Fifty-one pharmacokinetic profiles were obtained from kidney recipients (age 13.1 ± 2.9 years). When normalizing AUC(0–24) by TAC-D significant differences were found between CYP3A5 expressors and non-expressors (1701.9 vs. 2718.1 ng*h/mL/mg/kg, p < 0.05). C0 had a poor fit with AUC(0–24) (r2 = 0.5011). The model which included C0, C1 and C4, showed the best performance to predict LSS-AUC(0–24) (r2 = 0.8765) and yielded the lowest precision error (7.1% ± 6.4%) with the lowest fraction (9.8%) of deviated AUC(0–24), in comparison to other LSS equations.Conclusion: Estimation of LSS-AUC(0–24) with 3 time-points is an advisable and clinically useful option for pediatric kidney recipients using extended-release TAC to provide better guidance of decisions if toxicity or drug inefficacy is suspected. The different CYP3A5 genotypes associated with variable dose requirements reinforce considering genotyping before KTx. Further multi-centric studies with admixed cohorts are needed to determine the short- and long-term clinical benefits.https://www.frontiersin.org/articles/10.3389/fphar.2023.1044050/fullpediatric kidney transplanttacrolimuslimited sampling strategiesarea under a curve (AUC)CYP3A5 |
| spellingShingle | Carla Galvez Pía Boza Mariluz González Catalina Hormazabal Marlene Encina Manuel Azócar Luis E. Castañeda Angélica Rojo María Luisa Ceballos María Luisa Ceballos Paola Krall Paola Krall Evaluation of limited-sampling strategies to calculate AUC(0–24) and the role of CYP3A5 in Chilean pediatric kidney recipients using extended-release tacrolimus Frontiers in Pharmacology pediatric kidney transplant tacrolimus limited sampling strategies area under a curve (AUC) CYP3A5 |
| title | Evaluation of limited-sampling strategies to calculate AUC(0–24) and the role of CYP3A5 in Chilean pediatric kidney recipients using extended-release tacrolimus |
| title_full | Evaluation of limited-sampling strategies to calculate AUC(0–24) and the role of CYP3A5 in Chilean pediatric kidney recipients using extended-release tacrolimus |
| title_fullStr | Evaluation of limited-sampling strategies to calculate AUC(0–24) and the role of CYP3A5 in Chilean pediatric kidney recipients using extended-release tacrolimus |
| title_full_unstemmed | Evaluation of limited-sampling strategies to calculate AUC(0–24) and the role of CYP3A5 in Chilean pediatric kidney recipients using extended-release tacrolimus |
| title_short | Evaluation of limited-sampling strategies to calculate AUC(0–24) and the role of CYP3A5 in Chilean pediatric kidney recipients using extended-release tacrolimus |
| title_sort | evaluation of limited sampling strategies to calculate auc 0 24 and the role of cyp3a5 in chilean pediatric kidney recipients using extended release tacrolimus |
| topic | pediatric kidney transplant tacrolimus limited sampling strategies area under a curve (AUC) CYP3A5 |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1044050/full |
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