Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia
Objectives Methotrexate (MTX) is subject to therapeutic drug monitoring because of its high pharmacokinetic variability and safety risk outside the therapeutic window. This study aimed to develop a population pharmacokinetic model (popPK) of MTX for Brazilian pediatric acute lymphoblastic leukemia (...
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| Autor*in: |
de Oliveira Henz, Pricilla [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
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2023 |
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© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
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Enthalten in: Pharmaceutical research - Dordrecht [u.a.] : Springer Science + Business Media B.V, 1984, 40(2023), 7 vom: 08. Juni, Seite 1777-1787 |
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| Übergeordnetes Werk: |
volume:40 ; year:2023 ; number:7 ; day:08 ; month:06 ; pages:1777-1787 |
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| DOI / URN: |
10.1007/s11095-023-03544-7 |
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| Katalog-ID: |
SPR052717410 |
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| 245 | 1 | 0 | |a Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia |
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| 520 | |a Objectives Methotrexate (MTX) is subject to therapeutic drug monitoring because of its high pharmacokinetic variability and safety risk outside the therapeutic window. This study aimed to develop a population pharmacokinetic model (popPK) of MTX for Brazilian pediatric acute lymphoblastic leukemia (ALL) patients who attended the Hospital de Clínicas de Porto Alegre, Brazil. Methods The model was developed using NONMEM 7.4 (Icon®), ADVAN3 TRANS4, and FOCE-I. To explain inter-individual variability, we evaluated covariates from demographic, biochemical, and genetic data (single nucleotide polymorphisms [SNPs] related to the transport and metabolism of drugs). Results A two-compartment model was built using 483 data points from 45 patients (0.33–17.83 years of age) treated with MTX (0.25–5 g/$ m^{2} $) in different cycles. Serum creatinine (SCR), height (HT), blood urea nitrogen (BUN) and a low BMI stratification (according to the z-score defined by the World Health Organization [LowBMI]) were added as clearance covariates. The final model described MTX clearance as %$CL (L/h)= 8.02 \;x {\left(\frac{SCR}{{Median}_{SCR}}\right)}^{-0.401} \;x\; {{\left(\frac{HT}{{Median}_{HT}}\right)}^{0.957}\;x\; {\left(\frac{BUN}{{Median}_{BUN}}\right)}^{-0.181}\;x\; \left(1-0.266\right)}_{LowBMI}%$. In the two-compartment structural model, the central and peripheral compartment volumes were 26.8 L and 8.47 L, respectively, and the inter-compartmental clearance was 0.218 L/h. External validation of the model was performed through a visual predictive test and metrics using data from 15 other pediatric ALL patients. Conclusion The first popPK model of MTX was developed for Brazilian pediatric ALL patients, which showed that inter-individual variability was explained by renal function and factors related to body size. | ||
| 650 | 4 | |a acute lymphoblastic leukemia |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Brazilian pediatric patients |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a methotrexate |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a population pharmacokinetic model |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Pinhatti, Amanda Valle |4 aut | |
| 700 | 1 | |a Gregianin, Lauro José |4 aut | |
| 700 | 1 | |a Martins, Manoela |4 aut | |
| 700 | 1 | |a Curra, Marina |4 aut | |
| 700 | 1 | |a de Araújo, Bibiana Verlindo |4 aut | |
| 700 | 1 | |a Dalla Costa, Teresa |0 (orcid)0000-0001-9227-2991 |4 aut | |
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10.1007/s11095-023-03544-7 doi (DE-627)SPR052717410 (SPR)s11095-023-03544-7-e DE-627 ger DE-627 rakwb eng de Oliveira Henz, Pricilla verfasserin aut Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Objectives Methotrexate (MTX) is subject to therapeutic drug monitoring because of its high pharmacokinetic variability and safety risk outside the therapeutic window. This study aimed to develop a population pharmacokinetic model (popPK) of MTX for Brazilian pediatric acute lymphoblastic leukemia (ALL) patients who attended the Hospital de Clínicas de Porto Alegre, Brazil. Methods The model was developed using NONMEM 7.4 (Icon®), ADVAN3 TRANS4, and FOCE-I. To explain inter-individual variability, we evaluated covariates from demographic, biochemical, and genetic data (single nucleotide polymorphisms [SNPs] related to the transport and metabolism of drugs). Results A two-compartment model was built using 483 data points from 45 patients (0.33–17.83 years of age) treated with MTX (0.25–5 g/$ m^{2} $) in different cycles. Serum creatinine (SCR), height (HT), blood urea nitrogen (BUN) and a low BMI stratification (according to the z-score defined by the World Health Organization [LowBMI]) were added as clearance covariates. The final model described MTX clearance as %$CL (L/h)= 8.02 \;x {\left(\frac{SCR}{{Median}_{SCR}}\right)}^{-0.401} \;x\; {{\left(\frac{HT}{{Median}_{HT}}\right)}^{0.957}\;x\; {\left(\frac{BUN}{{Median}_{BUN}}\right)}^{-0.181}\;x\; \left(1-0.266\right)}_{LowBMI}%$. In the two-compartment structural model, the central and peripheral compartment volumes were 26.8 L and 8.47 L, respectively, and the inter-compartmental clearance was 0.218 L/h. External validation of the model was performed through a visual predictive test and metrics using data from 15 other pediatric ALL patients. Conclusion The first popPK model of MTX was developed for Brazilian pediatric ALL patients, which showed that inter-individual variability was explained by renal function and factors related to body size. acute lymphoblastic leukemia (dpeaa)DE-He213 Brazilian pediatric patients (dpeaa)DE-He213 methotrexate (dpeaa)DE-He213 population pharmacokinetic model (dpeaa)DE-He213 Pinhatti, Amanda Valle aut Gregianin, Lauro José aut Martins, Manoela aut Curra, Marina aut de Araújo, Bibiana Verlindo aut Dalla Costa, Teresa (orcid)0000-0001-9227-2991 aut Enthalten in Pharmaceutical research Dordrecht [u.a.] : Springer Science + Business Media B.V, 1984 40(2023), 7 vom: 08. Juni, Seite 1777-1787 (DE-627)325485291 (DE-600)2036232-8 1573-904X nnns volume:40 year:2023 number:7 day:08 month:06 pages:1777-1787 https://dx.doi.org/10.1007/s11095-023-03544-7 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 40 2023 7 08 06 1777-1787 |
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10.1007/s11095-023-03544-7 doi (DE-627)SPR052717410 (SPR)s11095-023-03544-7-e DE-627 ger DE-627 rakwb eng de Oliveira Henz, Pricilla verfasserin aut Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Objectives Methotrexate (MTX) is subject to therapeutic drug monitoring because of its high pharmacokinetic variability and safety risk outside the therapeutic window. This study aimed to develop a population pharmacokinetic model (popPK) of MTX for Brazilian pediatric acute lymphoblastic leukemia (ALL) patients who attended the Hospital de Clínicas de Porto Alegre, Brazil. Methods The model was developed using NONMEM 7.4 (Icon®), ADVAN3 TRANS4, and FOCE-I. To explain inter-individual variability, we evaluated covariates from demographic, biochemical, and genetic data (single nucleotide polymorphisms [SNPs] related to the transport and metabolism of drugs). Results A two-compartment model was built using 483 data points from 45 patients (0.33–17.83 years of age) treated with MTX (0.25–5 g/$ m^{2} $) in different cycles. Serum creatinine (SCR), height (HT), blood urea nitrogen (BUN) and a low BMI stratification (according to the z-score defined by the World Health Organization [LowBMI]) were added as clearance covariates. The final model described MTX clearance as %$CL (L/h)= 8.02 \;x {\left(\frac{SCR}{{Median}_{SCR}}\right)}^{-0.401} \;x\; {{\left(\frac{HT}{{Median}_{HT}}\right)}^{0.957}\;x\; {\left(\frac{BUN}{{Median}_{BUN}}\right)}^{-0.181}\;x\; \left(1-0.266\right)}_{LowBMI}%$. In the two-compartment structural model, the central and peripheral compartment volumes were 26.8 L and 8.47 L, respectively, and the inter-compartmental clearance was 0.218 L/h. External validation of the model was performed through a visual predictive test and metrics using data from 15 other pediatric ALL patients. Conclusion The first popPK model of MTX was developed for Brazilian pediatric ALL patients, which showed that inter-individual variability was explained by renal function and factors related to body size. acute lymphoblastic leukemia (dpeaa)DE-He213 Brazilian pediatric patients (dpeaa)DE-He213 methotrexate (dpeaa)DE-He213 population pharmacokinetic model (dpeaa)DE-He213 Pinhatti, Amanda Valle aut Gregianin, Lauro José aut Martins, Manoela aut Curra, Marina aut de Araújo, Bibiana Verlindo aut Dalla Costa, Teresa (orcid)0000-0001-9227-2991 aut Enthalten in Pharmaceutical research Dordrecht [u.a.] : Springer Science + Business Media B.V, 1984 40(2023), 7 vom: 08. Juni, Seite 1777-1787 (DE-627)325485291 (DE-600)2036232-8 1573-904X nnns volume:40 year:2023 number:7 day:08 month:06 pages:1777-1787 https://dx.doi.org/10.1007/s11095-023-03544-7 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 40 2023 7 08 06 1777-1787 |
| allfields_unstemmed |
10.1007/s11095-023-03544-7 doi (DE-627)SPR052717410 (SPR)s11095-023-03544-7-e DE-627 ger DE-627 rakwb eng de Oliveira Henz, Pricilla verfasserin aut Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Objectives Methotrexate (MTX) is subject to therapeutic drug monitoring because of its high pharmacokinetic variability and safety risk outside the therapeutic window. This study aimed to develop a population pharmacokinetic model (popPK) of MTX for Brazilian pediatric acute lymphoblastic leukemia (ALL) patients who attended the Hospital de Clínicas de Porto Alegre, Brazil. Methods The model was developed using NONMEM 7.4 (Icon®), ADVAN3 TRANS4, and FOCE-I. To explain inter-individual variability, we evaluated covariates from demographic, biochemical, and genetic data (single nucleotide polymorphisms [SNPs] related to the transport and metabolism of drugs). Results A two-compartment model was built using 483 data points from 45 patients (0.33–17.83 years of age) treated with MTX (0.25–5 g/$ m^{2} $) in different cycles. Serum creatinine (SCR), height (HT), blood urea nitrogen (BUN) and a low BMI stratification (according to the z-score defined by the World Health Organization [LowBMI]) were added as clearance covariates. The final model described MTX clearance as %$CL (L/h)= 8.02 \;x {\left(\frac{SCR}{{Median}_{SCR}}\right)}^{-0.401} \;x\; {{\left(\frac{HT}{{Median}_{HT}}\right)}^{0.957}\;x\; {\left(\frac{BUN}{{Median}_{BUN}}\right)}^{-0.181}\;x\; \left(1-0.266\right)}_{LowBMI}%$. In the two-compartment structural model, the central and peripheral compartment volumes were 26.8 L and 8.47 L, respectively, and the inter-compartmental clearance was 0.218 L/h. External validation of the model was performed through a visual predictive test and metrics using data from 15 other pediatric ALL patients. Conclusion The first popPK model of MTX was developed for Brazilian pediatric ALL patients, which showed that inter-individual variability was explained by renal function and factors related to body size. acute lymphoblastic leukemia (dpeaa)DE-He213 Brazilian pediatric patients (dpeaa)DE-He213 methotrexate (dpeaa)DE-He213 population pharmacokinetic model (dpeaa)DE-He213 Pinhatti, Amanda Valle aut Gregianin, Lauro José aut Martins, Manoela aut Curra, Marina aut de Araújo, Bibiana Verlindo aut Dalla Costa, Teresa (orcid)0000-0001-9227-2991 aut Enthalten in Pharmaceutical research Dordrecht [u.a.] : Springer Science + Business Media B.V, 1984 40(2023), 7 vom: 08. Juni, Seite 1777-1787 (DE-627)325485291 (DE-600)2036232-8 1573-904X nnns volume:40 year:2023 number:7 day:08 month:06 pages:1777-1787 https://dx.doi.org/10.1007/s11095-023-03544-7 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 40 2023 7 08 06 1777-1787 |
| allfieldsGer |
10.1007/s11095-023-03544-7 doi (DE-627)SPR052717410 (SPR)s11095-023-03544-7-e DE-627 ger DE-627 rakwb eng de Oliveira Henz, Pricilla verfasserin aut Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Objectives Methotrexate (MTX) is subject to therapeutic drug monitoring because of its high pharmacokinetic variability and safety risk outside the therapeutic window. This study aimed to develop a population pharmacokinetic model (popPK) of MTX for Brazilian pediatric acute lymphoblastic leukemia (ALL) patients who attended the Hospital de Clínicas de Porto Alegre, Brazil. Methods The model was developed using NONMEM 7.4 (Icon®), ADVAN3 TRANS4, and FOCE-I. To explain inter-individual variability, we evaluated covariates from demographic, biochemical, and genetic data (single nucleotide polymorphisms [SNPs] related to the transport and metabolism of drugs). Results A two-compartment model was built using 483 data points from 45 patients (0.33–17.83 years of age) treated with MTX (0.25–5 g/$ m^{2} $) in different cycles. Serum creatinine (SCR), height (HT), blood urea nitrogen (BUN) and a low BMI stratification (according to the z-score defined by the World Health Organization [LowBMI]) were added as clearance covariates. The final model described MTX clearance as %$CL (L/h)= 8.02 \;x {\left(\frac{SCR}{{Median}_{SCR}}\right)}^{-0.401} \;x\; {{\left(\frac{HT}{{Median}_{HT}}\right)}^{0.957}\;x\; {\left(\frac{BUN}{{Median}_{BUN}}\right)}^{-0.181}\;x\; \left(1-0.266\right)}_{LowBMI}%$. In the two-compartment structural model, the central and peripheral compartment volumes were 26.8 L and 8.47 L, respectively, and the inter-compartmental clearance was 0.218 L/h. External validation of the model was performed through a visual predictive test and metrics using data from 15 other pediatric ALL patients. Conclusion The first popPK model of MTX was developed for Brazilian pediatric ALL patients, which showed that inter-individual variability was explained by renal function and factors related to body size. acute lymphoblastic leukemia (dpeaa)DE-He213 Brazilian pediatric patients (dpeaa)DE-He213 methotrexate (dpeaa)DE-He213 population pharmacokinetic model (dpeaa)DE-He213 Pinhatti, Amanda Valle aut Gregianin, Lauro José aut Martins, Manoela aut Curra, Marina aut de Araújo, Bibiana Verlindo aut Dalla Costa, Teresa (orcid)0000-0001-9227-2991 aut Enthalten in Pharmaceutical research Dordrecht [u.a.] : Springer Science + Business Media B.V, 1984 40(2023), 7 vom: 08. Juni, Seite 1777-1787 (DE-627)325485291 (DE-600)2036232-8 1573-904X nnns volume:40 year:2023 number:7 day:08 month:06 pages:1777-1787 https://dx.doi.org/10.1007/s11095-023-03544-7 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 40 2023 7 08 06 1777-1787 |
| allfieldsSound |
10.1007/s11095-023-03544-7 doi (DE-627)SPR052717410 (SPR)s11095-023-03544-7-e DE-627 ger DE-627 rakwb eng de Oliveira Henz, Pricilla verfasserin aut Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Objectives Methotrexate (MTX) is subject to therapeutic drug monitoring because of its high pharmacokinetic variability and safety risk outside the therapeutic window. This study aimed to develop a population pharmacokinetic model (popPK) of MTX for Brazilian pediatric acute lymphoblastic leukemia (ALL) patients who attended the Hospital de Clínicas de Porto Alegre, Brazil. Methods The model was developed using NONMEM 7.4 (Icon®), ADVAN3 TRANS4, and FOCE-I. To explain inter-individual variability, we evaluated covariates from demographic, biochemical, and genetic data (single nucleotide polymorphisms [SNPs] related to the transport and metabolism of drugs). Results A two-compartment model was built using 483 data points from 45 patients (0.33–17.83 years of age) treated with MTX (0.25–5 g/$ m^{2} $) in different cycles. Serum creatinine (SCR), height (HT), blood urea nitrogen (BUN) and a low BMI stratification (according to the z-score defined by the World Health Organization [LowBMI]) were added as clearance covariates. The final model described MTX clearance as %$CL (L/h)= 8.02 \;x {\left(\frac{SCR}{{Median}_{SCR}}\right)}^{-0.401} \;x\; {{\left(\frac{HT}{{Median}_{HT}}\right)}^{0.957}\;x\; {\left(\frac{BUN}{{Median}_{BUN}}\right)}^{-0.181}\;x\; \left(1-0.266\right)}_{LowBMI}%$. In the two-compartment structural model, the central and peripheral compartment volumes were 26.8 L and 8.47 L, respectively, and the inter-compartmental clearance was 0.218 L/h. External validation of the model was performed through a visual predictive test and metrics using data from 15 other pediatric ALL patients. Conclusion The first popPK model of MTX was developed for Brazilian pediatric ALL patients, which showed that inter-individual variability was explained by renal function and factors related to body size. acute lymphoblastic leukemia (dpeaa)DE-He213 Brazilian pediatric patients (dpeaa)DE-He213 methotrexate (dpeaa)DE-He213 population pharmacokinetic model (dpeaa)DE-He213 Pinhatti, Amanda Valle aut Gregianin, Lauro José aut Martins, Manoela aut Curra, Marina aut de Araújo, Bibiana Verlindo aut Dalla Costa, Teresa (orcid)0000-0001-9227-2991 aut Enthalten in Pharmaceutical research Dordrecht [u.a.] : Springer Science + Business Media B.V, 1984 40(2023), 7 vom: 08. Juni, Seite 1777-1787 (DE-627)325485291 (DE-600)2036232-8 1573-904X nnns volume:40 year:2023 number:7 day:08 month:06 pages:1777-1787 https://dx.doi.org/10.1007/s11095-023-03544-7 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 40 2023 7 08 06 1777-1787 |
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Enthalten in Pharmaceutical research 40(2023), 7 vom: 08. Juni, Seite 1777-1787 volume:40 year:2023 number:7 day:08 month:06 pages:1777-1787 |
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de Oliveira Henz, Pricilla @@aut@@ Pinhatti, Amanda Valle @@aut@@ Gregianin, Lauro José @@aut@@ Martins, Manoela @@aut@@ Curra, Marina @@aut@@ de Araújo, Bibiana Verlindo @@aut@@ Dalla Costa, Teresa @@aut@@ |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR052717410</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230812064840.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230812s2023 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1007/s11095-023-03544-7</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR052717410</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s11095-023-03544-7-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">de Oliveira Henz, Pricilla</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2023</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Objectives Methotrexate (MTX) is subject to therapeutic drug monitoring because of its high pharmacokinetic variability and safety risk outside the therapeutic window. This study aimed to develop a population pharmacokinetic model (popPK) of MTX for Brazilian pediatric acute lymphoblastic leukemia (ALL) patients who attended the Hospital de Clínicas de Porto Alegre, Brazil. Methods The model was developed using NONMEM 7.4 (Icon®), ADVAN3 TRANS4, and FOCE-I. To explain inter-individual variability, we evaluated covariates from demographic, biochemical, and genetic data (single nucleotide polymorphisms [SNPs] related to the transport and metabolism of drugs). Results A two-compartment model was built using 483 data points from 45 patients (0.33–17.83 years of age) treated with MTX (0.25–5 g/$ m^{2} $) in different cycles. Serum creatinine (SCR), height (HT), blood urea nitrogen (BUN) and a low BMI stratification (according to the z-score defined by the World Health Organization [LowBMI]) were added as clearance covariates. The final model described MTX clearance as %$CL (L/h)= 8.02 \;x {\left(\frac{SCR}{{Median}_{SCR}}\right)}^{-0.401} \;x\; {{\left(\frac{HT}{{Median}_{HT}}\right)}^{0.957}\;x\; {\left(\frac{BUN}{{Median}_{BUN}}\right)}^{-0.181}\;x\; \left(1-0.266\right)}_{LowBMI}%$. In the two-compartment structural model, the central and peripheral compartment volumes were 26.8 L and 8.47 L, respectively, and the inter-compartmental clearance was 0.218 L/h. External validation of the model was performed through a visual predictive test and metrics using data from 15 other pediatric ALL patients. Conclusion The first popPK model of MTX was developed for Brazilian pediatric ALL patients, which showed that inter-individual variability was explained by renal function and factors related to body size.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">acute lymphoblastic leukemia</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Brazilian pediatric patients</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">methotrexate</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">population pharmacokinetic model</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Pinhatti, Amanda Valle</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Gregianin, Lauro José</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Martins, Manoela</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Curra, Marina</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">de Araújo, Bibiana Verlindo</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Dalla Costa, Teresa</subfield><subfield code="0">(orcid)0000-0001-9227-2991</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Pharmaceutical research</subfield><subfield code="d">Dordrecht [u.a.] : Springer Science + Business Media B.V, 1984</subfield><subfield code="g">40(2023), 7 vom: 08. 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de Oliveira Henz, Pricilla |
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Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia acute lymphoblastic leukemia (dpeaa)DE-He213 Brazilian pediatric patients (dpeaa)DE-He213 methotrexate (dpeaa)DE-He213 population pharmacokinetic model (dpeaa)DE-He213 |
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Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia |
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Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia |
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de Oliveira Henz, Pricilla |
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de Oliveira Henz, Pricilla Pinhatti, Amanda Valle Gregianin, Lauro José Martins, Manoela Curra, Marina de Araújo, Bibiana Verlindo Dalla Costa, Teresa |
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population pharmacokinetic model of methotrexate in brazilian pediatric patients with acute lymphoblastic leukemia |
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Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia |
| abstract |
Objectives Methotrexate (MTX) is subject to therapeutic drug monitoring because of its high pharmacokinetic variability and safety risk outside the therapeutic window. This study aimed to develop a population pharmacokinetic model (popPK) of MTX for Brazilian pediatric acute lymphoblastic leukemia (ALL) patients who attended the Hospital de Clínicas de Porto Alegre, Brazil. Methods The model was developed using NONMEM 7.4 (Icon®), ADVAN3 TRANS4, and FOCE-I. To explain inter-individual variability, we evaluated covariates from demographic, biochemical, and genetic data (single nucleotide polymorphisms [SNPs] related to the transport and metabolism of drugs). Results A two-compartment model was built using 483 data points from 45 patients (0.33–17.83 years of age) treated with MTX (0.25–5 g/$ m^{2} $) in different cycles. Serum creatinine (SCR), height (HT), blood urea nitrogen (BUN) and a low BMI stratification (according to the z-score defined by the World Health Organization [LowBMI]) were added as clearance covariates. The final model described MTX clearance as %$CL (L/h)= 8.02 \;x {\left(\frac{SCR}{{Median}_{SCR}}\right)}^{-0.401} \;x\; {{\left(\frac{HT}{{Median}_{HT}}\right)}^{0.957}\;x\; {\left(\frac{BUN}{{Median}_{BUN}}\right)}^{-0.181}\;x\; \left(1-0.266\right)}_{LowBMI}%$. In the two-compartment structural model, the central and peripheral compartment volumes were 26.8 L and 8.47 L, respectively, and the inter-compartmental clearance was 0.218 L/h. External validation of the model was performed through a visual predictive test and metrics using data from 15 other pediatric ALL patients. Conclusion The first popPK model of MTX was developed for Brazilian pediatric ALL patients, which showed that inter-individual variability was explained by renal function and factors related to body size. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
| abstractGer |
Objectives Methotrexate (MTX) is subject to therapeutic drug monitoring because of its high pharmacokinetic variability and safety risk outside the therapeutic window. This study aimed to develop a population pharmacokinetic model (popPK) of MTX for Brazilian pediatric acute lymphoblastic leukemia (ALL) patients who attended the Hospital de Clínicas de Porto Alegre, Brazil. Methods The model was developed using NONMEM 7.4 (Icon®), ADVAN3 TRANS4, and FOCE-I. To explain inter-individual variability, we evaluated covariates from demographic, biochemical, and genetic data (single nucleotide polymorphisms [SNPs] related to the transport and metabolism of drugs). Results A two-compartment model was built using 483 data points from 45 patients (0.33–17.83 years of age) treated with MTX (0.25–5 g/$ m^{2} $) in different cycles. Serum creatinine (SCR), height (HT), blood urea nitrogen (BUN) and a low BMI stratification (according to the z-score defined by the World Health Organization [LowBMI]) were added as clearance covariates. The final model described MTX clearance as %$CL (L/h)= 8.02 \;x {\left(\frac{SCR}{{Median}_{SCR}}\right)}^{-0.401} \;x\; {{\left(\frac{HT}{{Median}_{HT}}\right)}^{0.957}\;x\; {\left(\frac{BUN}{{Median}_{BUN}}\right)}^{-0.181}\;x\; \left(1-0.266\right)}_{LowBMI}%$. In the two-compartment structural model, the central and peripheral compartment volumes were 26.8 L and 8.47 L, respectively, and the inter-compartmental clearance was 0.218 L/h. External validation of the model was performed through a visual predictive test and metrics using data from 15 other pediatric ALL patients. Conclusion The first popPK model of MTX was developed for Brazilian pediatric ALL patients, which showed that inter-individual variability was explained by renal function and factors related to body size. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
| abstract_unstemmed |
Objectives Methotrexate (MTX) is subject to therapeutic drug monitoring because of its high pharmacokinetic variability and safety risk outside the therapeutic window. This study aimed to develop a population pharmacokinetic model (popPK) of MTX for Brazilian pediatric acute lymphoblastic leukemia (ALL) patients who attended the Hospital de Clínicas de Porto Alegre, Brazil. Methods The model was developed using NONMEM 7.4 (Icon®), ADVAN3 TRANS4, and FOCE-I. To explain inter-individual variability, we evaluated covariates from demographic, biochemical, and genetic data (single nucleotide polymorphisms [SNPs] related to the transport and metabolism of drugs). Results A two-compartment model was built using 483 data points from 45 patients (0.33–17.83 years of age) treated with MTX (0.25–5 g/$ m^{2} $) in different cycles. Serum creatinine (SCR), height (HT), blood urea nitrogen (BUN) and a low BMI stratification (according to the z-score defined by the World Health Organization [LowBMI]) were added as clearance covariates. The final model described MTX clearance as %$CL (L/h)= 8.02 \;x {\left(\frac{SCR}{{Median}_{SCR}}\right)}^{-0.401} \;x\; {{\left(\frac{HT}{{Median}_{HT}}\right)}^{0.957}\;x\; {\left(\frac{BUN}{{Median}_{BUN}}\right)}^{-0.181}\;x\; \left(1-0.266\right)}_{LowBMI}%$. In the two-compartment structural model, the central and peripheral compartment volumes were 26.8 L and 8.47 L, respectively, and the inter-compartmental clearance was 0.218 L/h. External validation of the model was performed through a visual predictive test and metrics using data from 15 other pediatric ALL patients. Conclusion The first popPK model of MTX was developed for Brazilian pediatric ALL patients, which showed that inter-individual variability was explained by renal function and factors related to body size. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
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Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia |
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https://dx.doi.org/10.1007/s11095-023-03544-7 |
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Pinhatti, Amanda Valle Gregianin, Lauro José Martins, Manoela Curra, Marina de Araújo, Bibiana Verlindo Dalla Costa, Teresa |
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Pinhatti, Amanda Valle Gregianin, Lauro José Martins, Manoela Curra, Marina de Araújo, Bibiana Verlindo Dalla Costa, Teresa |
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10.1007/s11095-023-03544-7 |
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2024-07-03T14:17:35.539Z |
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| score |
7.3992214 |