Daunorubicin and Its Active Metabolite Pharmacokinetic Profiles in Acute Myeloid Leukaemia Patients: A Pharmacokinetic Ancillary Study of the BIG-1 Trial
Daunorubicin pharmacokinetics (PK) are characterised by an important inter-individual variability, which raises questions about the optimal dose regimen in patients with acute myeloid leukaemia. The aim of the study is to assess the joint daunorubicin/daunorubicinol PK profile and to define an optim...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-04-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/4/792 |
| _version_ | 1797444239731195904 |
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| author | Guillaume Drevin Marie Briet Caroline Bazzoli Emmanuel Gyan Aline Schmidt Hervé Dombret Corentin Orvain Aurelien Giltat Christian Recher Norbert Ifrah Philippe Guardiola Mathilde Hunault-Berger Chadi Abbara |
| author_facet | Guillaume Drevin Marie Briet Caroline Bazzoli Emmanuel Gyan Aline Schmidt Hervé Dombret Corentin Orvain Aurelien Giltat Christian Recher Norbert Ifrah Philippe Guardiola Mathilde Hunault-Berger Chadi Abbara |
| author_sort | Guillaume Drevin |
| collection | DOAJ |
| description | Daunorubicin pharmacokinetics (PK) are characterised by an important inter-individual variability, which raises questions about the optimal dose regimen in patients with acute myeloid leukaemia. The aim of the study is to assess the joint daunorubicin/daunorubicinol PK profile and to define an optimal population PK study design. Fourteen patients were enrolled in the PK ancillary study of the BIG-1 trial and 6–8 samples were taken up to 24 h after administration of the first dose of daunorubicin (90 mg/m<sup>2</sup>/day). Daunorubicin and daunorubicinol quantifications were assessed using a validated liquid chromatography technique coupled with a fluorescence detector method. Data were analysed using a non-compartmental approach and non-linear mixed effects modelling. Optimal sampling strategy was proposed using the R function PFIM. The median daunorubicin and daunorubicinol AUC0-tlast were 577 ng/mL·hr (Range: 375–1167) and 2200 ng/mL·hr (range: 933–4683), respectively. The median metabolic ratio was 0.32 (range: 0.1–0.44). Daunorubicin PK was best described by a three-compartment parent, two-compartment metabolite model, with a double first-order transformation of daunorubicin to metabolite. Body surface area and plasma creatinine had a significant impact on the daunorubicin and daunorubicinol PK. A practical optimal population design has been derived from this model with five sampling times per subject (0.5, 0.75, 2, 9, 24 h) and this can be used for a future population PK study. |
| first_indexed | 2024-03-09T13:08:48Z |
| format | Article |
| id | doaj.art-8686c66fdabb490b9fbcf1b70949d057 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T13:08:48Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-8686c66fdabb490b9fbcf1b70949d0572023-11-30T21:44:17ZengMDPI AGPharmaceutics1999-49232022-04-0114479210.3390/pharmaceutics14040792Daunorubicin and Its Active Metabolite Pharmacokinetic Profiles in Acute Myeloid Leukaemia Patients: A Pharmacokinetic Ancillary Study of the BIG-1 TrialGuillaume Drevin0Marie Briet1Caroline Bazzoli2Emmanuel Gyan3Aline Schmidt4Hervé Dombret5Corentin Orvain6Aurelien Giltat7Christian Recher8Norbert Ifrah9Philippe Guardiola10Mathilde Hunault-Berger11Chadi Abbara12Service de Pharmacologie-Toxicologie et Pharmacovigilance, Centre Hospitalo-Universitaire d’Angers, F-49100 Angers, FranceService de Pharmacologie-Toxicologie et Pharmacovigilance, Centre Hospitalo-Universitaire d’Angers, F-49100 Angers, FranceGrenoble INP, TIMC-IMAG, Université Grenoble Alpes, CNRS, F-38000 Grenoble, FranceService d’Hématologie et Thérapie Cellulaire, Equipe LNOx, ERL CNRS 7001, Centre Hospitalier Universitaire, Université de Tours, F-37000 Tours, FranceUFR Santé, Université Angers, F-49100 Angers, FranceBlood Disease Department, University Hospital Saint Louis AP-HP, F-75010 Paris, FranceFédération Hospitalo-Universitaire GOAL, F-49033 Angers, FranceFédération Hospitalo-Universitaire GOAL, F-49033 Angers, FranceInsitut Universitaire du Cancer de Toulouse Oncolpole, Unversité Toulouse III Paul Sabatier, F-31000 Toulouse, FranceUFR Santé, Université Angers, F-49100 Angers, FranceUFR Santé, Université Angers, F-49100 Angers, FranceUFR Santé, Université Angers, F-49100 Angers, FranceService de Pharmacologie-Toxicologie et Pharmacovigilance, Centre Hospitalo-Universitaire d’Angers, F-49100 Angers, FranceDaunorubicin pharmacokinetics (PK) are characterised by an important inter-individual variability, which raises questions about the optimal dose regimen in patients with acute myeloid leukaemia. The aim of the study is to assess the joint daunorubicin/daunorubicinol PK profile and to define an optimal population PK study design. Fourteen patients were enrolled in the PK ancillary study of the BIG-1 trial and 6–8 samples were taken up to 24 h after administration of the first dose of daunorubicin (90 mg/m<sup>2</sup>/day). Daunorubicin and daunorubicinol quantifications were assessed using a validated liquid chromatography technique coupled with a fluorescence detector method. Data were analysed using a non-compartmental approach and non-linear mixed effects modelling. Optimal sampling strategy was proposed using the R function PFIM. The median daunorubicin and daunorubicinol AUC0-tlast were 577 ng/mL·hr (Range: 375–1167) and 2200 ng/mL·hr (range: 933–4683), respectively. The median metabolic ratio was 0.32 (range: 0.1–0.44). Daunorubicin PK was best described by a three-compartment parent, two-compartment metabolite model, with a double first-order transformation of daunorubicin to metabolite. Body surface area and plasma creatinine had a significant impact on the daunorubicin and daunorubicinol PK. A practical optimal population design has been derived from this model with five sampling times per subject (0.5, 0.75, 2, 9, 24 h) and this can be used for a future population PK study.https://www.mdpi.com/1999-4923/14/4/792daunorubicinpharmacokineticsacute myeloid leukaemiamodelling |
| spellingShingle | Guillaume Drevin Marie Briet Caroline Bazzoli Emmanuel Gyan Aline Schmidt Hervé Dombret Corentin Orvain Aurelien Giltat Christian Recher Norbert Ifrah Philippe Guardiola Mathilde Hunault-Berger Chadi Abbara Daunorubicin and Its Active Metabolite Pharmacokinetic Profiles in Acute Myeloid Leukaemia Patients: A Pharmacokinetic Ancillary Study of the BIG-1 Trial Pharmaceutics daunorubicin pharmacokinetics acute myeloid leukaemia modelling |
| title | Daunorubicin and Its Active Metabolite Pharmacokinetic Profiles in Acute Myeloid Leukaemia Patients: A Pharmacokinetic Ancillary Study of the BIG-1 Trial |
| title_full | Daunorubicin and Its Active Metabolite Pharmacokinetic Profiles in Acute Myeloid Leukaemia Patients: A Pharmacokinetic Ancillary Study of the BIG-1 Trial |
| title_fullStr | Daunorubicin and Its Active Metabolite Pharmacokinetic Profiles in Acute Myeloid Leukaemia Patients: A Pharmacokinetic Ancillary Study of the BIG-1 Trial |
| title_full_unstemmed | Daunorubicin and Its Active Metabolite Pharmacokinetic Profiles in Acute Myeloid Leukaemia Patients: A Pharmacokinetic Ancillary Study of the BIG-1 Trial |
| title_short | Daunorubicin and Its Active Metabolite Pharmacokinetic Profiles in Acute Myeloid Leukaemia Patients: A Pharmacokinetic Ancillary Study of the BIG-1 Trial |
| title_sort | daunorubicin and its active metabolite pharmacokinetic profiles in acute myeloid leukaemia patients a pharmacokinetic ancillary study of the big 1 trial |
| topic | daunorubicin pharmacokinetics acute myeloid leukaemia modelling |
| url | https://www.mdpi.com/1999-4923/14/4/792 |
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