Analysis of daunorubicin and its metabolite daunorubicinol in plasma and urine with application in the evaluation of total, renal and metabolic formation clearances in patients with acute myeloid leukemia

Oliveira, Milena Locci de; Rocha, Adriana; Nardotto, Glauco Henrique Balthazar; Pippa, Leandro Francisco; Simões, Belinda Pinto; Lanchote, Vera Lúcia

doi:10.1016/j.jpba.2020.113576

Cited by 6 publications

(6 citation statements)

References 28 publications

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“…Previous studies have described PK modelling of daunorubicin and its metabolite in adults and children but with different dosage regimens [3,6,7,[12][13][14][15][16][17]. The present study provided a joint PK model of daunorubicin, and its metabolite in the current dosage scheme of daunorubicin is considered the most effective one to achieve a complete remission and to improve the outcome of adult AML patients [18].…”

Section: Discussionmentioning

confidence: 83%

“…This can be explained by the fact that only a part of daunorobicinol elimination is mediated by the kidneys. Indeed, a recent clinical study demonstrated that the daunorubicin dose fraction recovered in urine up to 144 h was 4.4% as the unchanged drug and 7.91% as daunorobicinol [7].…”

Section: Discussionmentioning

confidence: 99%

“…Several randomised clinical trials have demonstrated that increasing the doses of anthracyclines during the induction phase significantly improved the outcomes of AML patients [3,4]. In addition, inter-individual variability in daunorubicin metabolism can result in potential complications regarding toxicity, as well as efficacy [5][6][7]. These observations raise questions about the optimal dose regimen for daunorubicin administration and daunorubicinol contribution with respect to the clinical outcome.…”

Section: Introductionmentioning

confidence: 99%

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Daunorubicin and Its Active Metabolite Pharmacokinetic Profiles in Acute Myeloid Leukaemia Patients: A Pharmacokinetic Ancillary Study of the BIG-1 Trial

et al. 2022

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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/m2/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.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Daunorubicin and Its Active Metabolite Pharmacokinetic Profiles in Acute Myeloid Leukaemia Patients: A Pharmacokinetic Ancillary Study of the BIG-1 Trial

et al. 2022

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“…Another potential limitation of this study is that the drugs might have bound to the serum present in the media. For example, both doxorubicin and daunorubicin, as well as their main active metabolites (doxorubicinol and daunorubicinol), have been reported to bind to plasma proteins to levels of approximately 75% 3 , 40 . However, these limitations would not be expected to impact the outcomes of the study due to the strategic comparative study design, which used mirror conditions for each drug and formulation under study, and the fact that we were able to recapitulate the different cardiotoxicities that have been documented in the clinic with liposomal versus free doxorubicin, which provides further evidence of the relevance of the model.…”

Section: Discussionmentioning

confidence: 99%

Lower cardiotoxicity of CPX-351 relative to daunorubicin plus cytarabine free-drug combination in hiPSC-derived cardiomyocytes in vitro

Fortin,

LaCroix,

Grammatopoulos

et al. 2023

Sci Rep

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Liposomal formulations are hypothesized to alleviate anthracycline cardiotoxicity, although this has only been documented clinically for doxorubicin. We developed an in vitro multiparametric model using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) to assess the relative toxicity of anthracyclines across formulations. Proof of concept was established by treating hiPSC-CM with equivalent concentrations of free and liposomal doxorubicin. The study was then repeated with free daunorubicin plus cytarabine and CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine. hiPSC-CM were treated with free-drug or liposomal formulations for 24 h on Days 1, 3, and 5 at equivalent concentrations ranging from 0 to 1000 ng/mL and assessed on subsequent days. Free-drug treatment resulted in concentration-dependent cumulative cytotoxicity (microscopy), more profound decrease in ATP levels, and significant time- and concentration-dependent decreases in oxygen consumption versus liposomal formulations (p < 0.01). Repeated free-drug exposure also resulted in greater release of biomarkers (cardiac troponin I, FABP3) and lactate dehydrogenase, as well as in a biphasic rhythmicity response (initial increase followed by slowing/quiescence of beating) indicating significant injury, which was not observed after repeated exposure to liposomal formulations. Overall, liposomal formulations were considerably less toxic to hiPSC-CM than their free-drug counterparts. Clinical data will be needed to confirm findings for CPX-351.

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“…Following administration, DOX is rapidly cleared from the circulation and preferentially localizes within the liver and kidneys [ 4 ]. In addition to its disposition within these tissues, the hepatic and renal systems play a primary role in the metabolism and excretion of DOX [ 5 , 6 ]. Specifically, it is estimated that greater than 50% of DOX is excreted by the hepatobiliary pathway within 7 days of administration and ~12% is excreted in the urine, with the greatest portion retaining its original structure or metabolized to doxorubicinol [ 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of Exercise Preconditioning on Doxorubicin-Induced Liver and Kidney Toxicity in Male and Female Rats

Boeno,

Patel,

Montalvo

et al. 2023

IJMS

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Doxorubicin (DOX) is a highly effective chemotherapy agent prescribed for cancer treatment. However, the clinical use of DOX is limited due to off-target toxicity in healthy tissues. In this regard, hepatic and renal metabolic clearance results in DOX accumulation within these organ systems. Within the liver and kidneys, DOX causes inflammation and oxidative stress, which promotes cytotoxic cellular signaling. While there is currently no standard of care to treat DOX hepatic- and nephrotoxicity, endurance exercise preconditioning may be an effective intervention to prevent elevations in liver alanine transaminase (ALT) and aspartate aminotransferase (AST) and to improve kidney creatinine clearance. To determine whether exercise preconditioning is sufficient to reduce liver and kidney toxicity resulting from acute exposure to DOX chemotherapy treatment, male and female Sprague–Dawley rats remained sedentary or were exercise trained prior to saline or DOX exposure. Our findings demonstrate that DOX treatment elevated AST and AST/ALT in male rats, with no effects of exercise preconditioning to prevent these increases. We also showed increased plasma markers of renin–angiotensin–aldosterone system (RAAS) activation and urine markers of proteinuria and proximal tubule damage, with male rats revealing greater differences compared to females. Exercise preconditioning showed improved urine creatinine clearance and reduced cystatin c in males, while females had reduced plasma angiotensin II (AngII) levels. Our results demonstrate both tissue- and sex-specific responses related to the effects of exercise preconditioning and DOX treatment on markers of liver and kidney toxicity.

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Analysis of daunorubicin and its metabolite daunorubicinol in plasma and urine with application in the evaluation of total, renal and metabolic formation clearances in patients with acute myeloid leukemia

Cited by 6 publications

References 28 publications

Daunorubicin and Its Active Metabolite Pharmacokinetic Profiles in Acute Myeloid Leukaemia Patients: A Pharmacokinetic Ancillary Study of the BIG-1 Trial

Daunorubicin and Its Active Metabolite Pharmacokinetic Profiles in Acute Myeloid Leukaemia Patients: A Pharmacokinetic Ancillary Study of the BIG-1 Trial

Lower cardiotoxicity of CPX-351 relative to daunorubicin plus cytarabine free-drug combination in hiPSC-derived cardiomyocytes in vitro

Effects of Exercise Preconditioning on Doxorubicin-Induced Liver and Kidney Toxicity in Male and Female Rats

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