Clinical pharmacokinetics and safety profile of single agent arsenic trioxide by continuous slow-rate infusion in patients with newly diagnosed acute promyelocytic leukemia

Gao, Chunlu; Hu, Shuang; Guo, Meihua; Hai, Xin; Zhou, Jin

doi:10.1007/s00280-018-3606-8

Cited by 16 publications

(4 citation statements)

References 23 publications

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“…The results showed that As III in CSF was detected first, then MMA V or DMA V during administration, which was consistent with that in blood 16 . Our recent studies demonstrated that arsenic gradually accumulated with administration frequency in plasma and red blood cells from APL patients 16,17 . In this study, we found that the levels of As III , MMA V and DMA V in CSF increased substantially from Days 3 to 10, which suggested that arsenicals tended to accumulate with time in CSF in the initial treatment stage.…”

Section: Discussionsupporting

confidence: 84%

Characteristics of arsenic species in cerebrospinal fluid (CSF) of acute promyelocytic leukaemia (APL) patients treated with arsenic trioxide plus mannitol

Guo

Zhao

Fan

et al. 2021

Brit J Clinical Pharma

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Arsenic speciation in cerebrospinal fluid (CSF) is critical for treatment/prevention of central nervous system (CNS) relapse in acute promyelocytic leukaemia (APL) patients treated with arsenic trioxide (ATO). Previous study showed low total arsenic level in CSF of APL patients. Mannitol infusion was applied to improve blood–brain barrier (BBB) permeability for arsenic. Arsenite (AsIII), monomethylarsonic acid (MMAV), dimethylarsinic acid (DMAV), and arsenate (AsV) in CSF and plasma were analysed by high performance liquid chromatography‐hydride generation‐atomic fluorescence spectrometry (HPLC‐HG‐AFS). The profile and concentration of arsenic species in CSF from APL patients administered ATO alone and in combination with mannitol were compared. The overall distribution trend of arsenic species in CSF was AsIII, DMAV > MMAV > AsV. Arsenicals accumulated in CSF with administration frequency. The permeability of BBB for AsIII was higher than that for MMAV and DMAV. Arsenic concentration in CSF was much lower than that in plasma. There were significantly higher arsenic species concentrations in CSF of APL patients treated with mannitol than that without mannitol. Mannitol infusion significantly increased AsIII penetration into CSF, which was beneficial to optimize efficacy in APL patients with CNS relapse.

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Section: Discussionsupporting

confidence: 84%

Characteristics of arsenic species in cerebrospinal fluid (CSF) of acute promyelocytic leukaemia (APL) patients treated with arsenic trioxide plus mannitol

Guo

Zhao

Fan

et al. 2021

Brit J Clinical Pharma

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“…However, Sweeney et al found that the percentage of arsenic dose excreted as As III was reduced in patients with renal impairment . In our study, CL t of As III in the patient with AKI had no significant difference with that in patients with normal renal function (0.55 L/kg/h vs 0.6 L/kg/h), suggesting that renal elimination may not be the major way of clearance of As III . There are probably other pathways for the elimination of ATO.…”

Section: Discussioncontrasting

confidence: 68%

“…Since information on the effect of CVVHD on ATO dosing requirements is lacking, conventional administration with 0.16 mg/kg of ATO was chosen. Continuously slow‐rate infusion of ATO was conducted in this patient, as it achieves lower peak plasma concentrations of arsenic species and a favourable safety profile, which could be advantageous for critical ill patients. The clinical outcome for APL patients with CVVHD is equal to those without CVVHD.…”

Section: Discussionmentioning

confidence: 99%

Effect of continuous venovenous haemodialysis on outcome and pharmacokinetics of arsenic species in a patient with acute promyelocytic leukaemia and acute kidney injury

Gao

Fan

Hostetter

et al. 2019

Brit J Clinical Pharma

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This study presents outcome and pharmacokinetics of arsenic trioxide (ATO) metabolites in patients on continuous venovenous haemodialysis (CVVHD). Of 3 acute promyelocytic leukaemia patients receiving CVVHD in management of acute kidney injury, only 1 patient was included. The patient presented disseminated intravascular coagulation and acute kidney injury before induction therapy was conducted. CVVHD was performed and ATO was initiated. Species of ATO metabolites in plasma and effluent were analysed using high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry. Plasma concentrations of As III , monomethylarsonic acid and dimethylarsinic acid with CVVHD were lower than those without CVVHD. Area under the concentration-time curve from 0 to the last sample with quantifiable concentration of As III without CVVHD was significantly higher than that with CVVHD (292.10 ng h/mL vs 195.86 ng h/mL, P = .037), which were not observed for monomethylarsonic acid and dimethylarsinic acid. Dialysate saturation of arsenic species was remarkable, especially for As III . Complete remission was achieved and renal function recovered. In this study, ATO can be used safely and effectively to treat acute promyelocytic leukaemia patients undergoing CVVHD without dose adjustment.

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“…Five patients with newly diagnosed APL were intravenously administered at a dose of 0.16 mg/kg for 40 min infusion on the first day followed by 18–20 h daily at a very slow rate with an infusion speed of 8 drips/min ( Gao et al, 2018 ). All patients achieved hematologic complete remission after induction therapy, but also experienced side effects such as abnormal coagulation and anemia.…”

Section: Dna Methyltransferase Inhibitorsmentioning

confidence: 99%

Recent progress in DNA methyltransferase inhibitors as anticancer agents

Zhang

Wang

et al. 2022

Front. Pharmacol.

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DNA methylation mediated by DNA methyltransferase is an important epigenetic process that regulates gene expression in mammals, which plays a key role in silencing certain genes, such as tumor suppressor genes, in cancer, and it has become a promising therapeutic target for cancer treatment. Similar to other epigenetic targets, DNA methyltransferase can also be modulated by chemical agents. Four agents have already been approved to treat hematological cancers. In order to promote the development of a DNA methyltransferase inhibitor as an anti-tumor agent, in the current review, we discuss the relationship between DNA methylation and tumor, the anti-tumor mechanism, the research progress and pharmacological properties of DNA methyltransferase inhibitors, and the future research trend of DNA methyltransferase inhibitors.

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Clinical pharmacokinetics and safety profile of single agent arsenic trioxide by continuous slow-rate infusion in patients with newly diagnosed acute promyelocytic leukemia

Abstract: Continuous slow-rate ATO infusion provided an alternative administration for ATO therapy with few toxic effects. Degree of methylation from MMA to DMA is inconsistent with that from iAs to MMA. PK of arsenic species is considered important for clinical use of ATO.

Cited by 16 publications

References 23 publications

Characteristics of arsenic species in cerebrospinal fluid (CSF) of acute promyelocytic leukaemia (APL) patients treated with arsenic trioxide plus mannitol

Characteristics of arsenic species in cerebrospinal fluid (CSF) of acute promyelocytic leukaemia (APL) patients treated with arsenic trioxide plus mannitol

Effect of continuous venovenous haemodialysis on outcome and pharmacokinetics of arsenic species in a patient with acute promyelocytic leukaemia and acute kidney injury

Recent progress in DNA methyltransferase inhibitors as anticancer agents

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