Pharmacokinetics of liposomal daunorubicin (DaunoXome) during a phase I-II study in children with relapsed acute lymphoblastic leukaemia

Bellott, Ricardo; Auvrignon, Anne; Leblanc, Thierry; Pérel, Yves; Gandemer, Virginie; Bertrand, Yves; Méchinaud, Françoise; Bellenger, Patrice; Vernois, J; Leverger, Guy; Baruchel, André; Robert, Jacques

doi:10.1007/s002800000206

Cited by 57 publications

(29 citation statements)

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“…Measured parameters for DaunoXome were similar to those reported previously (Bellott et al, 2001). Liposomal Daunorubicin showed one-compartment elimination kinetics in all patients, and parameters were not dose-dependent.…”

Section: Pharmacokineticssupporting

confidence: 83%

A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours

et al. 2006

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Anthracyclines are widely used in paediatric oncology, but their use is limited by the risk of cumulative cardiac toxicity. Encapsulating anthracyclines in liposomes may reduce cardiac toxicity and possibly increase drug availability to tumours. A phase I study in paediatric patients was designed to establish the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) after a single course of liposomal daunorubicin, ‘DaunoXome', as a 1 h infusion on day 1 of a 21 day cycle. Patients were stratified into two groups according to prior treatment: Group A (conventional) and group B (heavily pretreated patients). Dose limiting toxicity was expected to be haematological, and a two-step escalation was planned, with and without G-CSF support. Pharmacokinetic studies were carried out in parallel. In all, 48 patients aged from 1 to 18 years were treated. Dose limiting toxicity was neutropenia for both groups. Maximum tolerated dose was defined as 155 mg m −2 for Group A and 100 mg m −2 for Group B. The second phase with G-CSF was interrupted because of evidence of cumulative cardiac toxicity. Cardiac toxicity was reported in a total of 15 patients in this study. DaunoXome shares the early cardiotoxicity of conventional anthracyclines in paediatric oncology. This study has successfully defined a haematological MTD for DaunoXome, but the significance of this is limited given the concerns of delayed cardiac toxicity. The importance of longer-term follow-up in patients enrolled into phase I studies has been underestimated previously, and may lead to an under-recognition of important adverse events.

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Section: Pharmacokineticssupporting

confidence: 83%

A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours

et al. 2006

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“…The pharmacokinetic profile of DaunoXome is different from conventional daunorubicin with a 36-fold increase in the area under the plasma concentration curve and a first phase elimination half-life of 5.3 to 8.3 h (Rahman et al, 1984a;Forssen and Ross, 1994;Gill et al, 1995;Bellott et al, 2001). In vivo experiments indicate increased uptake of daunoXome in tumour tissue at 24 h compared to conventional daunorubicin (Forssen et al, 1992(Forssen et al, , 1996.…”

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confidence: 99%

A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast cancer

et al. 2002

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The aims of this phase I study were to establish the maximum tolerated dose, safety profile and activity of liposomal daunorubicin, DaunoXome (NeXstar Pharmaceuticals), in the treatment of metastatic breast cancer. DaunoXome was administered intravenously over 2 h in 21 day cycles and doses were increased from 80 to 100, 120 and 150 mg m 2 . Sixteen patients were enrolled. A total of 70 cycles of DaunoXome were administered. The maximum tolerated dose was 120 mg m 2 , the dose-limiting toxicity being prolonged grade 4 neutropenia or neutropenic pyrexia necessitating dose reductions at 120 and 150 mg m 2 . Asymptomatic cardiotoxicity was observed in three patients: grade 1 in one treated with a cumulative dose of 800 mg m 2 and grade 2 in two, one who received a cumulative dose of 960 mg m 2 and the other a cumulative dose of 600 mg m 2 with a previous neoadjuvant doxorubicin chemotherapy of 300 mg m 2 . Tumour response was evaluable in 15 patients, of whom two had objective responses, six had stable disease and seven had progressive disease. In conclusion, DaunoXome is associated with mild, manageable toxicities and has anti-tumour activity in metastatic breast cancer. The findings support further phase II evaluation of DaunoXome alone and in combination with other standard nonanthracycline cytotoxic or novel targeted agents. Although the dose-limiting toxicity for DaunoXome was febrile neutropenia at 120 mg m 2 , we would recommend this dose for further evaluation, as the febrile neutropenia occurred after four or more cycles in three of the four episodes seen, was short lived and uncomplicated.

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“…On one hand, compared to Doxil ® , DaunoXome ® exhibits a higher C max and a much shorter t 1/2 and a faster Cl. [115] It is obvious for the nanomedicines formulation that has a longer t 1/2 and mean resident time, the drugs are protected both from metabolizing enzymes in the liver before they are released, and also from renal clearance due to the increased size; this leads to the longer exposure time of the drug to the tumor, which partly explains the promoted drug therapeutic index. On other hand, Abraxane ® has a fast Cl than DaunoXome ® with large volume of distribution, and t 1/2 similar to DaunoXome ® .…”

Section: Pharmacokinetics Of Nanomedicinesmentioning

confidence: 99%

Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines

Balasubramanian

Liu

Hirvonen

et al. 2017

Adv Healthcare Materials

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Explosive growth of nanomedicines continues to significantly impact the therapeutic strategies for effective cancer treatment. Despite the significant progress in the development of advanced nanomedicines, successful clinical translation remains challenging. As cancer nanomedicine is a multidisciplinary field, the fundamental problem is that the knowledge gaps stem from different vantage points in the understanding of cancer nanomedicines. The complexities and heterogenecity of both nanomedicines and cancer are further demanding the integration of highly diverse expertise to develop clinically translatable cancer nanomedicines. This progress report aims to discuss the current understanding of cancer nanomedicines between different research areas in terms of nanoparticle engineering, formulation, tumor patho-physiology and clinical medicine, as well as to identify the knowledge gaps lying at the interface between the different fields of research in nanomedicine. Here we also highlight for the necessity to harmonize the multidisciplinary effort in the research of nanomedicines in order to bridge the knowledge and to advance the full understanding in cancer nanomedicines. A paradigm shift is needed in the strategic development of disease specific nanomedicines in order to foster the successful translation into clinic of future cancer nanomedicines.

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Pharmacokinetics of liposomal daunorubicin (DaunoXome) during a phase I-II study in children with relapsed acute lymphoblastic leukaemia

Cited by 57 publications

References 0 publications

A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours

A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours

A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast cancer

Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines

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