Liposomal formulation of a fixed combination of daunorubicin and cytarabine in a 1:5 molar ratio. The 1:5 molar ratio has been shown in vitro and in vivo to maximise synergistic antitumour activity in AML.
Daunorubicin has antimitotic and cytotoxic activity, which is achieved by forming complexes with DNA, inhibiting topoisomerase II activity, inhibiting DNA polymerase activity, affecting regulation of gene expression, and producing DNA-damaging free radicals.
Cytarabine is a cell cycle phase-specific antineoplastic agent, affecting cells only during the S-phase of cell division. Intracellularly, cytarabine is converted into cytarabine-5-triphosphate (ara-CTP), which is the active metabolite. The mechanism of action is not completely understood, but it appears that ara-CTP acts primarily through inhibition of DNA synthesis. Incorporation into DNA and RNA may also contribute to cytarabine cytotoxicity. Cytarabine is cytotoxic to proliferating mammalian cells in culture.
Daunorubicin/cytarabine liposomes exhibit a prolonged plasma half-life following intravenous infusion, with greater than 99% of the daunorubicin and cytarabine in the plasma remaining encapsulated within the liposomes. Daunorubicin/cytarabine fixed-dose combination delivers a synergistic combination of daunorubicin and cytarabine to leukaemia cells for a prolonged period of time. Based on data in animals, daunorubicin/cytarabine liposomes accumulate and persist in high concentration in the bone marrow, where they are preferentially taken up intact by leukaemia cells in an active engulfment process. In leukaemia-bearing mice, the liposomes are taken up by leukaemia cells to a greater extent than by normal bone marrow cells. After internalisation, daunorubicin/cytarabine liposomes undergo degradation, releasing daunorubicin and cytarabine within the intracellular environment, enabling the medicinal products to exert their synergistic antineoplastic activity.
The pharmacokinetics of daunorubicin and cytarabine administered as daunorubicin/cytarabine fixed-dose combination were investigated in adult patients who received a dose of daunorubicin 44 mg/m² and cytarabine 100 mg/m² administered as a 90-minute intravenous infusion on days 1, 3, and 5. The pharmacokinetics of each medicinal product was based on total plasma concentrations (i.e., encapsulated plus unencapsulated medicinal product). Following the dose administered on day 5, the mean (% coefficient of variation [CV]) maximum plasma concentrations (Cmax) for daunorubicin was 26.0 (32.7%) mcg/mL and cytarabine was 62.2 (33.7%) mcg/mL. The mean (CV) area under the curve (AUC) during one dosing interval for daunorubicin was 637 (38.4) mcg.h/mL and cytarabine was 1900 (44.3%) mcg.h/mL.
When daunorubicin and cytarabine are administered as components of daunorubicin/cytarabine fixed-dose combination, the liposomes appear to govern their tissue distribution and rates of elimination; therefore, while the nonliposomal medicinal products have markedly different clearance (CL), volume of distribution (V), and terminal half-life (t½) daunorubicin/cytarabine causes these pharmacokinetic parameters to converge.
The accumulation ratio was 1.3 for daunorubicin and 1.4 for cytarabine. There was no evidence of time-dependent kinetics or major departures from dose proportionality over the range of 1.3 mg/3 mg per m² to 59 mg/134 mg per m² (0.03 to 1.3 times the approved recommended dose).
The volume of distribution (CV) for daunorubicin is 6.6 L (36.8) and cytarabine is 7.1 L (49.2%). Plasma protein binding was not evaluated.
Similar to non-liposomal daunorubicin and cytarabine, subsequent to release from daunorubicin/cytarabine liposomes, both daunorubicin and cytarabine are extensively metabolised in the body. Daunorubicin is mostly catalysed by hepatic and non-hepatic aldo-keto reductase and carbonyl reductase to the active metabolite daunorubicinol. Cytarabine is metabolised by cytidine deaminase to the inactive metabolite 1-β (beta)-D-arabinofuranosyluracil (AraU). Unlike non-liposomal daunorubicin and cytarabine, which are quickly metabolised to the respective metabolites, daunorubicin and cytarabine after daunorubicin/cytarabine administration are free bases encapsulated in liposomes. Plasma concentration-time profiles obtained from 13 to 26 patients who received daunorubicin/cytarabine 100 units/m² (equivalent to 44 mg/ m² of daunorubicin and 100 mg/m² of cytarabine) on days 1, 3, and 5 show the mean AUClast metabolite:parent ratio for daunorubicinol and AraU were 1.79% and 3.22% to that for daunorubicin and cytarabine, respectively; which are lower than those typically reported for non-liposomal products, ~40-60% for daunorubicinol:daunorubicin and ~80% for AraU:cytarabine. The lower percentages of metabolite:parent ratios after daunorubicin/cytarabine administration indicate that most of the total daunorubicin and cytarabine in the circulation is trapped inside the daunorubicin/cytarabine liposomes, where they are inaccessible to medicinal product-metabolising enzymes.
Daunorubicin/cytarabine fixed-dose combination exhibits a prolonged half-life (CV) of 31.5 h (28.5) for daunorubicin and 40.4 h (24.2%) for cytarabine with greater than 99% of the daunorubicin and cytarabine in the plasma remaining encapsulated within the liposomes. The clearance (CV) is 0.16 L/h (53.3) for daunorubicin and 0.13 L/h (60.2%) for cytarabine.
Urinary excretion of daunorubicin and daunorubicinol accounts for 9% of the administered dose of daunorubicin, and urinary excretion of cytarabine and AraU accounts for 71% of the administered dose of cytarabine.
In a population pharmacokinetic analysis, no clinically meaningful effects on clearance and volume parameters of daunorubicin and cytarabine by age (1 to 81 years), sex, race, body weight, body mass index, and white blood cell count were observed.
The dose-normalized mean exposures of total daunorubicin and cytarabine observed in paediatric patients after 59 mg/135 mg/m² were comparable to those of daunorubicin and cytarabine after 44 mg/100 mg/m² in adults.
The pharmacokinetics of daunorubicin/cytarabine in patients aged >85 years has not yet been evaluated. No data are available.
Based on a dedicated study to evaluate the impact of moderate to severe renal impairment on the pharmacokinetics of daunorubicin/cytarabine and a population pharmacokinetic analysis using data from clinical studies in patients with mild to moderate renal impairment, no significant difference in clearance of daunorubicin or cytarabine was observed in patients with pre-existing mild, moderate or severe renal impairment compared to patients with baseline normal renal function. The potential effects of end-stage renal disease managed with dialysis on the pharmacokinetics of daunorubicin and cytarabine administered as daunorubicin/cytarabine fixed-dose combination are unknown.
The pharmacokinetics of total daunorubicin and cytarabine were not altered in patients with bilirubin ≤50 µmol/L. The pharmacokinetics in patients with bilirubin greater than 50 µmol/L is unknown.
The repeat-dose toxicity of daunorubicin/cytarabine was tested in two-cycle intravenous infusion toxicity studies with 28-day recovery periods conducted in rats and dogs. Adverse effects of daunorubicin/cytarabine occurred at all dose levels (low to no safety margins as based on systemic exposures) and were generally consistent with those documented for non-liposomal daunorubicin and/or cytarabine, comprising mainly gastrointestinal and hematological findings. Although central nervous system (CNS) and cardiovascular system parameters were included in these studies, given the observed morbidity and mortality, there was insufficient information to conduct an integrated assessment of the safety pharmacology of daunorubicin/cytarabine.
Genotoxicity, carcinogenicity, and reproductive and developmental toxicity studies have not been conducted with daunorubicin/cytarabine. However studies are available with the single agents.
Cytarabine or its active metabolite Ara-C was mutagenic (bacterial mutagenicity assay) and clastogenic in vitro (chromosome aberrations and sister-chromatid exchanges (SCE) in human leukocytes) and in vivo (chromosome aberrations and SCE assay in rodent). Cytarabine caused the transformation of hamster embryo cells and rat H43 cells in vitro and was clastogenic to meiotic cells. Daunorubicin was mutagenic (bacterial mutagenicity assay, V79 hamster cell assay), and clastogenic in vitro (CCRF-CEM human lymphoblasts) and in vivo (SCE assay in mouse bone marrow).
Studies with cytarabine were not identified. Published data with Ara-C, the active metabolite of cytarabine, did not provide evidence of carcinogenicity. Published data with daunorubicin suggest possible tumorigenicity in rats after a single dose of 5 or 10 mg/kg (0.68 to 1.4 times the RHD based on mg/m²). The IARC Working Group (IARC 2000) classified daunorubicin in Group 2B (possibly carcinogenic to humans).
Cytarabine was embryotoxic in mice and teratogenic in mice and rats when administered during organogenesis. Cytarabine also caused sperm-head abnormalities in mice and impaired spermatogenesis in rats. A single dose of cytarabine in rats, administered on day 14 of gestation, reduced prenatal and postnatal brain size and caused permanent impairment of learning ability. Daunorubicin was embryotoxic and caused fetal malformations when given during the period of organogenesis in rats. Daunorubicin caused testicular atrophy and total aplasia of spermatocytes in the seminiferous tubules in dogs.
Environmental risk assessment has shown that daunorubicin/cytarabine is not anticipated to have the potential to be persistent, bioaccumulative, or toxic to the environment.
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