Chemical formula: C₁₁H₁₅N₅O₅ Molecular mass: 297.267 g/mol PubChem compound: 3011155
Nelarabine is a pro-drug of the deoxyguanosine analogue ara-G. Nelarabine is rapidly demethylated by adenosine deaminase (ADA) to ara-G and then phosphorylated intracellularly by deoxyguanosine kinase and deoxycytidine kinase to its 5'-monophosphate metabolite. The monophosphate metabolite is subsequently converted to the active 5'-triphosphate form, ara-GTP. Accumulation of ara-GTP in leukaemic blasts allows for preferential incorporation of ara-GTP into deoxyribonucleic acid (DNA) leading to inhibition of DNA synthesis. This results in cell death. Other mechanisms may contribute to the cytotoxic effects of nelarabine. In vitro, T-cells are more sensitive than B-cells to the cytotoxic effects of nelarabine.
Nelarabine is a pro-drug of the deoxyguanosine analogue ara-G. Nelarabine is rapidly demethylated by adenosine deaminase (ADA) to ara-G and then phosphorylated intracellularly by deoxyguanosine kinase and deoxycytidine kinase to its 5'-monophosphate metabolite. The monophosphate metabolite is subsequently converted to the active 5'-triphosphate from, ara-GTP. Accumulation of ara-GTP in leukaemic blasts allows for preferential incorporation of ara-GTP into deoxyribonucleic acid (DNA) leading to inhibition of DNA synthesis. This results in cell death. Other mechanisms may contribute to the cytotoxic effects of nelarabine. In vitro, T-cells are more sensitive than B-cells to the cytotoxic effects of nelarabine.
In a cross-study analysis using data from four Phase I studies, the pharmacokinetics of nelarabine and ara-G were characterized in patients aged less than 18 years and adult patients with refractory leukaemia or lymphoma.
Plasma ara-G Cmax values generally occurred at the end of the nelarabine infusion and were generally higher than nelarabine Cmax values, suggesting rapid and extensive conversion of nelarabine to ara-G. After infusion of 1,500 mg/m² nelarabine over two hours in adult patients, mean (CV) plasma nelarabine Cmax and AUCinf values were 13.9 μM (81) and 13.5 μM.h (56%) respectively. Mean plasma ara-G Cmax and AUCinf values were 115 μM (16%) and 571 μM.h (30%), respectively.
Intracellular Cmax for ara-GTP appeared within 3 to 25 hours on day 1. Mean (CV) intracellular ara-GTP Cmax and AUC values were 95.6 μM (139) and 2214 μM.h (263%) at this dose.
After infusion of 400 or 650 mg/m² nelarabine over one hour in 6 paediatric patients, mean (CV) plasma nelarabine Cmax and AUCinf values, adjusted to a 650 mg/m² dose, were 45.0 μM (40) and 38.0 μM.h (39%), respectively. Mean plasma ara-G Cmax and AUCinf values were 60.1 μM (17%) and 212 μM.h (18%), respectively.
Nelarabine and ara-G are extensively distributed throughout the body based on combined Phase I pharmacokinetic data at nelarabine doses of 104 to 2,900 mg/m². Specifically, for nelarabine, mean (CV) Vss values were 115 l/m² (159) and 89.4 l/m² (278%) in adult and paediatric patients, respectively. For ara-G, mean Vss/F values were 44.8 l/m² (32%) and 32.1 l/m² (25%) in adult and paediatric patients, respectively.
Nelarabine and ara-G are not substantially bound to human plasma proteins (less than 25%) in vitro, and binding is independent of nelarabine or ara-G concentrations up to 600 μM.
No accumulation of nelarabine or ara-G was observed in plasma after nelarabine administration on either a daily or a day 1, 3, 5 schedule.
Intracellular ara-GTP concentrations in leukaemic blasts were quantifiable for a prolonged period after nelarabine administration. Intracellular ara-GTP accumulated with repeated administration of nelarabine. On the day 1, 3, and 5 schedule, Cmax and AUC(0-t) values on day 3 were approximately 50% and 30%, respectively, greater than Cmax and AUC(0-t) values on day 1.
The principal route of metabolism for nelarabine is O-demethylation by adenosine deaminase to form ara-G, which undergoes hydrolysis to form guanine. In addition, some nelarabine is hydrolysed to form methylguanine, which is O-demethylated to form guanine. Guanine is N-deaminated to form xanthine, which is further oxidized to yield uric acid.
Nelarabine and ara-G are rapidly eliminated from plasma with a half-life of approximately 30 minutes and 3 hours, respectively. These findings were demonstrated in patients with refractory leukaemia or lymphoma given a dose of 1,500 mg/m² nelarabine (adults) or a 650 mg/m² (paediatrics).
Combined Phase 1 pharmacokinetic data at nelarabine doses of 104 to 2,900 mg/m² indicate that mean (CV) clearance (Cl) values for nelarabine are 138 l/h/m² (104) and 125 l/h/m² (214%) in adult and paediatric patients, respectively, on day 1 (n=65 adults, n=21 paediatric patients). The apparent clearance of ara-G (Cl/F) is comparable between the two groups [9.5 l/h/m² (35%) in adult patients and 10.8 l/h/m² (36%) in paediatric patients] on day 1.
Nelarabine and ara-G are partially eliminated by the kidneys. In 28 adult patients, 24 hours after nelarabine infusion on day 1, mean urinary excretion of nelarabine and ara-G was 5.3% and 23.2% of the administered dose, respectively. Renal clearance averaged 9.0 l/h/m² (151%) for nelarabine and 2.6 l/h/m² (83%) for ara-G in 21 adult patients.
Because the timecourse of intracellular ara-GTP was prolonged, its elimination half-life could not be accurately estimated.
Limited clinical pharmacology data are available for patients below the age of 4 years.
Combined Phase 1 pharmacokinetic data at nelarabine doses of 104 to 2,900 mg/m² indicate that the clearance (Cl) and Vss values for nelarabine and ara-G are comparable between the two groups. Further data with respect to nelarabine and ara-G pharmacokinetics in the paediatric population are provided in other subsections.
Gender has no effect on nelarabine or ara-G plasma pharmacokinetics. Intracellular ara-GTP Cmax and AUC(0–t) values at the same dose level were 2– to 3– fold greater on average in adult female than in adult male patients.
The effect of race on nelarabine and ara-G pharmacokinetics has not been specifically studied. In a pharmacokinetic/pharmacodynamic cross study analysis, race had no apparent effect on nelarabine, ara-G, or intracellular ara-GTP pharmacokinetics.
The pharmacokinetics of nelarabine and ara-G have not been specifically studied in renally impaired or haemodialysed patients. Nelarabine is excreted by the kidney to a small extent (5 to 10% of the administered dose). Ara-G is excreted by the kidney to a greater extent (20 to 30% of the administered nelarabine dose). Adults and children in clinical studies were categorized into the three groups according to renal impairment: normal with Clcr greater than 80 ml/min (n=56), mild with Clcr equalling 50 to 80 ml/min (n=12), and moderate with Clcr less than 50 ml/min (n=2). The mean apparent clearance (Cl/F) of ara-G was about 7% lower in patients with mild renal impairment than in patients with normal renal function. No data are available to provide a dose advice for patients with Clcr less than 50 ml/min.
Age has no effect on the pharmacokinetics of nelarabine or ara-G. Decreased renal function, which is more common in the elderly, may reduce ara-G clearance.
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows: nelarabine caused histopathological changes to the central nervous system (white matter vacuolation and degenerative changes in cerebrum, cerebellum and spinal cord) of monkeys after daily treatment with nelarabine for 23 days, at exposures below the human therapeutic exposure. Nelarabine showed in vitro cytotoxicity to monocytes and macrophages.
Carcinogenicity testing of nelarabine has not been performed.
Nelarabine was mutagenic to L5178Y/TK mouse lymphoma cells with and without metabolic activation.
Compared to controls, nelarabine caused increased incidences of foetal malformations, anomalies, and variations in rabbits when given at doses approximately 24% of the adult human dose on a mg/m² basis during the period of organogenesis. Cleft palate was seen in rabbits given a dose approximately 2-fold the adult human dose, absent pollices in rabbits given a dose approximately 79% of the adult human dose while absent gall bladder, accessory lung lobes, fused or extra sternebrae and delayed ossification was seen at all doses. Maternal body weight gain and foetal body weights were reduced in rabbits given a dose approximately 2-fold the adult human dose.
No studies have been conducted in animals to assess the effects of nelarabine on fertility. However, no undesirable effects were seen in the testes or ovaries of monkeys given nelarabine intravenously at doses up to approximately 32% of the adult human dose on a mg/m² basis for 30 consecutive days.
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