Nelarabine;Sorafenib

Mechanism of Action

Nelarabine is the water-soluble prodrug of 9-beta-D-arabinofuranosylguanine (Ara-G), a deoxyguanosine analogue. Nelarabine is demethylated by adenosine deaminase to Ara-G, which is transported into leukemic blast cells by nucleoside transporters and mono-phosphorylated by nucleoside kinase. Ara-G is phosphorylated to arabinosylguanine triphosphate (Ara-GTP), the active 5'-triphosphate, by deoxyguanosine kinase and deoxycytidine kinase. Ara-GTP is incorporated into the DNA of T-cell lymphoblasts and lymphocytes, leading to inhibition of DNA synthesis and cell death.

Pharmacokinetics

Nelarabine and Ara-G are rapidly eliminated from plasma with half-lives of approximately 30 minutes and 3 hours, respectively, after a 1,500 mg/m² dose in adult patients. Peak plasma levels of Ara-G typically occur at the end of nelarabine infusions and are usually higher than peak plasma nelarabine levels, suggesting rapid and extensive conversion of nelarabine to Ara-G. Mean plasma nelarabine and Ara-G peak levels were 5 mcg/mL and 31.4 mcg/mL, respectively, after a 1,500 mg/m² IV infusion over 2 hours in adult patients; the Ara-G AUC was 37 times higher than that of nelarabine. After the same dose, a mean intracellular peak level of Ara-GTP occurred between 3 and 25 hours. The intracellular Ara-GTP AUC was 532 times higher than that for nelarabine and 14 times higher than that for Ara-G. Intracellular Ara-GTP elimination half-life cannot be accurately measured because of the prolonged intracellular Ara-GTP levels. Mean clearance of nelarabine is 30% higher in pediatric than adult patients with values of 259 L/h/m² and 197 L/h/m², respectively. The apparent clearance of Ara-G is comparable, with values of 10.5 L/h/m² for adult patients and 11.3 L/h/m² for pediatric patients. Both nelarabine and Ara-G are extensively distributed in the body, with steady state volumes of distribution (V_d) of 197 L/m² and 213 L/m² for nelarabine in adult and pediatric patients, respectively, and steady state apparent V_d of 50 L/m² and 33 L/m² for Ara-G in adult and pediatric patients, respectively. Neither nelarabine nor Ara-G is substantially bound to plasma proteins (less than 25% in vitro). Nelarabine is metabolized by adenosine deaminase-mediated O-demethylation to Ara-G, which is hydrolyzed to guanine. Some nelarabine is hydrolyzed to methylguanine, which is O-demethylated to guanine. Guanine is N-deaminated to xanthine. Nelarabine and Ara-G are partially eliminated by the kidneys, with mean urinary excretion of 6.6% and 27% of the administered dose, respectively, over 24 hours in adult patients. Renal clearance averaged 24 L/h and 6.2 L/h for nelarabine and Ara-G, respectively, in adult patients.

Selected therapeutic regimens of nelarabine appear in Table 1.

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Table 1.

Selected Therapeutic Regimens of Nelarabine

Daily Dose	Route of Administration	Administered on Day(s)	Cycle Length	Total Dose/Cycle	References
Adult
1,500 mg/m2	IV	1, 3, 5	21 days	4,500 mg/m2	1, 2, 3 *
1,500 mg/m2	IV	1, 3, 5	28 days	4,500 mg/m2	4
30 mg/kg	IV	1, 2, 3, 4, 5	21 to 28 days	150 mg/kg	6
Pediatric
650 mg/m2	IV	1, 2, 3, 4, 5	21 days	3,250 mg/m2	1 *
400 to 650 mg/m2	IV	1, 2, 3, 4, 5	21 days	2,000 to 3,250 mg/m2	5
40 mg/kg	IV	1, 2, 3, 4, 5	21 to 28 days	200 mg/kg	6

*

Conforms to dosing information listed in the manufacturer's labeling

IV = intravenous

Preparation

Nelarabine is prepared without dilution by transferring the dose into an empty, sterile glass or polyvinyl chloride (PVC) container.

Stability

Nelarabine is stable at room temperature in glass or PVC containers for up to 8 hours after dispensing.

Administration

Nelarabine is administered as a 1 or 2-hour infusion.

Toxicities

Mechanism of Action

Raf kinase activates the Raf/MEK/ERK pathway, a signaling cascade that mediates cellular proliferation, differentiation, and transformation. Sorafenib inhibits Raf kinase and thus reduces deregulated proliferation of malignant cells. Sorafenib also inhibits the vascular endothelial growth factor (VEGF) receptors, VEGFR-2 and VEGFR-3, which are involved in tumor progression and angiogenesis.

Pharmacokinetics

Mean relative bioavailability of orally administered sorafenib tablets is 38% to 49% in the fasting state, with peak levels reached in about 3 hours. When given with a high-fat meal, sorafenib absorption is reduced by 29% compared to the fasting state. Mean elimination half-life is 25 to 48 hours. Multiple dosing for 7 days can produce a 2.5- to 7-fold accumulation compared to single-dose administration. Steady state plasma levels are achieved within 7 days, with a peak-to-trough ratio of mean concentrations of less than 2. Mean C_max and AUC increase less than proportionately when a dose of greater than 400 mg twice a day is given. In vitro, sorafenib is 99.5% bound to human plasma proteins. Metabolism is primarily by the liver through CYP3A4-mediated oxidation and UGT1A9-mediated glucuronidation. The pyridine N-oxide metabolite has in vitro potency similar to that of sorafenib. Following a 100 mg oral dose, 96% of the dose was recovered within 14 days, with 77% excreted in feces and 19% in urine as glucuronidated metabolite. Unchanged sorafenib accounted for 51% of excretion, all in the feces.

Selected therapeutic regimens of sorafenib appear in Table 2.

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Table 2.

Selected Therapeutic Regimens of Sorafenib

Daily Dose	Route of Administration	Administered on Day(s)	Cycle Length	Total Dose/Cycle	References
400 mg twice daily	Oral	Daily	–	–	7, 8, 9 *
50 to 400 mg twice daily	Oral	Daily	–	–	10
50 to 400 mg twice daily	Oral	1 through 21	28 days	2,100 to 16,800 mg	11
100 to 600 mg twice daily	Oral	1,2,3,4,5,6,7	14 days	1,400 to 8,400 mg	12

*

Conforms to dosing information listed in the manufacturer's labeling

Administration

Sorafenib is administered orally twice daily on an empty stomach (1 hour before or 2 hours after eating).

Toxicities