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CAPRELSA is a brand name for Vandetanib, supplied as a tablet. The medicine, its uses, side effects and dosage are the same regardless of brand.
Verbatim from this product's HC label. Tap a section to expand.
and 7 WARNINGS AND PRECAUTIONS; Cardiovascular). 5 Drug-Food Interactions Exposure to CAPRELSA is not affected by a meal. Products and juices containing grapefruit, star fruit, pomegranate, Seville oranges and other similar fruits that are known to inhibit CYP3A4 should be avoided at any time.
6 Drug-Herb Interactions Interactions with herbal products have not been studied. St. John’s Wort is a potent CYP3A4 inducer. PrCAPRELSA® (vandetanib) Page 26 of 47 Protected B / Protégé B Co-administration with CAPRELSA may lead to increased CAPRELSA metabolism, therefore decreased CAPRELSA serum concentrations.
Co-administration with CAPRELSA should be avoided. 7 Drug-Laboratory Test Interactions Interactions with laboratory tests have not been established. 1 Mechanism of Action Vandetanib is a potent and selective inhibitor of vascular endothelial growth factor receptor-2 (VEGFR- 2, KDR), epidermal growth factor receptor (EGFR), and Rearranged during Transfection (RET) receptor tyrosine kinases.
At sub-micromolar concentrations vandetanib also inhibits VEGFR-3 (Flt-4) and VEGFR-1 (Flt-1) with approximately 3 – 7 fold selectivity, respectively. Vandetanib inhibits VEGF-stimulated endothelial cell migration, proliferation, survival and new blood vessel formation in in vitro models of angiogenesis.
In vivo vandetanib administration reduced tumour cell-induced angiogenesis, tumour vessel permeability and tumour microvessel density, and inhibited tumour growth and metastasis in human xenograft models of lung cancer in athymic mice.
In addition, vandetanib inhibits epidermal growth factor (EGF)-stimulated EGF receptor tyrosine kinase in tumour cells and endothelial cells. Vandetanib inhibits EGFR-dependent cell proliferation and cell survival in vitro. In cellular assays, vandetanib has been shown to inhibit wild-type RET kinase activity and the kinase activity of the majority of RET kinase mutants that occur in both sporadic and hereditary forms of medullary thyroid cancer.
1μM) receptor tyrosine kinases, and a potent inhibitor of both wild-type and many mutant variants of RET kinase. In cellular assays, vandetanib treatment reduced intracellular levels of phosphorylated RET in cells expressing two prevalent gain-of-function activating mutations found in papillary thyroid cancer (PTC) and MTC.
In addition, vandetanib inhibited the proliferation of two human PTC cell lines (TPC-1 and FB2) carrying RET/PTC1 genetic rearrangements. The inhibitory activities of the two predominant metabolites of vandetanib, N-desmethyl vandetanib and vandetanib N-oxide, were found to retain potency broadly similar to vandetanib for inhibition of VEGFR-2, EGFR and FGFR-1 (fibroblast growth factor receptor-1) in recombinant enzyme assays.
In contrast, while N-desmethyl vandetanib inhibited VEGF-, EGF- and bFGF (basic fibroblast growth factor)-stimulated HUVEC proliferation with similar potency to vandetanib, vandetanib N-oxide had only weak inhibitory activity in these cellular assays.
; Cardiovascular). 5 Drug-Food Interactions Exposure to CAPRELSA is not affected by a meal. Products and juices containing grapefruit, star fruit, pomegranate, Seville oranges and other similar fruits that are known to inhibit CYP3A4 should be avoided at any time.
6 Drug-Herb Interactions Interactions with herbal products have not been studied. St. John’s Wort is a potent CYP3A4 inducer. PrCAPRELSA® (vandetanib) Page 26 of 47 Protected B / Protégé B Co-administration with CAPRELSA may lead to increased CAPRELSA metabolism, therefore decreased CAPRELSA serum concentrations.
Co-administration with CAPRELSA should be avoided. 7 Drug-Laboratory Test Interactions Interactions with laboratory tests have not been established. 1 Mechanism of Action Vandetanib is a potent and selective inhibitor of vascular endothelial growth factor receptor-2 (VEGFR- 2, KDR), epidermal growth factor receptor (EGFR), and Rearranged during Transfection (RET) receptor tyrosine kinases.
At sub-micromolar concentrations vandetanib also inhibits VEGFR-3 (Flt-4) and VEGFR-1 (Flt-1) with approximately 3 – 7 fold selectivity, respectively. Vandetanib inhibits VEGF-stimulated endothelial cell migration, proliferation, survival and new blood vessel formation in in vitro models of angiogenesis.
In vivo vandetanib administration reduced tumour cell-induced angiogenesis, tumour vessel permeability and tumour microvessel density, and inhibited tumour growth and metastasis in human xenograft models of lung cancer in athymic mice.
In addition, vandetanib inhibits epidermal growth factor (EGF)-stimulated EGF receptor tyrosine kinase in tumour cells and endothelial cells. Vandetanib inhibits EGFR-dependent cell proliferation and cell survival in vitro. In cellular assays, vandetanib has been shown to inhibit wild-type RET kinase activity and the kinase activity of the majority of RET kinase mutants that occur in both sporadic and hereditary forms of medullary thyroid cancer.
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Vandetanib has broad spectrum antitumour activity in a range of tumour models in vivo. Treatment with vandetanib significantly inhibited established NIH-RET/PTC3 tumour growth, reducing both tumour blood vessel density and levels of phosphorylated RET protein.
Animal data suggests that hemoglobin levels may increase due to increased hepatic erythropoietin production in patients receiving VEGF inhibitors. At various exposure durations, median hemoglobin levels in patients treated with vandetanib were increased by 5–15 g/L compared to baseline.
3 Pharmacokinetics The pharmacokinetics of vandetanib at the 300 mg dose in medullary thyroid cancer patients is characterized in Table 7 below. The half-life of vandetanib is 19 days. 2 7450 18782 Absorption Following a single oral administration of vandetanib absorption is slow with peak plasma concentrations typically achieved at a median of 6 hours, range 4 - 10 hours, after dosing.
Vandetanib accumulates ~8-fold on multiple dosing with steady state achieved from ~2 months.
Distribution:
Vandetanib binds to human serum albumin and α1-acid-glycoprotein with in vitro protein binding being ~90%. 7 %).
Metabolism:
Following oral dosing of 14C- vandetanib, unchanged vandetanib and metabolites vandetanib N-oxide and N-desmethyl vandetanib were detected in plasma, urine and feces. Glucuronide conjugate was seen as a minor metabolite in excreta only.
4% of those of vandetanib.
Elimination:
Within a 21 day collection period after a single dose of 14C-vandetanib, ~69% was recovered with 44% in faeces and 25% in urine. Excretion of the dose was slow and further excretion beyond 21 days would be expected based on the plasma half-life.
Across the clinical program the pharmacokinetics of vandetanib have been shown to be linear in both healthy volunteers (up to 1200 mg single dose) and patients receiving once daily dosing (100 mg and 300 mg multiple doses). Vandetanib was not a substrate of hOCT2 expressed in HEK293 cells.
Vandetanib was an inhibitor of OCT2 inhibiting the uptake of the selective OCT2 marker substrate 14C-creatinine by […]
1μM) receptor tyrosine kinases, and a potent inhibitor of both wild-type and many mutant variants of RET kinase. In cellular assays, vandetanib treatment reduced intracellular levels of phosphorylated RET in cells expressing two prevalent gain-of-function activating mutations found in papillary thyroid cancer (PTC) and MTC.
In addition, vandetanib inhibited the proliferation of two human PTC cell lines (TPC-1 and FB2) carrying RET/PTC1 genetic rearrangements. The inhibitory activities of the two predominant metabolites of vandetanib, N-desmethyl vandetanib and vandetanib N-oxide, were found to retain potency broadly similar to vandetanib for inhibition of VEGFR-2, EGFR and FGFR-1 (fibroblast growth factor receptor-1) in recombinant enzyme assays.
In contrast, while N-desmethyl vandetanib inhibited VEGF-, EGF- and bFGF (basic fibroblast growth factor)-stimulated HUVEC proliferation with similar potency to vandetanib, vandetanib N-oxide had only weak inhibitory activity in these cellular assays.
Vandetanib has broad spectrum antitumour activity in a range of tumour models in vivo. Treatment with vandetanib significantly inhibited established NIH-RET/PTC3 tumour growth, reducing both tumour blood vessel density and levels of phosphorylated RET protein.
Animal data suggests that hemoglobin levels may increase due to increased hepatic erythropoietin production in patients receiving VEGF inhibitors. At various exposure durations, median hemoglobin levels in patients treated with vandetanib were increased by 5–15 g/L compared to baseline.
3 Pharmacokinetics The pharmacokinetics of vandetanib at the 300 mg dose in medullary thyroid cancer patients is characterized in Table 7 below. The half-life of vandetanib is 19 days. 2 7450 18782 Absorption Following a single oral administration of vandetanib absorption is slow with peak plasma concentrations typically achieved at a median of 6 hours, range 4 - 10 hours, after dosing.
Vandetanib accumulates ~8-fold on multiple dosing with steady state achieved from ~2 months.
Distribution:
Vandetanib binds to human serum albumin and α1-acid-glycoprotein with in vitro protein binding being ~90%. 7 %).
Metabolism:
Following oral dosing of 14C- vandetanib, unchanged vandetanib and metabolites vandetanib N-oxide and N-desmethyl vandetanib were detected in plasma, urine and feces. Glucuronide conjugate was seen as a minor metabolite in excreta only.
4% of those of vandetanib.
Elimination:
Within a 21 day collection period after a single dose of 14C-vandetanib, ~69% was recovered with 44% in faeces and 25% in urine. Excretion of the dose was slow and further excretion beyond 21 days would be expected based on the plasma half-life.
Across the clinical program the pharmacokinetics of vandetanib have been shown to be linear in both healthy volunteers (up to 1200 mg single dose) and patients receiving once daily dosing (100 mg and 300 mg multiple doses). Vandetanib was not a substrate of hOCT2 expressed in HEK293 cells.
Vandetanib was an inhibitor of OCT2 inhibiting the uptake of the selective OCT2 marker substrate 14C-creatinine by HEKC-OCT2 cells, with a mean IC50 of […]