SUTRIBAX 25 mg CAPSULES

Indications

• Support in energy metabolism
• Management of metabolic disorders
• Potential role in exercise performance enhancement

Dosage

Children: Refer to specific guidance in the BNF for Children.

Adults: Refer to specific guidance in the BNF.

Mechanism of action

Malate participates in the malate-aspartate shuttle, which is essential for transferring reducing equivalents across the mitochondrial membrane. This shuttle allows for the conversion of NADH produced during glycolysis to NADH within the mitochondria, thus facilitating ATP production. Additionally, malate is involved in gluconeogenesis, where it contributes to the synthesis of glucose from non-carbohydrate precursors.

Pharmacodynamics

Malate aids in energy metabolism, particularly in the conversion of nutrients to ATP. It supports the regeneration of NAD+, which is crucial for numerous metabolic reactions. By participating in the TCA cycle, malate enhances aerobic respiration and plays a role in maintaining the balance of metabolic intermediates necessary for cellular function.

Pharmacokinetics

Malate is readily absorbed in the gastrointestinal tract and is distributed throughout the body, where it enters various metabolic pathways. It is primarily metabolized in the liver and muscle tissues. The elimination of malate is through metabolic conversion, with its metabolites being further processed in the TCA cycle.

Pregnancy

There are no well-controlled studies of malate in pregnant women. Use only if clearly needed.

Breast-feeding

Malate is considered to be safe during breastfeeding, though limited data are available.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Malate salts
• Malic acid

Indications

• Treatment of advanced renal cell carcinoma
• Treatment of progressive, locally advanced, or metastatic differentiated thyroid carcinoma that is refractory to radioactive iodine
• Treatment of unresectable or metastatic hepatocellular carcinoma

Dosage

Children: Refer to the BNF for Children for paediatric dosing information.

Adults: 400 mg once daily. For dose adjustments due to side effects, consult product literature.

Mechanism of action

Sunitinib inhibits multiple receptor tyrosine kinases (RTKs) such as PDGFRα, PDGFRβ, VEGFR1, VEGFR2, VEGFR3, KIT, FLT3, CSF-1R, and RET. By blocking these RTKs, it disrupts signaling pathways involved in cell proliferation, angiogenesis, and metastatic progression of cancer, ultimately leading to reduced tumor growth.

Pharmacodynamics

Sunitinib exhibits a multi-targeted approach in cancer treatment, demonstrating potent inhibition against over 80 kinases involved in oncogenic processes. It is effective in reducing tumor vascularization and proliferation through its action on both tumor and endothelial cells, contributing to its therapeutic efficacy in various cancers.

Pharmacokinetics

Sunitinib is administered orally and is known to have a half-life that allows for once-daily dosing. It undergoes extensive metabolism in the liver, primarily via cytochrome P450 enzymes. Its pharmacokinetic profile allows for significant inter-patient variability, which may necessitate dose adjustments based on individual tolerance and side effect profiles.

Contra-indications

• Hypersensitivity to sunitinib or any of its excipients
• Severe hepatic impairment
• History of aneurysm or artery dissection

Adverse effects

• Alopecia
• Anaemia
• Decreased appetite
• Arthralgia
• Asthenia
• Congestive heart failure
• Constipation
• Decreased leucocytes
• Depression
• Diarrhoea

Interactions

• Grapefruit juice - severe (increases exposure)
• Elbasvir - moderate (increases concentration)
• Grazoprevir - moderate (increases concentration)
• Dronedarone - unknown (increases exposure)
• Antifungal azoles - unknown (increases exposure)
• Cobicistat - unknown (increases exposure)
• Crizotinib - unknown (increases exposure)
• Dabrafenib - unknown (decreases exposure)
• Bosentan - unknown (decreases exposure)
• Idelalisib - unknown (increases exposure)

Precautions

• Monitor blood pressure regularly during treatment
• Assess for potential risk of bleeding in patients with tracheal, bronchial, or oesophageal infiltration
• Consider monitoring ECG and electrolytes in patients susceptible to QT-interval prolongation
• Monitor plasma-calcium concentration due to risk of hypocalcaemia in patients with a history of hypoparathyroidism
• Monitor thyroid stimulating hormone in patients with differentiated thyroid carcinoma

Pregnancy

Manufacturer advises avoidance unless essential due to toxicity in animal studies.

Breast-feeding

Discontinue breast-feeding during treatment.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Sunitinib malate 12.5 mg capsules
• Sunitinib malate 25 mg capsules
• Sunitinib malate 37.5 mg capsules
• Sunitinib malate 50 mg capsules

Mechanism of action

Sunitinib is a small molecule that inhibits multiple RTKs, some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against a variety of kinases (>80 kinases) and was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRa and PDGFRb), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the activity of these RTKs has been demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays. Sunitinib malate, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent. Receptor tyrosine kinases (RTKs) are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (eg, angiogenesis, metastasis, inhibition of apoptosis), based on the respective kinase. Although the exact mechanism of antineoplastic activity of sunitinib has not been fully elucidated, data from biochemical and cellular assays indicate that sunitinib may inhibit signal transduction pathways involving multiple receptor (ie, cell surface) tyrosine kinases, including platelet-derived growth factor receptors (ie, PDGFR-alpha, PDGFR-beta), vascular endothelial growth factor receptors (ie, VEGFR-1, VEGFR-2, VEGFR-3), stem cell factor receptor (ie, c-Kit), fms-like tyrosine kinase 3 (Flt-3), colony stimulating factor receptor type 1 (CSF-1R), and the glial cell line-derived neurotrophic factor receptor (RET). Sunitinib-induced inhibition of signal transduction pathways involving PDGFR-beta, VEGFR-2, and c-Kit has been confirmed in tumor xenografts expressing receptor tyrosine kinase targets in vivo. Sunitinib has been shown to inhibit growth of tumor cells expressing dysregulated target receptor tyrosine kinases (ie, PDGFR, RET, c-Kit) in vitro; the drug also has been shown to inhibit PDGFR-beta- and VEGFR-2-dependent tumor angiogenesis in vivo. Sunitinib inhibited the phosphorylation of multiple RTKs (PDGFR-beta, VEGFR2, KIT) in tumor xenografts expressing RTK targets in vivo and demonstrated inhibition of tumor growth or tumor regression and/or inhibited metastases in some experimental models of cancer. Sunitinib demonstrated the ability to inhibit growth of tumor cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFR-beta- and VEGFR2-dependent tumor angiogenesis in vivo. ... Sunitinib malate is an oral, multitargeted kinase inhibitor with antiangiogenic and antitumor activity due to inhibition of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor alpha (PDGFR-alpha), and the tyrosine kinases c-KIT and FLT3. Sunitinib has antitumor activity in various cancers, including imatinib-resistant gastrointestinal stromal tumors, metastatic breast cancer, neuroendocrine tumors, and renal-cell carcinoma. ... Sunitinib, which is a multitargeted tyrosine-kinase inhibitor, exhibits antiangiogenic and antitumor activity, and extends survival of patients with metastatic renal-cell carcinoma (mRCC) and gastrointestinal stromal tumors (GIST). This molecule has also been reported to be associated with cardiotoxicity at a high frequency, but the mechanism is still unknown. In the present study, /investigators/ observed that Sunitinib showed high anti-proliferative effect on H9c2 cardiac muscle cells measured by PI staining and the MTT assay. But apoptotic markers (PARP cleavage, caspase 3 cleavage and chromatin condensation) were uniformly negative i

Pharmacodynamics

Sunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA on January 26, 2006.