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Chapter: Clinical Pharmacology: Antineoplastic drugs

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Targeted therapies

A groundbreaking approach to anticancer therapies involves tar-geting proteins associated with the growth patterns of specific types of cancer.

Targeted therapies

A groundbreaking approach to anticancer therapies involves tar-geting proteins associated with the growth patterns of specific types of cancer. Drugs used for this new approach to cancer treat-ment include:

 

·                 bortezomib

 

·                 gefitinib

 

·                 imatinib.

 

Pharmacokinetics

 

Bortezomib isn’t absorbed orally and must be given I.V. It’s exten-sively distributed into body tissues and metabolized by the liver.

 

·                 Gefitinib is available in an oral form, and about half of thedose is absorbed. The drug is widely distributed in tissues. It un-dergoes hepatic metabolism with minimal urinary excretion.

 

·                 Imatinib is also available in an oral form and is almost com-pletely absorbed. It’s 95% bound to plasma proteins and is exten-sively metabolized by the liver. The half-life of imatinib is about 15 hours.

Pharmacodynamics

 

Bortezomib inhibits proteosomes, which are involved in integral cell-cycle function and promote tumor growth. Proteolysis by bortezomib results in disruption of the normal homeostatic mech-anisms and leads to cell death.

Too much of this…

 

Gefitinib inhibits the epidermal growth factor receptor-1 tyrosine kinase, which is overexpressed in such cancers as non–small-cell lung cancer. This inhibition blocks signaling pathways for growth, survival, and metastasis of cancer.

 

…too many of those

 

In patients with chronic myeloid leukemia, the BCR-ABL protein stimulates other tyrosine kinase proteins, causing an abnormally high production of WBCs. Imatinib binds to the adenosine triphos-phate–binding domain of the BCR-ABL protein, effectively shut-ting down the abnormal WBC production.

Pharmacotherapeutics

 

Bortezomib is used to treat multiple myeloma that has relapsed af-ter standard chemotherapy.

 

·                 Gefitinib is used as a single agent for patients with non–small-cell lung cancer that hasn’t responded to two standard chemother-apy regimens.

 

·                 Imatinib is used to treat chronic myeloid leukemia, acute lym-phoid leukemia, and GI stomal tumors.

 

Drug interactions

 

Bortezomib, gefitinib, and imatinib have been associated with some drug interactions.

 

·                 Bortezomib when taken with drugs that inhibit cytochrome CYP3A4 (such as amiodarone, cimetidine, erythromycin, dilti-azem, fluoxetine, verapamil, zafirlukast, and zileuton) or induce cytochrome CYP3A4 (such as amiodarone, carbamazepine, nevir-apine, phenobarbital, phenytoin, and rifampin), could cause either toxicities or reduced efficacy of these drugs.

 

·                 Bortezomib when taken with oral hypoglycemics could cause hypoglycemia and hyperglycemia in patients with diabetes.

 

·                 Plasma levels of gefitinib and imatinib are reduced, sometimes substantially, when these drugs are given with carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, or St. John’s wort.

 

·                 High doses of ranitidine with sodium bicarbonate when taken with gefitinib reduce gefitinib levels.

 

·                 Administration of gefitinib or imatinib with warfarin causes ele-vations in the International Normalized Ratio, increasing the risk of bleeding.

 

·                  Clarithromycin, erythromycin, itraconazole, and ketoconazole, when taken with imatinibor may increase imatinib plasma levels.


·                 Carbamazepine, dexamethasone, phenobarbital, phenytoin, or rifampin given with imatinib may increase metabolism of imatinib and decrease imatinib level.

 

·                 Imatinib given with simvastatin increases simvastatin levels about threefold.

 

·                 Imatinib increases plasma levels of other CYP3A4-metabolized drugs, such as triazolo-benzodiazepines, calcium channel block-ers, and certain HMG-CoA reductase inhibitors. (See Adverse re-actions to targeted therapies.)

 

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