Ixabepilone;Nilotinib

Abstract

The increasing complexity of cancer chemotherapy now requires that pharmacists be familiar with these highly toxic agents. This column will review various issues related to preparation, dispensing, and administration of cancer chemotherapy, and review various agents, both commercially available and investigational, used to treat malignant diseases.

Mechanism of Action

Agent: IXABEPILONE

Synonyms: Ixempra; BMS-247550; NSC-710428

Ixabepilone is the first of a new group of antineoplastic agents called epothilones to be approved for clinical use. The drug suppresses the dynamic instability of alpha beta-II and alpha beta-III microtubules by binding to the beta-tubulin subunit of the microtubule. This stabilizes microtubular function, arresting the cell cycle in the G2/M phase and inducing apoptosis.

Pharmacokinetics

The maximum concentration (C_max) following a single intravenous (IV) dose of ixabepilone 40 mg/m² is 252 ng/mL. Ixabepilone is about 67% to 77% bound to plasma proteins and has a large (greater than 1,000 L/m²) volume of distribution (V_d). The drug is extensively metabolized by the liver, primarily by CYP3A4, into at least 30 inactive metabolites. The drug is not an inhibitor of CYP3A4, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6, nor an inducer of CYP1A2, CYP2B6, CYP2C9, or CYP3A4. Ixabepilone is excreted primarily (65%) in the feces with approximately 1.6% of the dose eliminated as unchanged drug. About 21% of a dose is excreted renally and 6% is as unchanged drug. Ixabepilone has an elimination half-life (T_½) of about 52 hours.

Selected therapeutic regimens of ixabepilone appear in Table 1.

Table 1.

Selected Therapeutic Regimens of Ixabepilone^a

Daily Dose	Route of Administration	Administered on Day(s)	Total Dose/Cycle	References
6 mg/m²	IV	1,2,3,4,5	30 mg/m²	1,6,9,12
8 mg/m² (cycle 1) then	IV	1,2,3	24 mg/m² then	2
10 mg/m²			30 mg/m²
50 mg/m²	IV	1	50 mg/m²	3,14
40 mg/m² ^b	IV	1	40 mg/m²	3-5,8,10,11,13,14,16
35 mg/m²	IV	1	35 mg/m²	7
32 mg/m²	IV	1	32 mg/m²	12
8 mg/m²	IV	1,2,3	24 mg/m²	15
10 mg/m²	IV	1,2,3	30 mg/m²	2

All cycle lengths were 21 days;

Conforms to dosing information listed in the manufacturer's labeling; IV = intravenous.

Preparation

The drug and diluent should be allowed to reach room temperature prior to reconstitution. The diluent may contain a white precipitate, which should dissolve when the solution reaches room temperature. Ixabepilone must be reconstituted to a concentration of 2 mg/mL with the provided diluent prior to dilution for infusion. This ixabepilone solution is further diluted in Ringer's lactate to a final concentration of 0.2 to 0.6 mg/mL (250 or 500 mL for most patients). The drug should be dispensed in a glass, polypropylene, or polyolefin (non-diethylhexyl phthalate) container.

Stability

Reconstituted vials are stable for 1 hour at room temperature; solutions diluted in Ringer's lactate for infusion are stable for 6 hours at room temperature.

Administration

Ixabepilone is administered as an IV infusion, usually over 3 hours.

Ixabepilone should be administered through a 0.22 micron filter using a polyethylene-lined (non-sorbing) infusion set.

Drug Interactions

Ixabepilone is a substrate of CYP3A4; therefore, inducers of CYP3A4 may decrease the effects of the drug, while CYP3A4 inhibiters may increase its effect. Due to limited experience with the drug, with the exception of ketoconazole, these interactions are based on theoretical considerations of the drugs' mechanisms of action rather than documented clinical cases.

CYP3A4 inducers: Agents such as aminoglutethimide, carbamazepine, dexamethasone, nafcillin, nevirapine, phenobarbital, phenytoin, rifamycins, and St. John's Wort may decrease the effect of ixabepilone.

CYP3A4 inhibitors: Agents such as azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, grapefruit juice, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil may increase the effect of ixabepilone.

Toxicities

Incidence values are rounded to the nearest whole percent unless incidence was less than or equal to 0.5%. A.

Cardiovascular Cerebrovascular ischemia (grade 3) 3%¹⁰; edema 3% to 5%¹²; thrombosis (grade 1 or 2) 2%⁷; supraventricular arrhythmia 2%¹³; unspecified 14%,³ (grade 1) 4% to 17%,^3,8 (grade 2) 6% to 22%,^3,8 (grade 3) 2% to 4%.^3,8

Central Nervous System Dizziness 7%,⁴ (grade 2) 2%⁴; headache 3% to 14%,^4,5,12 (grade 2) 6%,⁴ (grade 3) 2%¹⁰; insomnia (grade 1) 14%,⁸ (grade 2) 2%.⁸

Dermatologic Alopecia 35% to 92%,^3-5,9,12 (grade 1) 6% to 26%,^1-3,6 (grade 2) 25% to 61%^1-4,6; nail changes 5% to 17%,^3-5,12 (grade 1) 1% to 30%,^1-3,6 (grade 2) 2% to 26%,^1-3,6 (grade 3) 2% to 4%^3,4; pruritus (grade 3) 2%¹⁰; rash 6% to 22%,^3,5,9,12 (grade 1) 6%,³ (grad 2) 4%,³ (grade 3) 2% to 4%^3,9; unspecified (grade 1) 24%,⁸ (grade 2) 29%,⁸ (grade 3) 2%.⁸

Gastrointestinal Anorexia 18% to 43%,^3-5,9,12 (grade 1) 10%,³ (grade 2) 3% to 6%,^3,4 (grade 3) 2% to 17%^3,4,9,10; constipation 14% to 22%,^3-5,9,12 (grade 1) 5% to 33%%,^1-3,6 (grade 2) 6% to 43%,^1,2,4,6 (grade 3) 1% to 4%^3,4,10,12; dehydration 8%,⁹ (grade 3) 4% to 9%^9,10,13; diarrhea 17% to 33%,^3-5,9,12 (grade 1) 19% to 39%,^1-3,6 (grade 2) 4% to 17%,^1-4,6 (grade 3) 1% to 11%^1,3-6,9,12; duodenal ulcer (grade 3) 2%¹⁰; dysphagia/esophagitis/odynophagia 26%,⁹ (grade 3) 4%,⁹ (grade 4) 2%¹⁰; dysgeusia 6%,⁴ (grade 1) 19% to 50%,^1,2,6 (grade 2) 1% to 22%^1,4,6; gastroesophageal reflux 6%,⁴ (grade 2) 2%⁴; mucositis 6% to 10%,^3,12 (grade 1) 8%,³ (grade 2) 2%³; nausea 31% to 70%,^3,5,9,12 (grade 1) 27% to 50%,^1-3,6 (grade 2) 3% to 25%,^1-4,6 (grade 3) 2% to 13%^{1,3-6,9,10-12}; rectal bleeding/hematochezia (grade 3) 2%¹⁰; stomatitis/pharyngitis 12% to 32%,^3-5,9,12 (grade 1) 10%,³ (grade 2) 4% to 7%,^3,4 (grade 3) 1% to 8%,^3-5,10-12 (grade 4) 1% to 2%^4,10; taste changes 4% to 11%^5,12; vomiting 19% to 48%,^3-5,9,12 (grade 1) 8% to 26%,^1-3,4 (grade 1 or 2) 28%,⁷ (grade 2) 8% to 20%,^1-4,6 (grade 3) 1% to 13%,^{1,3–5,9,10,12} (grade 4) 2%⁵; unspecified (grade 1) 40%,⁸ (grade 2) 38%,⁸ (grade 3) 7%.⁸

Genitourinary Increased creatinine (grade 4) 2%¹⁰; renal failure (grade 3) 2%^10,13; unspecified 8%,⁹ (grade 3) 4%.⁹

Hematologic Anemia 6% to 96%%,^3-5,9,12 (grade 1) 2% to 48%,^1-3,6,8 (grade 1 or 2) 70%,⁷ (grade 2) 12% to 58%,^1,2,4,6,8 (grade 3) 2% to 8%,^{3-5,8,9,11-13} (grade 4) 1% to 8%^3,4,9,11,12; leukopenia 4% to 92%,^4,5,9,12 (grade 1) 8% to 12%,^2,8 (grade 2) 4% to 25%,^2-4,8 (grade 3) 2% to 42%,^2-5,8,9-12 (grade 4) 2% to 17%^{2,4,5,8,10-12}; lymphopenia (grade 2) 10%,⁸ (grade 3) 2% to 33%^8,11; neutropenia 9% to 89%,^4,5,9,12 (grade 1) 8% to 25%,^1,2,6,8 (grade 1 or 2) 30%,⁷ (grade 2) 5% to 57%,^1,2,4,6,8 (grade 3) 4% to 42%,^1,2,4-12 (grade 3 or 4) 36%,¹³ (grade 4) 3% to 31%^1,4-12; febrile neutropenia 1% to 86%,^{1,3,7,9,12,13} (grade 1) 2%,³ (grade 2) 6%,³ (grade 3) 1% to 8%,^3,9,11,12 (grade 4) 2% to 3%,^3,12 (grade 5) 2%¹³; thrombocytopenia 24% to 44%,^4,5,12 (grade 1) 25% to 43%,^1,2,6 (grade 1 or 2) 15%,⁷ (grade 2) 4% to 17%,^2,4,6 (grade 3) 1% to 11%,^{1,2,4,6,11-13} (grade 4) 2% to 5%.^1,4,10

Hepatic Increased alkaline phosphatase (grade 3) 3% to 8%^9,11; increased bilirubin (grade 3) 4% to 8%^9,11; increased transaminases (grade 1) 33%,² (grade 2) 17%²; unspecified 4%,³ (grade 1) 12%,⁸ (grade 2) 2%,^3,8 (grade 3) 2%,⁸ (grade 4) 2%.³

Infection Unspecified (grade 2) 2%,⁸ (grade 3) 12%⁸; with grade 3 or 4 neutropenia (grade 1) 4%,⁹ (grade 3) 2% to 6%^5,9,10; without neutropenia 9% to 12%,^3,5 (grade 1) 2%,³ (grade 2) 6%,³ (grade 3) 2% to 3%,^3,5,10 (grade 4) 2%.³

Metabolic/Endocrine Allergic reactions 4% to 13%,^3,4,9,12 (grade 1) 8%,³ (grade 1 or 2) 2%,⁷ (grade 3) 1% to 4%^2,7,9,10; allergic/immune reactions 10%,³ (grade 1) 8%,³ (grade 2) 2%³; fatigue 50% to 83%,^3-5,9,12 (grade 1) 16% to 42%,^1-3,6 (grade 1 or 2) 68%,⁷ (grade 2) 21% to 42%,^1-4,6 (grade 3) 4% to 27%,^{1,3-7,9,10,13} (grade 4) 1% to 13%^1,4,9,10; fever 6% to 16%,^3-5,12 (grade 1) 10%,³ (grade 2) 2% to 6%,^3,4 (grade 3) 1% to 9%^4,12; flu-like symptoms (grade 1) 33%,⁸ (grade 2) 14%,⁸ (grade 3) 12%,⁸ (grade 5) 2%¹⁰; hot flushes 6%,⁴ (grade 2) 2%⁴; hyperglycemia (grade 3) 8%¹¹; hyperkalemia (grade 4) 2%¹⁰; hypoalbuminemia (grade 3) 2%¹⁰; hypocalcemia (grade 3) 2%¹⁰; hypoglycemia 8%¹¹; hypokalemia 8%¹¹; hyponatremia (grade 3) 8%¹¹; hypophosphatemia (grade 3) 17%¹¹; unspecified (grade 1) 4% to 19%,^8,9 (grade 2) 5%,⁸ (grade 3) 2% to 4%.^8,9

Musculoskeletal Abdominal pain/cramping 8% to 26%,^3,5,9 (grade 1) 4%,³ (grade 2) 3% to 4%,^3,4 (grade 3) 2% to 4%^3,4,9,10; arthralgia 13% to 35%,^3,5,9,12 (grade 1) 12% to 17%,^3,6 (grade 2) 9% to 20%,^3,6 (grade 3) 1% to 5%,^3,5,9,12 (grade 4) 4%⁶; bone pain 6% to 9%,^3,9 (grade 1) 6%,³ (grade 3) 4%⁹; musculoskeletal pain 20%,⁴ (grade 2) 9%,⁴(grade 3) 3%⁴; muscle weakness (grade 3) 2%¹⁰; myalgia 21% to 65%,^3,5,9,12 (grade 1) 12%,³ (grade 2) 27%,³ (grade 3) 1% to 10%,^3,5,9,12 (grade 4) 4%⁹; myalgia/arthralgia 49%,⁴ (grade 1) 41% to 50%,^1,2 (grade 2) 1% to 26%,^1,2,4 (grade 3) 3% to 8%^1,4; neuropathic pain 8% to 12%,^3,5,9 (grade 1) 2%,³ (grade 2) 6% to 7%,^3,8 (grade 3) 2% to 5%,^5,8,9 (grade 4) 4%⁹; unspecified 5% to 8%,^4,12 (grade 1) 2% to 31%,^4,8 (grade 2) 2% to 19%,^4,8 (grade 3) 2% to 3%.^4,8

Neurologic Autonomic (grade 2) 4%⁶; motor neuropathy 6% to 10%,^4,5 (grade 1) 2%,⁸ (grade 2) 2% to 7%,^4,6,8 (grade 3) 1% to 5%^4-6,8; palmar-plantar erythrodysesthesia 4% to 8%,^4,9 (grade 1) 4%,⁹ (grade 2) 3%,⁴ (grade 3) 2%⁴; sensory neuropathy 29% to 71%,^3-5,9,12 (grade 1) 17% to 39%,^1-3,6,8 (grade 2) 13% to 33%,^1-4,6,8 (grade 3) 3% to 20%,^{1,3-5,8-10,12,13} (grade 4) 1% to 5%^4,9,10,12; unspecified 4% to 6%,^3,9 (grade 1) 2% to 4%,^3,9 (grade 1 or 2) 54%,⁷ (grade 3) 4% to 13%.^3,7

Pulmonary Dyspnea 9% to 13%,^4,9,12 (grade 3) 1% to 2%,^4,9,12 (grade 4) 1% to 4%^4,9,12; pneumonitis (grade 3) 2%.¹³

Recommended Reviews

Cortes J, Baselga J. Targeting the microtubules in breast cancer beyond taxanes: the epothilones. Oncologist. 2007;12(3):271-280.

Pivot X, Dufresne A, Villanueva C. Efficacy and safety of ixabepilone, a novel epothilone analogue. Clin Breast Cancer. 2007(7);7:543-549.

Agent: NILOTINIB

Synonyms: Nilotinib hydrochloride monohydrate; AMN107; Tasigna

Mechanism of Action

Nilotinib is a selective tyrosine kinase inhibitor that targets BCR-ABL kinase, c-KIT and platelet derived growth factor receptor (PDGFR). Nilotinib inhibits BCR-ABL-mediated proliferation by connecting to the adenosine triphosphate (ATP)-binding site of BCR-ABL and inhibiting tyrosine kinase activity. Nilotinib is active against BCR-ABL kinase mutations but lacks activity against SRC enzymes.

Pharmacokinetics

Following oral administration, the C_max is about 3 hours. Nilotinib is highly (about 98%) bound to plasma proteins. The peak concentration and area under the time curve (AUC) increase is about 112% and 82% if nilotinib is given after a high-fat meal. The drug is metabolized in the liver by oxidation and hydroxylation via CYP3A4 to primarily inactive metabolites. The elimination T_1/2 of nilotinib is about 15 to 17 hours. Excretion is primarily fecal (93%, 69% as unchanged drug). Selected therapeutic regimens of nilotinib appear in Table 2.

Table 2.

Selected Therapeutic Regimens of Nilotinib

Daily Dose	Route of Administration	Administered on Day(s)	Cycle Length	Total Dose/Cycle	References
400 mg twice a day^a	PO	Daily	—	24,000 mg	17-35
600 mg twice a day^b	PO	Daily	—	36,000 mg	17,21,23,28-30
800 mg once a day	PO	Daily	—	24,000 mg	19

Conforms to dosing information listed in the manufacturer's labeling;

Recommended for patients who do not respond to the initial 400 mg twice a day regimen; PO = oral.

Availability

Nilotinib is available as 200 mg capsules.

Administration

Nilotinib is given orally, preferably on an empty stomach (1 hour before or 2 hours after a meal).

Interactions

Nilotinib is a substrate of CYP3A4 and p-glycoprotein; therefore inducers of CYP3A4 or p-glycoprotein may decrease the effects of the drug, while CYP3A4 or p-glycoprotein inhibitors may increase its effect. Nilotinib is an inducer of CYP2C8, 2C9, and 2D6 and may decrease the effect of drugs which are substrates of these isoenzymes. A.

CYP3A4 Inducers Agents such as aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, rifamycins, and St. John's Wort may decrease the effect of nilotinib.

CYP3A4 Inhibitors Agents such as azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil may increase the effect of nilotinib.

CYP3A4 Substrates Agents such as benzodiazepines, calcium channel blockers, cyclosporine, midazolam, mirtazapine, nateglinide, nefazodone, PDE5 inhibitors, tacrolimus, and venlafaxine may either increase or decrease the effects of nilotinib.

QT_c-Prolonging Agents Nilotinib may prolong the QT_c interval, which increases the risk of arrhythmias and Torsade de pointes. Concurrent nilotinib use with class IA and class III antiarrhythmic agents, moxifloxacin, cisapride, dolasetron, and thioridazine should be avoided if possible.

CYP2B6 Substrates The effect of agents such as bupropion, efavirenz, promethazine, selegiline, and sertraline may be decreased if given with nilotinib.

CYP2C8 Substrates The effect of agents such as amiodarone, paclitaxel, pioglitazone, repaglinide, and rosiglitazone may be increased or decreased if given with nilotinib.

CYP2C9 Substrates The effect of agents such as bosentan, celecoxib, dapsone, fluoxetine, glimepiride, glipizide, losartan, montelukast, nateglinide, paclitaxel, phenytoin, sulfonamides, trimethoprim, warfarin, and zafirlukast may be increased or decreased if given with nilotinib.

CYP2D6 Prodrug Substrates The effect of agents such as codeine and tramadol may be decreased if given with nilotinib.

CYP2D6 Substrates The effect of agents such as amphetamines, selected beta blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine may be increased or decreased if given with nilotinib.

Toxicities

Incidence values are rounded to the nearest whole percent unless incidence was less than or equal to 0.5%. A.

Central Nervous System Dizziness (grade 3 or 4) 23%²²; extramedullary toxicity (grade 3 or 4) 31%²⁰; headache 19%,¹⁸ (grade 3 or 4) 2% to 43%.^18,22

Dermatologic Dry skin (grade 1 or 2) 6%¹⁷; pruritus 24%,¹⁸ (grade 1 or 2) 6%,¹⁷ (grade 3 or 4) 1% to 16%^17,18,22,26; rash 28%,¹⁸ (grade 1 or 2) 22%,¹⁷ (grade 3 or 4) 3% to 25%,^18,22,26 (dose limiting) 11%.²⁷

Gastrointestinal Constipation 12%,¹⁸ (grade 3 or 4) 17%²²; diarrhea 11%,¹⁸ (grade 3 or 4) 2% to 35%^18,22; nausea 24%,¹⁸ (grade 3 or 4) 1% to 47%^18–22; nausea or vomiting (grade 1 or 2) 13%¹⁷; vomiting 11%,¹⁸ (grade 3 or 4) 37%²²; unspecified (grade 3 or 4) 6%.³²

Hematologic Anemia (grade 3 or 4) 5% to 27%^{17,21,23-26,28,30,31,34}; myelosuppression (unspecified) (grade 3 or 4) 23%²⁰; neutropenia (grade 3 or 4) 6% to 45%^{17,18,21,23-25,28-32,34}; thrombocytopenia (grade 1 or 2) 3%,¹⁷ (grade 3 or 4) 9% to 41%.^{17,18,21,23-25,28-32,34}

Hepatic Increased bilirubin (grade 1 or 2) 6%,¹⁷ (grade 3 or 4) 3% to 6%,^17,25 (dose limiting) 11%²⁷; increased transaminases (grade 1 or 2) 3%,¹⁷ (grade 3 or 4) 3% to 17%^17,22,25; unspecified (grade 3 or 4) 8%.³²

Infection Neutropenic sepsis (fatal) 9%²⁶; pneumonia (grade 3 or 4) 11%.³⁰

Metabolic/Endocrine Diabetes mellitus (grade 3 or 4) 9%²⁶; fatigue 19%,¹⁸ (grade 1 or 2) 16%,¹⁷ (grade 3 or 4) 1% to 42%^18,22; increased lipase (grade 3 or 4) 5% to 17%,^{20,21,23-28,29,31} (grade 4) 9%¹⁷; pyrexia (grade 3 or 4) 18%.²²

Musculoskeletal Arthralgia (grade 3 or 4) 9% to 17%^22,26; bone pain (grade 3 or 4) 6% to 20%^22,25; extremity pain 5%¹⁸; muscle spasms (grade 3 or 4) 23%²²; musculoskeletal pain (grade 3 or 4) 8%²⁰; myalgia 8%,¹⁸ (grade 3 or 4) 1% to 18%.^18,22,26

Pulmonary Edema 3%²⁸; dyspnea (grade 3 or 4) 17%.²²

Recommended Reviews

Piccaluga PP, Paolini S, Martinelli G. Tyrosine kinase inhibitors for the treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia. Cancer. 2007;110(6):1178-1186.

Weisberg E, Manley P, Mestan J, Cowan-Jacob S, Ray A, Griffin JD. AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br J Cancer. 2006;94(12):1765-1769.

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