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. 2013 Nov 7;48(10):818–821. doi: 10.1310/hpj4810-818

Drug Monographs: Dabrafenib and Trametinib

J Aubrey Waddell, Dominic A Solimando Jr
PMCID: PMC3859275  PMID: 24421433

Abstract

The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@aol.comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net.

Name: Dabrafenib

Synonyms: Tafinlar, GSK2118436

Mechanism Of Action

Dabrafenib is a selective kinase inhibitor that is active against several mutated forms of BRAF kinase including BRAF V600E, BRAF V600K, and BRAF V600D.1 BRAF kinases are part of the mitogen-activated protein kinase (MAPK) pathway, which promotes cellular proliferation. Oncogenic mutations leading to activation of BRAF occur in a variety of tumor types, including cutaneous melanoma (50% of cases), papillary thyroid cancer (46% of cases), borderline ovarian tumors (34% of cases), and hairy cell leukemia (100% of cases).2 In cutaneous melanoma, the activating mutation in the BRAF gene is V600E in 70% to 95% of cases and V600K in 5% to 30% of cases. Mutant BRAF predicts a poor prognosis in metastatic melanoma.3

Pharmacokinetics

Following oral administration of 150 mg every 12 hours, the median time to peak plasma concentration (Tmax) is 2 hours1,2,4 and the mean absolute bioavailability is 95%.1 The geometric mean area under the plasma concentration-time curve (AUC) is 2619 ng•h/mL; the mean maximum plasma concentration (Cmax) is 806 ng/mL.2 Administration of dabrafenib with a high-fat meal causes a decrease in Cmax of 51%, a decrease in AUC of 31%, and an increase in Tmax to 3.6 hours compared to fasting state administration.1 Dabrafenib is 99.7% protein bound, with an apparent volume of distribution (Vd) of 70.3 L. Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4 to hydroxy-dabrafenib, probably an active metabolite, which is further oxidized by CYP3A4 to carboxy-dabrafenib, which is eliminated in bile and urine.1 The mean terminal half life (t½) is 5.2 to 8 hours,1,2 and the apparent clearance (CL) is 17 L/h following 14 days of twice-daily dosing.1 Radioactive dose testing reveals that 71% of dabrafenib is eliminated in the feces and 23% in the urine.1

Selected therapeutic regimens of dabrafenib appear in Table 1.

Table 1.

Selected therapeutic regimens of dabrafenib

Dose Route ofadministration Administered Cycle length Total dose/month References
75 mg PO Twice daily – 4,500 mg 4
150 mga PO Twice daily – 9,000 mg 1-5
200 mg PO Twice daily – 12,000 mg 2
300 mg PO Twice daily – 18,000 mg 2
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Note: PO = oral.

a

Conforms to dosing information listed in the manufacturer’s labeling.

Preparation

  1. Follow institutional policies for preparation of hazardous medications when dispensing dabrafenib.

  2. Dabrafenib is available as 50 mg and 75 mg capsules.

Storage

  1. Store at controlled room temperature of 20°C to 25°C (68°F to 77°F).

  2. Brief (less than 24 hours) exposure to temperatures up to 30°C (86°F) is acceptable.

Administration

  1. Dabrafenib is taken orally, with the daily dose divided and given twice a day.

  2. Dabrafenib should be taken 1 hour before or 2 hours after food.

Toxicities

  1. Cardiovascular: Hypertension (grade 1 or 2) 4%4; intracranial hemorrhage (all grades) 6%,3 (grade 4) 0.5%3; peripheral edema (grade 1 or 2) 17%.4

  2. Constitutional: Asthenia (grade 2) 3%,5 chills (grade 1 or 2) 17%,4 (grade 2) 2%,3 (grade 3) 0.5%3; fatigue (grade 1 or 2) 34%,4 (grade 2) 5% to 7%,2,3,5 (grade 3) 0.5% to 1%,2,3,5 (grade 3 or 4) 6%4; night sweats (grade 1 or 2) 6%4; pyrexia (all grades) 26%,3 (grade 1 or 2) 26%,4 (grade 2) 5% to 9%,2,3,5 (grade 3) 0.5% to 3%.2,3,5

  3. Dermatologic: Acneiform dermatitis (grade 1 or 2) 4%4; actinic keratosis (all grades) 5% to 10%,2,3 (grade 1) 9%,2 (grade 2 or above) 0.5%2; alopecia (grade 1 or 2) 34%,4(grade 2) 1%3; cutaneous basal cell carcinoma (all grades) 2%3,5; cutaneous squamous cell carcinoma (grade 1 or 2) 2%,4 (grade 2) 2%,5 (grade 3) 4% to 17%2-5; hyperkeratosis(grade 1) 23%,2 (grade 1 or 2) 30%,4 (grade 2) 8% to 12%,3,5 (grade 2 or above) 3%,2(grade 3) 0.5%,3,5 (grade 4) 0.5%5; keratocanthoma (all grades) 1% to 2%2,3; melanocytic nevus (grade 2) 0.5%3; mycosis fungoides (grade1) 0.5%5; new primary malignant melanoma (all grades) 1%5; palmar plantar erythrodysesthesia or hyperkeratosis (grade 2)5% to 6%,3,5 (grade 3) 2%3,5; papilloma (grade 1 or 2) 15%4; rash (grade 1 or 2) 36%,4(grade 2) 3%3; phototoxic reaction (grade 1) 2%,5 (grade 2) 1%.5

  4. Gastrointestinal: Constipation (grade 1 or 2) 11%4; decreased appetite (grade 1 or 2) 19%,4 (grade 2) 2%,3 (grade 3) 1%3; diarrhea (grade 1 or 2) 28%,4 (grade2) 1%,3 (grade 3) 0.5%3; nausea (grade 1 or 2) 21%,4 (grade 2) 1% to 2%,3,5 (grade 3) 0.5%3; vomiting (grade 1 or 2) 15%,4 (grade 2) 1% to 3%.3,5

  5. Hematologic: Agranulocytosis (grade 4) 0.5%3; neutopenia (grade 3) 0.5%,5 (grade 4) 0.5%3; thrombocytopenia (grade 3) 0.5%.5

  6. Hepatic: Alkaline phosphatase increase (grade 1 or 2) 2%4; alanine aminotransferase (ALT) increase (grade 2) 2%,3 (grade 3) 1%.3

  7. Metabolic: Amylase increase (grade 4) 0.5%,3 lipase increase (grade 4) 0.5%.3

  8. Musculoskeletal: Arthralgia (grade 1 or 2) 34%,4 (grade 2) 2% to 5%,3,5 (grade 2 or higher) 5%,2 (grade 3) 0.5%5; myalgia (grade 1 or 2) 21%,4 (grade 2) 2%,3 (grade 3 or 4) 2%.4

  9. Neurologic: Convulsion (grade 4) 0.5%3; headache (grade 1 or 2) 28%,4 (grade 2) 4% to 5%,3,5 (grade 3) 0.5%,3 pain in extremity (grade 2) 1%.3

  10. Respiratory: Cough (grade 1 or 2) 21%.4

Name: Trametinib

Synonyms: Mekinist, GSK1120212

Mechanism Of Action

Trametinib reversibly and selectively inhibits the activation of mitogen-activated extracellular signal regulated kinase (MEK) 1 and MEK2 and inhibits their kinase activity.6,7 MEK1 and MEK2 are downstream from BRAF in the MAPK pathway.6

Pharmacokinetics

Trametinib has a Tmax of 1.5 hours6,8 and a mean absolute bioavailability of 72% following a single 2 mg oral dose.6 With 2 mg once-daily dosing, the mean Cmax is 22.2 ng/mL and AUC is 370 ng•h/mL.8 Administration of trametinib with a high-fat meal decreased AUC by 24% and Cmax by 70% and prolonged Tmax out to 5.5 hours compared to fasting state administration.6 Trametinib is 97% protein bound and has an apparent Vd of 214 L.6 Metabolism is primarily by deacetylation, monooxygenation, and glucuronidation, with 80% of a radioactive dose recovered in the feces and less than 20% recovered in the urine.6 T½ is 3.8 to 4.8 days, and CL is 4.9 L/h.6,8 Selected therapeutic regimens of trametinib appear in Table 2.

Table 2.

Selected therapeutic regimens of trametinib

Daily dose Route of administration Administered on day(s) Cycle length Total dose/month References
2 mga PO Daily – 60 mg 6,7,9,10
2.5 mg PO Daily – 75 mg 8
3 mg PO Daily – 90 mg 8
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Note: PO = oral.

a

Conforms to dosing information listed in the manufacturer’s labeling.

Preparation

  1. Follow institutional policies for preparation of hazardous medications when dispensing trametinib.

  2. Trametinib is available as 0.5, 1, and 2 mg tablets.

  3. The product labeling states trametiniib be dispensed in the original bottle without removing the desiccant. The labeling provides no explanation for this requirement.

Storage

  1. Store refrigerated at 2°C to 8°C (36°F to 46°F).

  2. Brief (less than 24 hours) exposure to temperatures up to 30°C (86°F) is acceptable.

Administration

  1. Trametinib is taken orally once a day.

  2. Trametinib should be taken on an empty stomach (1 hour before or 2 hours after food).

Toxicities

  1. Cardiovascular: Hypertension (all grades) 15%,9 (grade 1 or 2) 6%,10 (grade 2) 3%,9 (grade 3) 12%9; left ventricular dysfunction or decrease in ejection fraction (all grades) 7% to 8%,8,9 (grade 1) 2% to 3%,7,8 (grade 2) 4%,7,8 (grade 3) 1%8; left ventricular ejection fraction reduction (grade 3) 3%10; peripheral edema (all grades) 26% to 35%,7-10 (grade 1) 23% to 31%,7,8 (grade 2) 4% to 6%,7-9 (grade 3) 0.5% to 3%8-10; pulmonary embolism (grade 4) 1%10; pulmonary hypertension (grade 3) 1%7; serious cardiac-related events causing permanent discontinuation of trametinib (grade 3) 1%.9

  2. Constitutional: Fatigue (all grades) 26% to 35%,7-10 (grade 1) 18% to 19%,7,8 (grade 2) 5% to 12%,7-9 (grade 3) 2% to 4%.7-10

  3. Dermatologic: Acneiform dermatitis (all grades) 19%,9 (grade 2) 9%,9 (grade 3) 1%9; alopecia (all grades) 17%,9 (grade 2) 1%,9 (grade 3) 0.5%9; dry skin (grade 1 or 2) 22%10; dry skin, chapped skin, or skin fissures (all grades) 18% to 31%,7,8 (grade 1) 15% to 23%,7,8 (grade 2) 3% to 8%7,8; pruritis (all grades) 14% to 27%,7,8,10 (grade 1) 9% to 15%,7,8 (grade 2) 5%,8 (grade 3) 1%10; rash (all grades) 57%,9 (grade 2) 19%,9 (grade 3) 3%,9 (grade 4) 0.5% to 1%7,9; rash or acneiform dermatitis (all grades) 75% to 85%,7,8,10 (grade 1) 38% to 39%,7,8 (grade 2) 33% to 38%,7,8 (grade 3) 7% to 9%,7,8,10 (grade 4) 0.5%.8

  4. Gastrointestinal: Constipation (all grades) 5% to 14%,8-10 (grade 1) 4%,8 (grade 2) 1%,8,9 (grade 1 or 2) 14%10; decreased appetite (all grades) 10% to 11%,8,10 (grade 1) 7%,8 (grade 2) 2%,8 (grade 3) 0.5% to 1%8,10; diarrhea (all grades) 42% to 52%,7-10 (grade 1) 31% to 35%,7,8 (grade 2) 6% to 11%,7-9 (grade 3) 1% to 4%,8,10 (grade 4) 0.5%9; dry mouth (all grades) 5% to 11%,8,10 (grade 1) 5%,8 (grade 1 or 2) 11%10; mucosal inflammation (all grades) 4% to 7%,7,8 (grade 1) 4% to 5%,7,8 (grade 2) 2%8; nausea (all grades) 12% to 30%,7-10 (grade 1) 12% to 22%,7,8 (grade 2) 2% to 5%,8,9 (grade 3) 1%9; vomiting (all grades) 8% to 18%,7-10 (grade 1) 8% to 11%,7,8 (grade 2) 1% to 5%,8,9 (grade 1 or 2) 18%,10 (grade 3) 0.5% to 1%.8,9

  5. Hematologic: Thrombocytopenia (all grades) 5%,8 (grade 1) 4%,8 (grade 2) 0.5%,8(grade 3) 0.5%,8 (grade 4) 0.5% to 1%.7,8

  6. Hepatic: Aminotransferase increase (grade 3) 2%.10

  7. Neurologic: Abdominal pain (grade 1 or 2) 15%.10

  8. Ocular: Blurred vision (grade 1) 2%,7 (grade 1 or 2) 4%9; central serous retinopathy (all grades) 2%10; dry eyes (grade 1) 2%7; ocular toxic effects (any) (all grades) 9% to 15%,8,9 (grade 1) 13%,8 (grade 2) 2%,8 (grade 3) 0.5%8; periorbital edema (all grades) 5%,8 (grade 1) 5%,8 (grade 2) 0.5%8; reversible chorioretinopathy (grade 3) 0.5%9; visual impairment (grade 1) 4%.7

References

  • 1. Tafinlar [package insert]. Research Triangle Park, NC: GlaxoSmithKline 2013.
  • 2.Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: A phase I dose-escalation trial. Lancet. 2012;379(9829):1893–1901 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): A multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(11):1087–1095 [DOI] [PubMed] [Google Scholar]
  • 4.Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–1703 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–365 [DOI] [PubMed] [Google Scholar]
  • 6. Mekinist [package insert]. Research Triangle Park, NC: GlaxoSmithKline 2013.
  • 7.Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: A phase 1 dose-escalation trial. Lancet Oncol. 2012;13(8):782–789 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Infante JR, Fecher LA, Falchook GS, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: A phase 1 dose-escalation trial. Lancet Oncol. 2012;13(8):773–781 [DOI] [PubMed] [Google Scholar]
  • 9.Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107–114 [DOI] [PubMed] [Google Scholar]
  • 10.Kim KB, Kefford R, Pavlick AC, et al. Phase II study of the MEK1/MEK2 inhibitor trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 2013;31(4):482–489 [DOI] [PMC free article] [PubMed] [Google Scholar]

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