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• 1. Pharmacology

Mechanism of Action
Imidazotetrazine derivative prodrug; active metabolite MTIC methylates guanine-rich areas of DNA that initiate transcription, which lead to DNA double strand breaks and apoptosis

2. Indications

Anaplastic Astrocytoma

Indicated for the treatment of adults with refractory anaplastic astrocytoma (ie, patients with disease progression on a drug regimen containing nitrosourea and procarbazine)
Initial: 150 mg/m² PO/IV qDay for 5 days; repeat at 28-day cycles 
Maintenance: May increase/maintain dose at 200 mg/m² PO/IV qDay for 5 days/28-day cycle if ANC >1500 mm³ and platelets >100,000 mm³
Infuse IV over 90 minutes
Dosage modifications

• Measure ANC and platelet on days 22 and 29 (day 1 of next cycle); modify dose for following cycle if:
• ANC 1000-1500/mm³ or platelet 50,000-100,000/mm³: Postpone treatment until ANC >1500/mm³ and platelet >100,000/mm³; maintain initial dose
• ANC <1000/mm³ or platelets <50,000/mm&sup3
• Postpone therapy until ANC >1,500/mm³ and platelets >100,000/mm³
• Decrease dose by 50 mg/m²/day for subsequent cycles
• Do NOT administer drug at dose <100 mg/m² for anaplastic astrocytoma

Decrease maintenance dose

• Reduce from 200 mg/m²/day to 150 mg/m²/day and from 150 mg/m²/day to 100 mg/m²/day if
• ANC <10,000/mm³
• Platelets <50,000/mm²
• CTC Grade 3 nonhematologic toxicity                                                          

Glioblastoma Multiforme

Indicated for the treatment of adults with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment
Initial: 75 mg/m² PO/IV qDay for 42 days concomitant with focal radiotherapy 
Infuse IV over 90 minutes
Continue treatment

• Continue for up to 49 days if the criteria listed below are met
• ANC ≥1,500/mm³, Platelet >100,000/mm³; CTC Grade 1 or lower

Dosage modifications (initial treatment and radiotherapy)

• Interrupt if
• ANC ≥500/mm³ but <1,500/mm³; CTC ≤Grade 1
• Platelets: ≥10,000/mm³ but ≤100,000/mm³
• CTC Grade 2 nonhematologic toxicity
• Discontinue if
• ANC <500/mm³
• Platelets <10,000/mm³
• CTC Grade 3 or 4 nonhematologic toxicity

Maintenance

• Cycle 1 (Start 4 weeks AFTER temozolomide + radiotherapy): 150 mg/m² PO/IV qDay for 5 days, then 23-treatment free days
• Cycle 2-6: may increase to 200 mg/m²/day if ANC >1500/mm³, platelets >100,000/mm³; CTC Grade <2

Newly Diagnosed High Grade Glioma (Orphan)

Orphan designation for treatment of newly diagnosed high grade glioma

Advanced Metastatic Melanoma (Orphan)

Orphan designation for treatment of advanced metastatic melanoma

Nasopharyngeal Carcinoma (Orphan)

Orphan designation for treatment of nasopharyngeal carcinoma

3. Absorption
Rapidly and completely absorbed after oral administration
Peak Plasma Time: 1 hr (empty stomach); 2.25 hr (high-fat meal)
Bioequivalence: 100%; IV infusion (when administered over 90 min) is bioequivalent to same dose of oral capsule
Mean peak plasma concentration and AUC decreased by 32% and 9%, respectively when administered after a high-fat breakfast
4. Distribution
Protein Bound: 15%
Vd: 0.4 L/kg
5. Metabolism
Metabolite: Hydrolyzed at physiologic pH to 3-methyl-(triazen-1-yl) imidazole-4-carboxamide (MTIC); MTIC further hydrolyzed to to 5-amino-imidazole-4-carboxamide (AIC), which is known to be an intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species
6. Elimination
Half-life: 1.8 hr
Clearance: 5.5 L/hr/m²
Excretion: primarily urine (~38%)

Oral Administration

Take capsule consistently either with or without food; preferably take on empty stomach HS to avoid N/V. May consider antiemetics before/after

7. Adverse Effects

10%	1-10% (selected)	Postmarketing Reports
Alopecia (55-69%)	Amnesia (10%)	Alveolitis
Lymphopenia (55%)	Insomnia (10%)	Interstitial pneumonitis
Nausea (53%)	Abdominal pain (5-9%)	Pulmonary fibrosis
Vomiting (42%)	Ataxia (8%)	Hepatotoxicity including elevations of liver enzymes, hyperbillirubinemia, cholestasis, and hepatitis
Headache (41%)	Back pain (8%)	Diabetes insipidus
Fatigue (34%)	Paresis (8%)	Reactivation of infections including cytomegalovirus and hepatitis B
Constipation (33%)	URI (8%)	Serious opportunistic infections, including some cases with fatal outcomes, can occur with bacterial, viral (primary and reactivated), fungal, and protozoan organisms
Anorexia (9-27%)	Urinary incontinence (8%)
Convulsions (23%)	UTI (8%)
Thrombocytopenia (19%)	Abnormal vision (5-8%)
Rash (8-19%)	Pruritus (5-8%)

8. Pack size: 5’s