Paclitaxel

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Contents 1 Introduction 2 Indications 3 Dosage 4 Pharmacokinetics 5 Adverse-effects 6 Drug-interactions 7 Mechanism-of-action 8 More General Terms 9 Additional Terms 10 Internet Database 11 References

Introduction

• Tradenames: Taxol, Abraxane.

Indications

• metastatic ovarian carcinoma after failure of 1st-line agent
• ovarian, breast, non small cell lung carcinomas
• gastric cancer
• metastatic melanoma
• acute leukemia

Dosage

• standard premedication

• 50 mg diphenhydramine
• 300 mg cimetidine
• 10-20 mg dexamethasone
• antiemetics

• depends upon nausea potential of combination chemotherapy
• prochlorperazine is sufficient if Taxol is used alone

• post chemotherapy dexamethasone 4 mg PO TID

• 135-175 mg/m2
• doses of 200-250 mg/m2 have been used
• radiosensitizer dose 30 mg/m2
• lower doses have been given weekly with better efficacy & less adverse effects
• paclitaxel is given prior to cisplatin when used in combination
• carboplatin is given prior to paclitaxel when used in combination
• administered in non PVC, with 0.22 micron filter

• Injection: in polyethoxylated castor oil (Camophor EL) 50% & alcohol: 6 mg/mL (5 mL).
• Abraxane: solvent-free, albumin-bound formulation

Pharmacokinetics

• high protein binding
• metabolized in the liver by cyt P450 3A4
• 1/2 life is triphasic, approximately 6 hours
  

• elimination via liver

Adverse-effects

• common (> 10%)

• myalgia
• abnormal liver function tests
• bone marrow suppression

• neutropenia

• onset 8 days
• nadir 11 days
• recovery 15-21 days

• thrombocytopenia

• less frequent & severe than neutropenia
• nadir 8-9 days

• more frequent & severe in patients with prior radiation

• alopecia

• observed in nearly all patients
• occurs suddenly after 14-21 days
• reversible

• other [2,3]

• mild nausea
• mucositis
• allergic reactions
• bronchospasm
• peripheral neuropathy [3]

• progressive, predominantly sensory neuropathy
• dose-dependent
• muscle strength is generally preserved
• results from inhibition of microtubule formation in the dorsal root ganglia

• arthralgias
• hypotension
• bradycardia

Drug-interactions

• aminoglycosides given within 3-5 days can increased risk of ototoxicity
• cisplatin exacerbates myelosuppression
• ketoconazole may inhibit metabolism of Taxol
• any drug that inhibits cyt P450 3A4 may increase levels of paclitaxel
• any drug that induces cyt P450 3A4 may diminish levels of paclitaxel

Mechanism-of-action

• stabilizes microtubules & inhibits tubulin disassembly
• causes cell-cycle arrest in metaphase

More General Terms

• taxane
• antineoplastic agent (chemotherapeutic agent)

Additional Terms

• cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

Internet Database

PubChem: 36314
PubChem: 441276
PubChem: 4666
PubChem: 60915

References

1. Wahl et al Nature Medicine 2:72 1996
2. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
3. Medical Knowledge Self Assessment Program (MKSAP) 11, American College of Physicians, Philadelphia 1998
4. Kaiser Permanente Northern California Regional Drug Formulary, 1998
5. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: [1] (subscription needed) [2]
6. Prescriber's Letter 13(2): 2006 Detail-Document#: [3] (subscription needed) [4]

paclitaxel (Taxol, Abraxane)