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DRUG RECORD

 

PACLITAXEL

OVERVIEW
Paclitaxel

 

Introduction

Paclitaxel is an antineoplastic agent which acts by inhibitor of cellular mitosis and which currently plays a central role in the therapy of ovarian, breast, and lung cancer.  Therapy with paclitaxel has been associated with a low rate of serum enzyme elevations, but has not been clearly linked to cases of clinically apparent acute liver injury.

 

Background

Paclitaxel (pak" li tax' el) is a complex diterpenoid molecule that contains a central 8-member taxane ring.  Paclitaxel was initially isolated from the bark of the Western Yew tree (Taxus breviflora) and found to have antitumor activity in high throughput assays.  It is a potent antineoplastic agent and its mechanism of action appears to be mediated by its binding to microtubulin, which is important in the mitototic phase of cell division.  The binding of paclitaxel prevents the disassembly of the cytoskeletal microtubules, preventing cell division and leading to cell death.  Paclitaxel was approved for use in the United States in 1992 and it remains an important agent in the therapy of several cancers.  Paclitaxel is considered a first line treatment for advanced ovarian carcinoma and is also used in breast cancer and advanced non-small cell lung cancer and AIDS-related Kaposi's sarcoma.  Paclitaxel is available in solution for injection (6 mg/mL) generically and under the brand names Taxol and Onxol.  Paclitaxel is also available as protein bound particles in a lyphophilized powder for injection under the brand name Abraxane.  Paclitaxel is administered intravenously, typically as 3 to 24 hour infusions every three weeks in cycles in combination with other antineoplastic agents.  The dose varies by indication and body weight and is reduced in persons with preexisting liver disease.  Side effects are common and include diarrhea, nausea, vomiting, mucositis, fatigue, mylagias, skin rash, alopecia, phlebitis, bone marrow suppression, fluid retention, cardiomyopathy, peripheral neuropathy and hypersensitivity reactions.

 

Hepatotoxicity

Paclitaxel has been associated with serum aminotransferase elevations in 7% to 26% of patients, but values greater than 5 times the upper limit of normal (ULN) in only 2% of those receiving the highest doses.  Similar rates of alkaline phosphatase elevations and occasional mild bilirubin elevations also occur.  The abnormalities are usually asymptomatic, mild and self-limited, rarely requiring dose modification or discontinuation.  Paclitaxel has not been linked convincingly to instances of idiosyncratic clinically apparent liver injury with jaundice.  However, there is at least one case report of acute hepatic necrosis arising within 1 to 2 days of the initial infusion of paclitaxel associated with rapid onset of multiorgan failure and death.  The characteristics of the case and of similar cases associated with docetaxel suggest that it was due to a severe hypersensitivity reaction. Because paclitaxel is often given with other antineoplastic agents, liver injury arising during therapy cannot always be reliably attributed to paclitaxel rather than to other specific agents.  Furthermore, paclitaxel in combination with other anticancer agents may be associated with reactivation of hepatitis B, increased risk of opportunistic viral infections, sinusoidal obstruction syndrome or sepsis, any of which can cause liver test abnormalities or clinically apparent liver injury. 

 

Likelihood score: D (possible cause of acute hepatic necrosis associated with a hypersensitivity reaction to the initial infusion).

 

Mechanism of Injury

The mild liver injury that arises during therapy is probably due to a direct effect of paclitaxel in inhibiting microtubular function.  Paclitaxel is metabolized by the cytochrome P450 system, largely CYP 2C8 and to a lesser extent 3A4.

 

Outcome and Management

The serum aminotransferase elevations that occur on paclitaxel therapy are usually self-limited and do not require dose modification or discontinuation of therapy.  No instances of idiosyncratic, clinically apparent or severe acute liver injury have been convincingly linked to paclitaxel therapy in the published literature.


References to paclitaxel hepatotoxicity are listed together with those for docetaxel in the Overview for Taxanes.

 

Drug Class:  Antineoplastic Agents, Taxanes

 

Other Drugs in the Subclass, TaxanesCabazitaxel, Docetaxel

 

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PRODUCT INFORMATION
Paclitaxel

 

REPRESENTATIVE TRADE NAMES
Paclitaxel – Generic, Onxol®, Taxol®
Paclitaxel (Powder for Inj.) – Generic, Abraxane®

 

DRUG CLASS
Antineoplastic Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Paclitaxel 33069-62-4 C47-H51-N-O14 Paclitaxel Chemical Structure

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REFERENCES
Paclitaxel

 

References updated: 15 January 2018

  1. Zimmerman HJ. Hepatotoxic effects of oncotherapeutic and immunosuppressive agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp.673-708.  (Textbook of hepatotoxicity published in 1999; paclitaxel is not mentioned).

  2. DeLeve LD. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 549-68.  (Review of hepatotoxicity of cancer chemotherapeutic agents; the taxanes are not specifically discussed).

  3. Chabner BA, Bertino J, Clearly J, Ortiz T, Lane A, Supko JG, Ryan DP. Taxanes. Cytotoxic agents. Chemotherapy of neoplastic diseases. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1707-9.  (Textbook of pharmacology and therapeutics).

  4. Onetto N, Canetta R, Winograd B, Catane R, Dougan M, Grechko J, Burroughs J, Rozencweig M. Overview of Taxol safety. J Natl Cancer Inst Monogr 1993;(15): 131-9. PubMed Citation  (Among 655 patients treated with paclitaxel, dose limiting toxicities included bone marrow suppression [especially neutropenia], mucositis, neuropathy and rarely cardiomyopathy; hypersensitivity reactions can be controlled with premedication; liver test abnormalities were dose dependent with any AST elevations in 7-26% of patients and values >5 times ULN in only 2% of those receiving the highest dose).

  5. Rowinsky EK, Eisenhauer EA, Chaudhry V, Arbuck SG, Donehower RC. Clinical toxicities encountered with paclitaxel(Taxol). Semin Oncol 1993; 20 (4 Suppl 3): 1-15. PubMed Citation  (Extensive review of toxicities of paclitaxel; according to data on file with the sponsor, elevations of AST, Alk P and bilirubin >5 times the ULN occurred in <1% of 402 patients in phase II and III trials).

  6. Horikoshi N, Inoue K, Aiba K, Mukaiyama T, Ogihara A, Sumida T, Akatsuka Y, et al. [Phase I study of paclitaxel]. Gan To Kagaku Ryoho 1994; 21: 2407-14. Japanese. PubMed Citation

  7. Von Hoff DD. The taxoids: same roots, different drugs. Semin Oncol 1997; 4(4 Suppl 13): S13-3-S13-10. PubMed Citation  (Review of the development of paclitaxel and docetaxel, clinical use, efficacy and toxicity stressing the differences between the two taxoids, which are due largely to differences in pharmacokinetics).  

  8. Fumoleau P. Efficacy and safety of docetaxel in clinical trials. Am J Health Syst Pharm 1997; 54 (24 Suppl 2): S19-24. PubMed Citation  (Overall response rates to docetaxel and paclitaxel in advanced breast cancer ranged from 29-68% of patients; major dose related toxicities included neutropenia, mucositis, cardiomyopathy and fluid retention; hepatotoxicity was not mentioned).

  9. Colomer R, Llombart A, Lluch A, Ojeda B, Barnadas A, Carana V, Fernandez Y, et al. Paclitaxel/gemcitabine administered every two weeks in advanced breast cancer: preliminary results of a phase II trial. Semin Oncol 2000; 27 (1 Suppl 2): 20-4. PubMed Citation  (Among 43 women with metastatic breast cancer treated with paclitaxel and gemcitabine for up to 8 cycles, 41% had serum aminotransferase elevations which were above 5 times ULN in 5%).

  10. De Pas T, de Braud F, Danesi R, Sessa C, Catania C, Curigliano G, Fogli S, et al. Phase I and pharmacologic study of weekly gemcitabine and paclitaxel in chemo-naive patients with advanced non-small-cell lung cancer. Ann Oncol 2000; 11: 821-7. PubMed Citation  (Among 35 patients with lung cancer given escalating doses of gemcitabine and paclitaxel, 33% of first and 20% of all cycles were associated with aminotransferase elevations >5 times ULN, but all were asymptomatic and reversible, although some led to dose reduction).

  11. Patnaik A, Warner E, Michael M, Egorin MJ, Moore MJ, Siu LL, Fracasso PM, et al. Phase I dose-finding and pharmacokinetic study of paclitaxel and carboplatin with oral valspodar in patients with advanced solid tumors. J Clin Oncol 2000; 18: 3677-89. PubMed Citation  (Among 58 patients with advanced cancers treated with cycles of paclitaxel, carboplatin and valspodar, 3 had aminotransferase elevations >5 times ULN, two of which were dose limiting).

  12. Douillard JY, Lerouge D, Monnier A, Bennouna J, Haller AM, Sun XS, Assouline D, et al. Combined paclitaxel and gemcitabine as first-line treatment in metastatic non-small cell lung cancer: a multicentre phase II study. Br J Cancer 2001; 84: 1179-84. PubMed Citation  (Among 54 patients with advanced lung cancer treated with cycles of paclitaxel and gemcitabine, 98% had some elevation in liver tests and 9% had ALT elevations of >5 times ULN, but all were asymptomatic and self-limited).

  13. Markman M, Zanotti K, Webster K, Belinson J, Rose P. Toxicity associated with carboplatin/paclitaxel/Irinotecan use in advanced ovarian cancer: preliminary analysis. Oncology (Williston Park) 2003; 17 (5 Suppl 5): 34-5. PubMed Citation  (Among 26 women with advanced ovarian cancer given paclitaxel, carboplatin and irinotecan, 1[4%] developed transient ALT elevations >5 times ULN).

  14. Harries M, O'Donnell A, Scurr M, Reade S, Cole C, Judson I, Greystoke A, et al. Phase I/II study of DHA-paclitaxel in combination with carboplatin in patients with advanced malignant solid tumours. Br J Cancer 2004; 91: 1651-5. PubMed Citation  (Among 15 patients with advanced solid cancers given carboplatin and paclitaxel conjugated to fatty acids, 5 [33%] developed transient ALT elevations >5 times ULN).

  15. Ohlmann CH, Kohlmorgen S, Sahi D, Engelmann U, Heidenreich A. [Lethal course after chemotherapy with docetaxel. Acute liver failure with accompanying erythema multiforme major]. Urologe A 2007; 46: 1425-7. German. PubMed Citation  (67 year old man with prostate cancer developed Stevens-Johnson Syndrome, neutropenia and thrombocytopenia after 5 weekly infusions of docetaxel, with subsequent rise in liver tests and jaundice that progressed to hepatic failure and death; few details provided).

  16. Bailey HH, Alberti DB, Thomas JP, Mulkerin DL, Binger KA, Gottardis MM, Martell RE, et al. Phase I trial of weekly paclitaxel and BMS-214662 in patients with advanced solid tumors. Clin Cancer Res 2007; 13: 3623-9. PubMed Citation  (Among 26 patients with advanced cancer treated with paclitaxel and an experimental farnesyl transferase inhibitor, 3 developed febrile neutropenia and raised ALT levels 1 to 3 days after the infusions, not attributed to paclitaxel).  

  17. Pignata S, Breda E, Scambia G, Pisano C, Zagonel V, Lorusso D, Greggi S, et al. A phase II study of weekly carboplatin and paclitaxel as first-line treatment of elderly patients with advanced ovarian cancer. A Multicentre Italian Trial in Ovarian cancer (MITO-5) study. Crit Rev Oncol Hematol 2008; 66: 229-36. PubMed Citation  (Among 27 elderly women with advanced ovarian cancer treated with weekly infusions of carboplatin and paclitaxel, one had ALT increase above 5 times ULN during first course, but without jaundice, and she subsequently tolerated 5 more courses).

  18. Campone M, Levy V, Bourbouloux E, Berton Rigaud D, Bootle D, Dutreix C, Zoellner U, et al. Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours. Br J Cancer 2009; 100: 315-21. PubMed Citation  (Among 16 patients with advanced malignancies treated with paclitaxel and oral everolimus, one developed transient ALT elevations >5 times ULN).

  19. Sun Q, Liu C, Zhong H, Zhong B, Xu H, Shen W, Wang D. Multi-center phase II trial of weekly paclitaxel plus cisplatin combination chemotherapy in patients with advanced gastric and gastro-esophageal cancer. Jpn J Clin Oncol 2009; 39: 237-43. PubMed Citation  (Among 49 patients with gastrointestinal cancers treated with cyclic regimens of paclitaxel and cisplatin, 9 [18%] developed transient ALT elevations which were greater than 5 times ULN in 1 [2%], but none had jaundice).

  20. Oshita F, Saito H, Murakami S, Kondo T, Yamada K. Phase II study of paclitaxel and irinotecan with intercalated gefitinib in patients with advanced non-small-cell lung cancer. Am J Clin Oncol 2010; 33: 66-9. PubMed Citation  (Among 16 patients with advanced non-small cell lung cancer treated with paclitaxel, irinotecan and gefitinib, 8 had ALT elevations [only one >5 times ULN], but none developed jaundice).

  21. Mandaliya H, Baghi P, Prawira A, George MK. A rare case of paclitaxel and/or trastuzumab induced acute hepatic necrosis. Case Rep Oncol Med 2015; 2015: 825603. PubMed Citation  (62 year old woman with metastatic breast cancer received 4 cycles of doxorubicin and cyclophosphamide and developed pulmonary edema and respiratory failure within 12 hours of the initial infusions of paclitaxel and trastuzumab, dying one day later and autopsy showing acute hepatic necrosis; no liver test results provided).

  22. Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. PubMed Citation  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 49 [5.5%] were attributed to antineoplastic agents of which only 1 was due to a taxane [docetaxel]).

  23. Fushida S, Kinoshita J, Kaji M, Oyama K, Hirono Y, Tsukada T, Fujimura T, et al. Paclitaxel plus valproic acid versus paclitaxel alone as second- or third-line therapy for advanced gastric cancer: a randomized Phase II trial. Drug Des Devel Ther 2016; 10: 2353-8. PubMed Citation  (Among 66 patients with advanced gastric cancer treated with paclitaxel with or without valproic acid, overall and progression free survival was similar in the two groups; one patient had acute liver injury, but no details provided).

  24. Kümmel S, Paepke S, Huober J, Schem C, Untch M, Blohmer JU, Eiermann W, et al. Randomised, open-label, phase II study comparing the efficacy and the safety of cabazitaxel versus weekly paclitaxel given as neoadjuvant treatment in patients with operable triple-negative or luminal B/HER2-negative breast cancer (GENEVIEVE). Eur J Cancer 2017; 84: 1-8. PubMed Citation  (Among 333 women with breast cancer given neoadjuvant therapy with cabazitaxel [every 3 weeks] or paclitaxel [weekly] for 12 weeks before definitive surgery, pathologic complete responses were lower with cabazitaxel [1% vs 11%] while serious adverse events were higher [25% vs 10%], ALT elevations occurring at similar rates [40% vs 45%] which were above 5 times ULN in only 1.2% vs 0.6%).

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OTHER REFERENCE LINKS
Paclitaxel
  1. PubMed logoRecent References on Paclitaxel

  2. Clinical Trials logoTrials on Paclitaxel

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