Summary of Drug-Induced Liver Injury

Paclitaxel

Last Update: September 7, 2020.

OVERVIEW

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 mitotic 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 lyophilized 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, myalgias, skin rash, alopecia, phlebitis, bone marrow suppression, fluid retention, cardiomyopathy, peripheral neuropathy and hypersensitivity reactions. Severe adverse reactions include acute hypersensitivity reactions which occur in up to 2% of patients, typically with the first few infusions, and which are marked by urticaria, rash, fever, facial edema, hypotension, dyspnea and shock which can lead to multiorgan failure and death.

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 delayed, idiosyncratic clinically apparent liver injury with jaundice. However, the hypersensitivity reactions that occur with infusions of paclitaxel can be severe and accompanied by acute hepatic necrosis. The liver injury may be relatively mild and anicteric (Case 1), but can also be severe with rapid onset of multiorgan failure and death. At least one instance of acute liver failure following a hypersensitivity reaction to paclitaxel has been published in the literature and recent modifications of the product labels for paclitaxel and docetaxel mention the occurrence of toxic deaths following severe infusion reactions. 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 infusions).

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. The severe liver injury that accompanies infusion reactions to paclitaxel is likely due to hypersensitivity and acute direct hepatic injury, perhaps due to hypotension and ischemia.

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. Patients with an acute hypersensitivity reaction to paclitaxel should have the infusion stopped and not be reexposed to paclitaxel or to docetaxel, a closely related taxane (Case 1). The acute hepatic necrosis that accompanies rare instances of hypersensitivity reactions to paclitaxel is usually treated with corticosteroids which may have an effect on the signs and symptoms of hypersensitivity, but may not affect the course of the acute liver injury.

Drug Class: Antineoplastic Agents, Taxanes

Other Drugs in the Subclass, Taxanes: Cabazitaxel, Docetaxel

CASE REPORT

Case 1. Acute hepatocellular injury after an infusion of docetaxel.(1)

A 31 year old woman with endometrial cancer developed abdominal pain and serum aminotransferase elevations the week following an initial infusion of docetaxel and carboplatin. She had no history of liver disease, drug allergies, alcohol abuse or risk factors for viral hepatitis. Her other medical conditions included seasonal allergies, reactive airway disease and dyspepsia. Her endometrial carcinoma was initially treated surgically with hysterectomy and bilateral oophorectomy followed by pelvic irradiation and intravenous cisplatin which was poorly tolerated. She then started paclitaxel and carboplatin but had an immediate hypersensitivity reaction during the infusion manifested by chest tightness with arm and facial flushing despite premedication with antihistamines and dexamethasone. The following week her chemotherapy regimen was switched to docetaxel and carboplatin with intravenous dexamethasone followed by oral dexamethasone. She had mild symptoms of hypersensitivity during the infusions, but during the ensuing week she developed fatigue and abdominal pain. At the time of the next planned infusion, serum ALT was found to be 649 U/L, AST 211 U/L and alkaline phosphatase 161 U/L (R=11.7: hepatocellular). Serum bilirubin and albumin were normal and INR 0.9. (Table). Therapy was held. The following day, serum ALT levels had decreased. Serologic markers for acute hepatitis A, B and C were negative. Serum ANA was weakly positive (1:80) but SMA and AMA were negative. Imaging of the liver was normal without evidence of biliary or portal venous obstruction. Her symptoms resolved and over the next few weeks her serum aminotransferase levels fell to near normal levels. She was restarted on carboplatin without docetaxel and serum enzymes remained normal or minimally elevated

Key Points

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Medication: Docetaxel (124 mg iv once)
Pattern: Hepatocellular (R=11.7)
Severity: 1+ symptomatic (no jaundice)
Latency: 1 week
Recovery: 5 weeks
Other medications: Carboplatin, dexamethasone

Laboratory Values

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Time After
Starting
Time After
Stopping
ALT
(U/L)
Alk P
(U/L)
Bilirubin
(mg/dL)
Other
Pre (-2 mo) Pre 25 73 0.2
Pre (-1 wk) Pre 35 66 0.3 Docetaxel and carboplatin
7 days 0 649 161 0.2 Therapy held
8 days 1 day 545 148 0.3 INR 0.9
14 days 7 days 295 92 0.3
19 days 12 days 126 78 0.2 Carboplatin restarted
26 days 19 days 64 87 0.3
35 days 28 days 94 95 0.3
44 days 37 days 30 84 0.2
Normal Values <40 <125 <1.2

Comment

This young woman with endometrial cancer and history of season allergies, had a mild hypersensitivity reaction during an infusion of paclitaxel and significant hepatic injury with a subsequent single infusion of docetaxel. The injury was symptomatic but without jaundice or evidence of hepatic synthetic dysfunction. The rapid rise and equally rapid fall in serum aminotransferase levels suggests direct hepatic injury and acute hepatic necrosis. In this case the injury was mild and self-limited injury, but paclitaxel hypersensitivity reactions can be severe and associated with jaundice and hepatic failure. This patient appeared to have cross sensitivity between paclitaxel and docetaxel.

PRODUCT INFORMATION

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

CHEMICAL FORMULA AND STRUCTURE

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

CITED REFERENCE

1.
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. [PMC free article: PMC4446235] [PubMed: 25754159]

ANNOTATED BIBLIOGRAPHY

References updated: 07 September 2020

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