Is there a recommended AST/ALT threshold for safe administration of gemcitabine?

Comment by InpharmD Researcher

Although gemcitabine is reported to cause elevations in serum aminotransferase levels, dose modification is typically only suggested according to bilirubin levels in the setting of liver dysfunction. Published literature assessing gemcitabine therapy in patients with liver dysfunction primarily report recruitment of patients with AST/ALT levels <2 times the upper limit of normal (ULN), though one small trial (Table 1) enrolled patients with AST/ALT >2x ULN. In this trial, doses were reduced when AST/ALT levels were >2.5-5 times higher than baseline, and maximum baseline AST and ALT values were 168 U/L and 134 U/L, respectively. Whether these values are safe to initiate or administer gemcitabine requires further investigation.

Background

Though gemcitabine can cause elevations in serum aminotransferase levels (up to 30-90%), these elevations are typically mild and self-limited, and rarely require dose modifications. However, more severe elevations above 5 times the upper limit of normal can occur in 1-4% of gemcitabine patients. Additionally, gemcitable has also been associated with rare cases of liver injury in patients with underlying chronic liver disease or extensive hepatic metastases, as well as complications like hepatitis B reactivation. Therefore, close monitoring is warranted, especially in patients with pre-existing liver dysfunction, and dose adjustments may be necessary to manage the potential for liver toxicity. [1]

A 2005 article reviewed the complexities of chemotherapy dosing in cancer patients with liver dysfunction, emphasizing the interplay between hepatic impairment and drug pharmacokinetics. Liver dysfunction alters drug clearance via reduced hepatic metabolism, compromised biliary excretion, and diminished protein binding due to hypoalbuminemia, factors that heighten toxicity risks with numerous agents. Continuous-infusion fluorouracil, capecitabine, mechlorethamine, cyclophosphamide, topotecan, and oxaliplatin are relatively well-tolerated options in mild-to-moderate hepatic impairment, while taxanes, vinca alkaloids, irinotecan, and anthracyclines are drugs requiring careful dose adjustments due to their substantial toxicity profiles in this population. The review compiled evidence from retrospective studies, limited phase I trials, and clinical experience to propose empiric dosing modifications across various chemotherapeutic agents. For example, gemcitabine dosing was tailored according to bilirubin levels, initially treated with a weekly gemcitabine dose of 800 mg/m2, and subsequently escalated doses if the therapy was tolerated. Despite these insights, the publication underscored the paucity of robust data, which often attributed dose adjustments to serum bilirubin alone rather than take into account the multifactorial nature of hepatic dysfunction. [2]

References: [1] LiverTox®: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Gemcitabine. [Updated 2018 Mar 9]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548575/
[2] Eklund JW, Trifilio S, Mulcahy MF. Chemotherapy dosing in the setting of liver dysfunction. Oncology (Williston Park). 2005;19(8):1057-1069.
Relevant Prescribing Information

Hepatic Toxicity: [3]
Drug-induced liver injury, including liver failure and death, has been reported in patients receiving gemcitabine alone or with other potentially hepatotoxic drugs. Administration of gemcitabine in patients with concurrent liver metastases or a pre-existing medical history of hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic insufficiency. Assess hepatic function prior to initiation of Gemcitabine Injection and periodically during treatment. Permanently discontinue Gemcitabine Injection in patients who develop severe hepatic toxicity.

References: [3] Gemcitabine injection. Prescribing information. Armas Pharmaceuticals Inc.; 2020.
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Is there a recommended AST/ALT threshold for safe administration of gemcitabine?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

Pharmacokinetics of Gemcitabine at Fixed-Dose Rate Infusion in Patients with Normal and Impaired Hepatic Function
Design

Prospective study

N= 13
Objective To evaluate the pharmacokinetics of dFdC and its metabolite difluorodeoxyuridine (dFdU) in patients with normal and impaired hepatic function
Study Groups

Cohort I (n= 4)

Cohort II (n= 9)
Inclusion Criteria Patients with pancreatic or biliary tract carcinoma and normal or impaired hepatic function tests. Cohort I: serum bilirubin <1.6 mg/dL and AST/ALT <2 times the ULN. Cohort II: serum bilirubin >1.6 mg/dL and/or AST/ALT >2 times the ULN
Exclusion Criteria Prior treatment with gemcitabine, known untreated brain metastases, uncontrolled or severe cardiac disease, concomitant medication affecting hepatic function, pregnant or lactating patients, patients not implementing adequate contraceptive measures, patients unable to be regularly followed up
Methods Patients received an FDR infusion of gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 4 weeks. Pharmacokinetic analysis of gemcitabine and dFdU was performed using high-performance liquid chromatography-tandem mass spectrometry assay in cycles 1 and 2
Duration Not specified
Outcome Measures

Primary: Pharmacokinetic disposition of dFdC and dFdU

Secondary: Toxicity evaluation in both groups, reproducibility of pharmacokinetic parameters in two cycles
Baseline Characteristics   Cohort I (n= 4) Cohort II (n= 9)
Age, years 59 67
Sex - male 1 5
Sex - female 3 4
WHO performance status 0-1 3 7
WHO performance status 2 1 2
Diagnosis - pancreatic adenocarcinoma 2 5
Diagnosis - biliary tree carcinoma 2 1
Diagnosis - gall-bladder adenocarcinoma 0 3
Locally advanced disease 1 6
Metastatic disease 3 3
Results   Cohort I Cohort II
Cmax, mg/mL - GEM 6.82 (0.73) 7.76 (1.77)
Cmax, mg/mL - dFdU 11.07 (1.58) 8.93 (2.39)
AUCexp, mg*h/mL - GEM 11.75 (2.61) 8.43 (2.29)
AUCexp, mg*h/mL - dFdU 37.70 (3.74) 25.14 (8.12)
AUC1, mg*h/mL - GEM 12.13 (3.12) 8.87 (2.50)
t1/2, h - GEM 0.92 (1.25) 0.18 (0.10)
CL, L/h/m2 - GEM 88.12 (18.65) 127.27 (37.43)
ke, h-1 - GEM 3.35 (3.62) 5.41 (4.11)
Adverse Events Grade 3 myelosuppression observed in both cohorts. No significant difference in toxicity between patients with normal and impaired hepatic function. Manageable toxicities with no dose reduction required for cohort II.
Study Author Conclusions Gemcitabine 1000 mg/m2 can be administered as an FDR infusion in patients with altered hepatic function without causing additional toxicity compared with patients with normal hepatic function.
Critique The study provides valuable insights into the pharmacokinetics of gemcitabine in patients with hepatic impairment, demonstrating that FDR infusion is feasible without increased toxicity. However, the small sample size limits the generalizability of the findings, and further studies with larger cohorts are needed to confirm these results.

 

References:
[1] [1] Felici A, Di Segni S, Milella M, et al. Pharmacokinetics of gemcitabine at fixed-dose rate infusion in patients with normal and impaired hepatic function. Clin Pharmacokinet. 2009;48(2):131-141. doi:10.2165/00003088-200948020-00005
Optimal dose of gemcitabine for the treatment of biliary tract or pancreatic cancer in patients with liver dysfunction
Design

Prospective study

N= 15
Objective To determine the optimal initial dose of gemcitabine as monotherapy for patients with biliary tract or pancreatic cancer who had mild, moderate, or severe liver dysfunction
Study Groups

Mild liver dysfunction (n= 1)

Moderate liver dysfunction (n= 6)

Severe liver dysfunction (n= 8)
Inclusion Criteria Adult patients aged 20 years or older with histologically/cytologically confirmed or radiologically diagnosed biliary tract or pancreatic cancer, indicated for gemcitabine monotherapy, with mild, moderate, or severe liver dysfunction, and adequate organ functions
Exclusion Criteria Patients serologically positive for hepatitis B surface antigen and/or hepatitis C antibody
Methods Gemcitabine was administered as an i.v. infusion at a dose of 800 or 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Pharmacokinetics of gemcitabine and its inactive metabolite, difluorodeoxyuridine, were studied. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events, version 4.0.
Duration January 2011 to June 2014
Outcome Measures

Primary: Optimal dose determination based on treatment-related adverse events during the first cycle

Secondary: Pharmacokinetics of gemcitabine and difluorodeoxyuridine
Baseline Characteristics   Mild (n= 1) Moderate (n= 6) Severe (n= 8)
Total bilirubin   1.5–3.0 x ULN 3.0–10.0 x ULN
Gender - Male 1 6 3
Gender - Female 0 0 5
Median age, years (range) 59 64.5 (48–80) 63.5 (51–77)
Results   Moderate (n= 6) Severe (n= 7)
Leucopenia 4 (100%) 3 (100%)
Neutropenia 2 (50%) 3 (50%)
Anemia 1 (25%) 4 (75%)
Thrombocytopenia 2 (50%) 5 (75%)
Fatigue 3 (75%) 2 (25%)
Anorexia 3 (75%) 3 (50%)
Adverse Events Cholangitis developed in one patient with moderate liver dysfunction at 1000 mg/m2. No other severe treatment-related adverse events resulting in omission or discontinuation of gemcitabine treatment.
Study Author Conclusions We conclude that the optimal initial dose of gemcitabine as monotherapy for the treatment of biliary tract or pancreatic cancer in patients with liver dysfunction is 1000 mg ⁄ m2 and that an initial dose reduction is unnecessary even in patients who have severe hyperbilirubinemia, provided that obstructive jaundice is well managed.
Critique The study provides valuable insights into the dosing of gemcitabine in patients with liver dysfunction, particularly those with obstructive jaundice. However, the small sample size and the specific patient population limit the generalizability of the findings to other patients with liver dysfunction not related to obstructive jaundice.

 

References:
[1] [1] Shibata T, Ebata T, Fujita K, et al. Optimal dose of gemcitabine for the treatment of biliary tract or pancreatic cancer in patients with liver dysfunction. Cancer Sci. 2016;107(2):168-172. doi:10.1111/cas.12851