Phase 1 and Pharmacokinetic Study of Intravenous Irinotecan in Refractory Solid Tumor Patients with Hepatic Dysfunction

Schaaf, Larry J.; Hammond, Lisa A.; Tipping, Stuart J.; Goldberg, Richard M.; Goel, Rakesh; Kuhn, John G.; Miller, Langdon L.; Compton, Linda D.; Cisar, Laura A.; Elfring, Gary L.; Gruia, G.; McGovren, J. Patrick; Pirotta, Nicoletta; Yin, Dong; Sharma, Amarnath; Duncan, B.M.; Rothenberg, Mace L.

doi:10.1158/1078-0432.ccr-05-2152

Cited by 32 publications

(13 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Irinotecan, known as a key chemotherapeutic agent in gastrointestinal (GI) cancer (3 -6), is activated by hydrolysis to SN-38, which is lost into the bile and feces, but it is contraindicated at high levels of serum bilirubin for safety reasons (7). Accordingly, achieving normal or near-normal hepatic function by successful PTBD is especially important for those patients in order to avoid excessive SN-38 toxicity.…”

Section: Introductionmentioning

confidence: 99%

Clinical Outcome of Biliary Drainage for Obstructive Jaundice Caused by Colorectal and Gastric Cancers

Kasuga

Ishii

Ozaka

et al. 2012

Japanese Journal of Clinical Oncology

View full text Add to dashboard Cite

Objective: To clarify the prognostic factors for patients with obstructive jaundice due to advanced colorectal and gastric cancers who had undergone percutaneous transhepatic biliary drainage. Methods: Baseline variables and clinical outcomes were evaluated for 92 consecutive patients treated with percutaneous transhepatic biliary drainage. Results: Of the 92 patients, 32 (35%) had colorectal cancer and the remaining 60 (65%) had gastric cancer. Percutaneous transhepatic biliary drainage was successfully achieved in 74 (80%) patients, and 39 of them could receive subsequent chemotherapy. The median survival after percutaneous transhepatic biliary drainage was 273 days in the 39 patients who had undergone successful percutaneous transhepatic biliary drainage and subsequent chemotherapy, 65 days in 35 patients who had undergone successful percutaneous transhepatic biliary drainage but who had not received subsequent chemotherapy and 34 days in the remaining 18 patients who had undergone unsuccessful percutaneous transhepatic biliary drainage (P , 0.001). Multiple liver metastases and hepatic hilar bile duct stricture were independently associated with unsuccessful percutaneous transhepatic biliary drainage. Poor performance status, multiple liver metastases, presence of ascites, multiple prior chemotherapy administrations, undifferentiated type histology and high serum CA19-9 level were independently associated with a poor prognosis. A prognostic index calculated based on the number of these six factors was used to classify the patients into a good-risk group (index 2) (n ¼ 56) and a poor-risk group (index 3) (n ¼ 36). The median survival time and 2-month survival rate for the two groups were 163 and 44 days, respectively, and 85.7 and 33.3%, respectively (P , 0.001). Conclusions: As regards the introduction of percutaneous transhepatic biliary drainage in patients with obstructive jaundice due to colorectal and gastric cancers, careful patient selection might be necessary. A prognostic model seems to be useful for making decisions as to whether percutaneous transhepatic biliary drainage is indicated for particular patients.

show abstract

Section: Introductionmentioning

confidence: 99%

Clinical Outcome of Biliary Drainage for Obstructive Jaundice Caused by Colorectal and Gastric Cancers

Kasuga

Ishii

Ozaka

et al. 2012

Japanese Journal of Clinical Oncology

View full text Add to dashboard Cite

show abstract

“…The ratio of the AUCs of SN‐38 and irinotecan was correlated with serum biochemical parameters indicative of liver function [27]. Accordingly, dose‐reduction is recommended if serum bilirubin concentrations exceed 1.5 times the upper limit of normal [11], which reflects the extent of liver dysfunction [13]. In the present study, impairment of microsomal irinotecan biotransformation was well correlated with serum bilirubin concentrations in patients with liver disease, but not with serum albumin or prothrombin times.…”

Section: Discussionmentioning

confidence: 45%

“…However, although information on the unbound intrahepatic concentration in patients during therapy would be most informative, it is impractical to measure this. Instead, clinically relevant concentrations of irinotecan in patient serum are around 2-4 mM [13,23]. Thus, in the present study irinotecan biotransformation was estimated at a concentration of 5 mM.…”

Section: Biotransformation Of Irinotecan In Microsomal Fractions Frommentioning

confidence: 96%

Impaired irinotecan biotransformation in hepatic microsomal fractions from patients with chronic liver disease

D'Esposito

Nebot

Edwards

et al. 2010

Brit J Clinical Pharma

View full text Add to dashboard Cite

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The anticancer agent irinotecan is a prodrug that is hydrolyzed by hepatic carboxylesterase to its active and toxic metabolite SN-38 and oxidized by CYP3A4 to its inactive metabolite APC.• Irinotecan therapy is complicated by co-administered drugs that inhibit CYP3A4 and decrease APC formation and that indirectly increase SN-38 formation. • Dose adjustment in cancer patients with liver disease has been recommended. WHAT THIS STUDY ADDS• In microsomal fractions from patients with severe hepatic dysfunction both APC and SN-38 formation were decreased due to down-regulation of CYP3A4 and carboxylesterase enzymes. Thus relative SN-38 : APC formation was preserved.• In some fractions the SN-38 : APC ratio was increased, thus providing a possible explanation for clinical reports of increased SN-38 exposure in some patients with liver dysfunction.• Close monitoring of SN-38 formation in patients with severe liver disease is warranted. AIMSDose modification with the anticancer agent irinotecan is recommended in patients with severe liver dysfunction.This study evaluated the impact of liver disease on the relative formation of phase I products of irinotecan biotransformation in human microsomes in vitro. METHODSMicrosomes from subjects with normal liver function and liver dysfunction (n = 20) were assessed for irinotecan biotransformation and the expression of cytochrome P450 (CYP) 3A4 and carboxylesterase (CES) enzymes. RESULTSLiver disease down-regulated CYP3A4 expression (median 33% of control, range 0-126%, P < 0.05) and impaired CYP3A4-dependent oxidation of irinotecan to the inactive 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC) (median 0.2, range 0-1.21 pmol mg protein -1 min -1 compared with median 0.66, range 0-2.35 in control, P < 0.01). CES-mediated hydrolysis of irinotecan to 7-ethyl-10-hydroxycamptothecin (SN-38) was also impaired in liver disease (median 8.38, range 0-20.7 pmol mg protein -1 min -1 compared with median 13.3, range 0-28.9 in control, P < 0.05). In seven of 20 liver disease microsomes neither metabolite was detected but in three the SN-38 : APC ratio was high (41-68) compared with the remaining 10 samples (ratio 11-36). CONCLUSIONSDown-regulation of CYP3A4 in liver disease decreased APC formation from irinotecan. SN-38 production was decreased and CES1 and 2 were down-regulated in most samples. However, in a subset of disease samples SN-38 production was relatively high because CYP3A4 activity was markedly impaired. This may account for clinical reports of increased SN-38 exposure in some patients with liver disease. Dose adjustments in cancer patients with liver disease who receive irinotecan are important and circulating SN-38 concentrations should be monitored closely.

show abstract

“…These processes occur mainly in the liver [11]. Therefore, irinotecan is typically contraindicated in patients with liver dysfunction and hyperbilirubinemia.…”

Section: Introductionmentioning

confidence: 99%

Patients with Metastatic Colorectal Cancer and Hyperbilirubinemia Treated with FOLFIRI plus Bevacizumab as First-Line Treatment

Huang

Yeh²,

Ma³

et al. 2016

Chemotherapy

View full text Add to dashboard Cite

Metastatic colorectal cancer (mCRC) combined with hyperbilirubinemia is typically considered a contraindication to irinotecan-based therapy, a proven first-line treatment of mCRC. Herein, we present 6 consecutive patients with mCRC combined with hyperbilirubinemia who underwent UGT1A1 genotyping before receiving FOLFIRI plus bevacizumab. Dose escalation of irinotecan was performed according to the results of UGT1A1 genotyping in all patients. Improvement in the serum total bilirubin level to a normal range was noted in all 6 patients. Disease control was 100%. The median progression-free survival was 7.5 months and the median overall survival was 8.5 months. FOLFIRI plus bevacizumab as a first-line chemotherapy may achieve effective disease control and be safe in patients with mCRC and hyperbilirubinemia based on UGT1A1 genotyping. More prospective clinical studies are necessary to evaluate the clinical benefits and safety of this treatment approach.

show abstract

Phase 1 and Pharmacokinetic Study of Intravenous Irinotecan in Refractory Solid Tumor Patients with Hepatic Dysfunction

Cited by 32 publications

References 28 publications

Clinical Outcome of Biliary Drainage for Obstructive Jaundice Caused by Colorectal and Gastric Cancers

Clinical Outcome of Biliary Drainage for Obstructive Jaundice Caused by Colorectal and Gastric Cancers

Impaired irinotecan biotransformation in hepatic microsomal fractions from patients with chronic liver disease

Patients with Metastatic Colorectal Cancer and Hyperbilirubinemia Treated with FOLFIRI plus Bevacizumab as First-Line Treatment

Contact Info

Product

Resources

About