Dosage Adjustment and Pharmacokinetic Profile of Irinotecan in Cancer Patients With Hepatic Dysfunction

Raymond, Éric; Boige, Valérie; Faivre, Sandrine; Sanderink, Gérard; Rixe, Olivier; Vernillet, Laurent; Jacques, Christian; Gatineau, Michel; Ducreux, Michel; Armand, Jean‐Pierre

doi:10.1200/jco.2002.03.123

Cited by 107 publications

(65 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous investigations have demonstrated that body surface area is an unimportant factor in explaining this variability (29). The interindividual variability in SN-38 pharmacokinetics is more likely related to a host of other factors, including hepatic function (30) and use of concomitant medication (31) in addition to multiple polymorphic pathways involved in the excretion and biotransformation of irinotecan. The latter include esterases regulating cleavage of irinotecan, cytochrome P450 3A4-and 3A5-mediated oxidations of the parent drug (32), and glucuronic acid conjugation of SN-38 by members of the UGT1A family (33).…”

Section: Discussionmentioning

confidence: 99%

ABCG2 Pharmacogenetics

Jong

Marsh

Mathijssen

et al. 2004

Clinical Cancer Research

197

110

View full text Add to dashboard Cite

Purpose: The ATP-binding cassette transporter ABCG2 (breast cancer resistance protein) is an efflux protein that plays a role in host detoxification of various xenobiotic substrates, including the irinotecan metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). The ABCG2 421C>A polymorphism has been associated with reduced protein expression and altered function in vitro. The aim of this study was to evaluate the ethnic distribution and potential functional consequence of the ABCG2 421C>A genotype in cancer patients treated with irinotecan.Experimental Design: ABCG2 genotyping was performed using Pyrosequencing on DNA from 88 American Caucasians, 94 African Americans, 938 Africans, and 95 Han Chinese, as well as in 84 European Caucasian patients treated with irinotecan undergoing additional blood sampling for pharmacokinetic studies.Results: Significant differences in allele frequencies were observed between the given world populations (P < 0.001), the variant allele being most common in the Han Chinese population with a frequency as high as 34%. The mean area under the curve of irinotecan and SN-38 were 19,851 and 639 ng ؋ hour/mL, respectively. The frequency of the variant allele (10.7%) was in line with results in American Caucasians. No significant changes in irinotecan pharmacokinetics were observed in relation to the ABCG2 421C>A genotype, although one of two homozygous variant allele carriers showed extensive accumulation of SN-38 and SN-38 glucuronide.Conclusions: The ABCG2 421C>A polymorphism appears to play a limited role in the disposition of irinotecan in European Caucasians. It is likely that the contribution of this genetic variant is obscured by a functional role of other polymorphic proteins.

show abstract

Section: Discussionmentioning

confidence: 99%

ABCG2 Pharmacogenetics

Jong

Marsh

Mathijssen

et al. 2004

Clinical Cancer Research

197

110

View full text Add to dashboard Cite

show abstract

“…Therefore, it is possible that in patients with even mildly elevated bilirubin, biliary elimination of irinotecan, epirubicin and their glucuronide metabolites could be impaired, resulting in increased toxicity. Indeed, baseline plasma bilirubin and alkaline phosphatase levels have recently been found to correlate with irinotecan exposure and clearance (Raymond et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Phase I study of cisplatin, irinotecan, and epirubicin administered every 3 weeks in patients with advanced solid tumours

et al. 2003

View full text Add to dashboard Cite

This phase I study was conducted to determine the recommended phase II doses, safety profile, and antitumour activity of a combination regimen of cisplatin, irinotecan, and epirubicin administered every 3 weeks in patients with advanced solid tumours. Cisplatin and epirubicin were given at fixed doses of 50 and 60 mg m À2 , respectively. The irinotecan dose was escalated at 10 mg m À2 increments from a starting dose level of 70 mg m À2 . Epirubicin, irinotecan, and their metabolites were measured with HPLC methods. In all, 35 patients received 141 courses of treatment. Irinotecan dose was escalated in seven cohorts up to 130 mg m À2 , and then finally de-escalated to 110 mg m À2 . The dose-limiting toxicity was neutropenic fever. Nonhaematologic toxicities included mild to moderate nausea/vomiting, diarrhoea and fatigue. Of 34 patients with evaluable disease, one patient had a complete response and nine patients had partial response, yielding an overall response rate of 29.4%. Pharmacokinetic parameters of epirubicin were not affected by the sequence of drug administration. However, the AUCs of irinotecan and its metabolites were increased significantly when irinotecan and epirubicin were administered concurrently. This combination regimen has promising broad antitumour activity, and will be further evaluated in phase II studies in multiple tumour types.

show abstract

“…The liver intervenes by many aspects in the metabolism of irinotecan and SN38, implicating the cytochromes, glucuro-conjugation by UDP-glucuronosyltransferase 1A1 (UGT1A1) and enterohepatic cycling, resulting in wide interpatient variability (Rivory, 2000). High bilirubin and alkaline phosphate levels are associated with toxicity (Raymond et al, 2002). Severe toxicity also has been observed in patients with unconjugated hyperbilirubinaemia due to UGT1A1 deficiency (Wasserman et al, 1997) encountered in Gilbert's syndrome (5% of the population).…”

Section: Sirmentioning

confidence: 99%

Oxaliplatin- or irinotecan-based chemotherapy for metastatic colorectal cancer in the elderly

Alliot¹,

Barrios²

2004

Br J Cancer

View full text Add to dashboard Cite

Dosage Adjustment and Pharmacokinetic Profile of Irinotecan in Cancer Patients With Hepatic Dysfunction

Abstract: We showed that baseline total bilirubin level could be used to determine the appropriate dose of irinotecan in cancer patients with hepatic dysfunction. Doses of 350 mg/m(2) and 200 mg/m(2) were considered RDs in patients with bilirubin values

Cited by 107 publications

References 14 publications

ABCG2 Pharmacogenetics

ABCG2 Pharmacogenetics

Phase I study of cisplatin, irinotecan, and epirubicin administered every 3 weeks in patients with advanced solid tumours

Oxaliplatin- or irinotecan-based chemotherapy for metastatic colorectal cancer in the elderly

Contact Info

Product

Resources

About