Irinotecan pharmacokinetics

Mathijssen RH, Verweij J, Loos WJ, et al. Irinotecan pharmacokinetics-pharmacodynamics the clinical relevance of prolonged exposure to SN-38. Br J Cancer 2002 87(2) 144-150. 

Aminopentane-carboxyUc acid (APC) is a second major metabolite of irinotecan it is formed by oxidation of the terminal piperidine ring, catalysed by CYP3A4. APC itself is not hydrolysed to SN-38 and is only a weak inhibitor of topoisomerase I (44-48). However, potent CYP3A4 inducers (for example St John s wort, carbamazepine, and phe-njdoin) or inhibitors (for example itraconazole) alter irinotecan pharmacokinetics (49-54). Other identified metabolites include NPC (7-ethyl-10-(4-amino-l-piperidono)-carbonyloxycamptothecin), 5-hydroxyirinotecan, and RPR112526 (a decarboxylated product of the acid form of the irinotecan lactone). 

Han, J.Y., Lim, H.S., Shin, E.S., Yoo, Y.K., Park, Y.H., Lee, J.E., Kim, H.T. and Lee, J.S. (2008) Influence of the organic anion-transporting polypeptide 1B1 (OATP1B1) polymorphisms on irinotecan-pharmacokinetics and clinical outcome of patients with advanced non-small cell lung cancer. Lung Cancer (Amsterdam, Netherlands), 59, 69-75. 

C. A., Sugiyama, Y., The potential for an interaction between MRP2 (ABCC2) and various therapeutic agents probenecid as a candidate inhibitor of the biliary excretion of irinotecan metabolites, Drug Metab. Pharmacokinet. 2002, 17, 23-33. 

Iyer L, Janisch L, Das S et al. UGT1A1 promoter genotype correlates with pharmacokinetics of irinotecan (CPT-11). Proc Am Soc Clin Oncol 2000 19 178a (abstract). 

Chabot GG (1997) Clinical pharmacokinetics of irinotecan. Clin Pharmacokinet 33 245-259... 

P-gp is responsible for transport of the carboxylate form of irinotecan (64). The homozygous mutant 8 polymorphism has been associated with significantly increased exposure to irinotecan and its active metabolite SN-38 (65). Furthermore, significantly decreased docetaxel clearance was found in patients homozygous mutant for P-gp 8 (66), although Goh et al. (67) did not find a significant effect of this polymorphism on docetaxel pharmacokinetics. Also, a trend to an increased AUC of tipifamib in patients with the homozygous mutant allele compared to patients with only one or no mutant alleles of 8 was found in a study by Sparreboom et al. (68). In a study by Kishi et al. (40), the mutant allele for 6 was also correlated with a lower clearance of etoposide in children with ALL. 

Mathijssen, R.H., Marsh, S., Karlsson, M.O., et al. (2003) Irinotecan pathway genotype analysis to predict pharmacokinetics. Clin. Cancer Res. 9, 3246-3253. 

Han, J. Y., Lim, H. S., Shin, E. S., et al. (2006) Comprehensive analysis of UGTIA polymorphisms predictive for pharmacokinetics and treatment outcome in patients with non-small-ceU lung cancer treated with irinotecan and cisplatin. J. Clin. Oncol. 24, 2237-2244. 

Drengler RL, Kuhn JG, Schaaf LJ, et al. Phase I and pharmacokinetic trial of oral irinotecan administered daily for 5 days every 3 weeks in patients with solid tumors. J Clin Oncol 1999 17(2) 685-696. 

Mathijssen RH, van Alphen RJ, Verweij J et al. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res 2001 21%2-2194. 

Association of UGTIA Haplotypes with Pharmacokinetics and Adverse Reactions of Irinotecan Relevance to Anti-Tumor Responses Regulatory Status of Irinotecan Therapy Concluding Remarks References... 

Toffoli G., Cecchin E, Corona G et al. The role of UGT1A1 28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancel. J Clin.Oncol 2006 24 3061-3068. 

Bevacizumab, a humanized IgG and cetuximab, a chimeric IgGx, are currently marketed in the US for treatment of metastatic colorectal cancer [92, 93]. Bevacizumab neutralizes the biological activity of vascular endothelial growth factor (VEGF), while cetuximab binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). Bevacizumab, in combination with IV 5-fluorouracil (5-FU) -based chemotherapy, is indicated for first-line treatment of metastatic colorectal cancer, whereas cetuximab is used in patients refractory to or intolerant to irinotecan-based chemotherapy. The clinical pharmacokinetics of cetuximab are discussed in detail in Chapter 14. 

Table 14.5 Pharmacokinetic parameters of irinotecan before and after cetuximab co-administration.

Table 14.6 Pharmacokinetic parameters of cetuximab before and after irinotecan co-administration.

A. Kovar, and E. Raymond. 2005. Pharmacokinetic profile of cetuximab (Erbitux ) alone and in combination with irinotecan in patients with advanced EGFR-positive adenocarcinoma. Eur. J. Cancer 41 1739-1745. 

Corona G, Vaccher E, Cattarossi G, et al. Potential hazard of pharmacokinetic interactions between lopinavir-ritonavir protease inhibitors and irinotecan. Aids 2005 19(17) 2043-2044. 

Gaudreault J, Shiu V, Bricarello A, Christian BJ, Zuch CL, Mounho B. Concomitant administration of bevacizumab, irinotecan, 5-fluorouracil, and leucovorin nonclin-cial safety and pharmacokinetics. Inti J Toxicol 2005 24 357-63. 

Detailed studies of irinotecan dose modification in patients with liver dysfunction are warranted. According to the results of pharmacokinetic studies, thrice-weekly intravenous doses of irinotecan have been recommended 350 mg/m in patients with bilirubin concentrations up to 1.5 times the upper limit of the reference range and 200 mg/m in patients with bilirubin concentrations 1.5-3.0 times the upper limit of the reference range (56). 

There is increasing evidence that the extent and severity of gastrointestinal toxicity correlates with concentrations of the active compound SN-38 in the plasma and bowel. The role of plasma pharmacokinetics in predicting the severity of irinotecan-induced diarrhea has been highlighted by the introduction of a biliary index, which is the product of the relative area ratio of SN-38 to SN-38 glucuronide and the total AUC. According to preUminary evidence, preventive measures should be considered when the biliary index exceeds 3.484 hours.micrograms/ ml (107,108). 

Diarrhea ameliorated in six of seven patients treated with irinotecan in combination with oral neomycin at 1000 mg tds (43). Neomycin had no effect on the pharmacokinetics of irinotecan and its major metabolites. 

Gupta E, Mick R, Ramirez J, Wang X, Lestingi TM, Vokes EE, Ratain MJ. Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients. J Clin Oncol 1997 15(4) 1502-10. 

Ratain MJ. Insights into the pharmacokinetics and pharmacodynamics of irinotecan. Clin Cancer Res 2000 6(9) 3393-4. 

Lokiec F, Canal P, Gay C, Chatelut E, Armand JP, Roche H, Bugat R, Goncalves E, Mathieu-Boue A. Pharmacokinetics of irinotecan and its metabohtes in human blood, bile, and urine. Cancer Chemother Pharmacol 1995 36(l) 79-82. 

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