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Irinotekan

Klassificering: C!

Preparat: Campto, Campto®, Irinokabi, Irinomedac, Irinotecan Accord, Irinotecan Accordpharma, Irinotecan Actavis, Irinotecan Ebewe, Irinotecan Fresenius Kabi, Irinotecan Hospira, Irinotecan Sandoz, Irinotecan Teva, Irinotecan Vianex, Irinotecan-Teva liquid, Onivyde pegylated liposomal

ATC kod: L01CE02

Substanser: irinotekan, irinotekanhydrokloridtrihydrat, irinotekansukrosofat

Sammanfattning

Kvinnligt kön är korrelerat med högre risk för biverkningar av irinotekan. Könsskillnader i farmakokinetiken för irinotekan har noterats och några studier pekar på ökad exponering för irinotekan hos kvinnor. Vid behandling av pankreascancer med FOLFIRINOX som inkluderar irinotekan har man noteraten tendens till något bättre svar hos kvinnor.

Additional information

Pharmacokinetics and dosing

According to the product information of irinotecan, pharmacokinetic population analysis of 196 men and 157 women shows that patient’s sex has no clinically significant effect on irinotecan and its active metabolite SN-38 exposure [1]. However, there are studies indicating higher exposure in women.

Irinotecan has a highly complex metabolism, including hydrolyzation by carboxylesterases to its active metabolite SN-38, which is 100- to 1000-fold more potent than irinotecan itself [2]. CYP3A4 has a major role in metabolism of both irinotecan and SN-38 [3]. A population pharmacokinetic model showed that variability in systemic exposure to SN‐38 was predicted by patient’s sex and hepatic function. The model indicated that the fraction of irinotecan metabolized to SN-38 was increased by 30% in female patients [4]. However no large sex-related difference was observed in SN-38 formation by human liver microsomes [5]. Women on average display higher expression and activity of CYP3A4. Sex-related differences in exposure could be of relevance for several substrates of the CYP3A family [6].

Thirty-six patients (28 men, and 8 women) with malignancy were included in a pharmacokinetic study. The patients received 100 mg/m2 CPT-11 (irinotecan) weekly for four consecutive weeks. AUCs of CPT-11 (µg/ml h) were 6.86 ± 1.68 for men and 5.12 ± 0.66 for women. Cmax (µg/ml) for men was 1.42 ± 0.31, and for women was 1.08 ± 0.22. AUC and Cmax were significantly higher in men than in women [7, 8]. A total number of 107 non-small cell lung cancer (NSCLC) patients (82 men, 25 women) treated with irinotecan was evaluated for pharmacokinetics and genotyped for 15 polymorphisms. A trend for higher AUC of SN-38 in multivariate analysis was found in women [9].

Effects

A non-significant trend towards better overall survival (OS), and progression-free survival (PFS), was observed for women (n=106) compared to men (n=65) with pancreas cancer who were treated with irinotecan-included regimen FOLFIRINOX (FOLic acid + Fluorouracil + IRInotecan + Oxaliplatin) [10]. Similar trend was observed in a retrospective review of 49 patients (24 men, 25 women) with unresectable pancreatic cancer who were treated with FOLFIRINOX regimen [11].

Adverse effects

Since irinotecan shares some adverse effects with other chemotherapeutic agents included in combinations, evaluation of adverse effects of this agent is not always easy.In a post marketing survey, case report forms of 13 935 patients (7791 men, 6143 women, 1 unknown) treated with irinotecan-based chemotherapy were collected. Major grade 3–4 adverse drug reactions were leukopenia (34.8%), thrombocytopenia (12.4%) and diarrhea (10.1%). Female sex was a risk factor for leukopenia, OR 1.48 [12]. The risk of delayed diarrhea, that may occur at any time 24 hours after administration of irinotecan and until the next course of treatment is greater for women [1].

In patients treated with oxaliplatin or irinotecan included combinations (83 men, 59 women), female sex was associated with a higher risk of grade 3-4 toxicities including fatigue, hematologic- and digestive side effects (61% in women vs 43.4% in men) [13]. In colorectal cancer patients receiving irinotecan- or oxaliplatin-based regimens (109 men, 70 women), female sex was a significant risk for chemotherapy-induced nausea and vomiting (20% of women vs 8% of men, OR 2.87, 95% CI=1.139-7.228; p=0.025) [14].

Reproductive health issues

Irinotecan, like other mitosis inhibitors, may be harmful to the fetus and should not be given during early pregnancy. For more information regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Försäljning på recept

Läkemedel innehållande irinotekan (ATC-kod L01XX19) används huvudsakligen på sjukhus och därför saknas könsspecifika användningsdata [15].

Uppdaterat: 2021-01-03

Litteratursökningsdatum: 2020-10-15

Referenser

  1. Irinotecan Accord (irinotecan). Summary of Product Characteristics. Swedish Medical Products Agency [updated 2020-04-14, cited 2020-10-15]
  2. de Man FM, Goey AKL, van Schaik RHN, Mathijssen RHJ, Bins S. Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics. Clin Pharmacokinet. 2018;57(10):1229-1254. PubMed
  3. Santos A, Zanetta S, Cresteil T, Deroussent A, Pein F, Raymond E et al. Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans. Clin Cancer Res. 2000;6(5):2012-20. PubMed
  4. Klein CE, Gupta E, Reid JM, Atherton PJ, Sloan JA, Pitot HC et al. Population pharmacokinetic model for irinotecan and two of its metabolites, SN-38 and SN-38 glucuronide. Clin Pharmacol Ther. 2002;72(6):638-47. PubMed
  5. Haaz MC, Rivory LP, Riché C, Robert J. The transformation of irinotecan (CPT-11) to its active metabolite SN-38 by human liver microsomes Differential hydrolysis for the lactone and carboxylate forms. Naunyn Schmiedebergs Arch Pharmacol. 1997;356(2):257-62. PubMed
  6. Vera Regitz-Zagrosek. Sex and Gender Differences in Pharmacology. Springer-Verlag Berlin Heidelberg; 2012.
  7. Miya T, Goya T, Fujii H, Ohtsu T, Itoh K, Igarashi T et al. Factors affecting the pharmacokinetics of CPT-11: the body mass index, age and sex are independent predictors of pharmacokinetic parameters of CPT-11. Invest New Drugs. 2001;19(1):61-7. PubMed
  8. Sasaki Y, Hakusui H, Mizuno S, Morita M, Miya T, Eguchi K et al. A pharmacokinetic and pharmacodynamic analysis of CPT-11 and its active metabolite SN-38. Jpn J Cancer Res. 1995;86(1):101-10. PubMed
  9. Han JY, Lim HS, Park YH, Lee SY, Lee JS. Integrated pharmacogenetic prediction of irinotecan pharmacokinetics and toxicity in patients with advanced non-small cell lung cancer. Lung Cancer. 2009;63(1):115-20. PubMed
  10. Lambert A, Jarlier M, Gourgou Bourgade S, Conroy T. Response to FOLFIRINOX by gender in patients with metastatic pancreatic cancer: Results from the PRODIGE 4/ ACCORD 11 randomized trial. PLoS One. 2017;12(9):e0183288. PubMed
  11. Hohla F, Hopfinger G, Romeder F, Rinnerthaler G, Bezan A, Stättner S et al. Female gender may predict response to FOLFIRINOX in patients with unresectable pancreatic cancer: a single institution retrospective review. Int J Oncol. 2014;44(1):319-26. PubMed
  12. Shiozawa T, Tadokoro J, Fujiki T, Fujino K, Kakihata K, Masatani S et al. Risk factors for severe adverse effects and treatment-related deaths in Japanese patients treated with irinotecan-based chemotherapy: a postmarketing survey. Jpn J Clin Oncol. 2013;43(5):483-91. PubMed
  13. Díaz R, Aparicio J, Molina J, Palomar L, Giménez A, Ponce J et al. Clinical predictors of severe toxicity in patients treated with combination chemotherapy with irinotecan and/or oxaliplatin for metastatic colorectal cancer: a single center experience. Med Oncol. 2006;23(3):347-57. PubMed
  14. Suzuki A, Kobayashi R, Fujii H, Iihara H, Takahashi T, Yoshida K et al. Control of Nausea and Vomiting in Patients with Colorectal Cancer Receiving Chemotherapy with Moderate Emetic Risk. Anticancer Res. 2016;36(12):6527-6533. PubMed
  15. Concise (INSIKT). Kalmar: eHälsomyndigheten. 2018 [cited 2019-03-14.] länk

Författare: Alan Fotoohi

Faktagranskat av: Diana Rydberg, Carl-Olav Stiller

Godkänt av: Karin Schenck-Gustafsson