ATC kod: L01CE02
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 noterat en tendens till något bättre svar hos kvinnor.
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].
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].
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].
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).
Läkemedel innehållande irinotekan (ATC-kod L01XX19) används huvudsakligen på sjukhus och därför saknas könsspecifika användningsdata [15].
Uppdaterat: 2021-01-03
Litteratursökningsdatum: 2020-10-15
Faktagranskat av: Diana Rydberg, Carl-Olav Stiller
Godkänt av: Karin Schenck-Gustafsson