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Docetaxel

Classification: C

Drug products: Docetaxel Accord, Docetaxel Actavis, Docetaxel Amring, Docetaxel Ebewe, DOCETAXEL KABI, Docetaxel Pfizer, Docetaxel Teva, TAXOTERE, Taxotere®

ATC code: L01CD02

Substances: docetaxel, docetaxel trihydrate

Summary

Restricted amount of evidence indicate that female sex is correlated with higher risk for adverse effects of docetaxel. Data on sex-related differences in pharmacokinetics (PK) of docetaxel are controversial. However, all the evidence that shows sex-related difference in PK of docetaxel are pointing to some increased exposure to docetaxel in women.

Additional information

Generally, women mount stronger innate and adaptive immune responses than men [1]. Women with lung cancer have a more favorable survival compared to men [2]. The 5-year survival is 17 percent among men, and 24 percent among women, in Sweden [3].

The incidence of lung cancer has decreased among men since from 1980s but has increased significantly among women, which reflects women's changing smoking habits. Now the proportion of smoking women is greater than the proportion of smoking men. In Sweden lung cancer made up 6.1% of all yearly cases of cancer, year 2016. The incidence was higher among women (6.8%, n=2067), compared to men (5.4%, n=1824) [3]

Pharmacokinetics and dosing

Due to the product information there is no sex-related difference in docetaxel PK, and no sex differentiation in dosing has been suggested [4]. However, there are some data indicating sex differences in PK of docetaxel. A study found that women had a 35% lower docetaxel clearance than men (51 men, 41 women) and a gender effect on docetaxel metabolism was suggested [5]. While other studies found no clear effect of patient’s sex on docetaxel PK [6, 7]. 

Lower AUC has been observed in premenopausal women [8], and also castrated men showed increased docetaxel clearance and a 2-fold decrease in AUC [9]. Therefore a review article suggests that hormonal factors such as castration status and menopausal status could be part of the underlying mechanisms explaining the discrepancy in the influence of patient's sex on docetaxel pharmacokinetics [10].

Docetaxel binds strongly to serum alpha1-acid glycoprotein and concentration of this protein is lower in young women compared to men and women in higher ages, and due to the fact that the expression and activity of CYP3A4, the main docetaxel metabolizing enzyme, is higher in women. Therefore  authors of the “Sex and Gender Differences in Pharmacology” book hypothesis that with standard dosing, the concentration of free drug might be much higher in young- and middle-aged women compared to men [2]. 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  [2].

Effects

There are no published data indicating sex-related difference in docetaxel efficacy. Considering the probability of higher exposure to docetaxel in women, especially in younger ages, and reports on increased risk of side effects among women, sex-related difference in efficacy is a probability that has not been studied.

Adverse effects

Due to European Medicines Agency, the onset of nausea, headache, skin local toxicity, and rash/itch have been seen more frequently in women (62 TCF (docetaxel/cisplatin/5-fluorouracil)-treated subjects) than in men (159 TCF-treated subjects) [11]. 

A population PK-PD model included 637 patients (272 men, 365 women) with carcinoma, melanoma, and sarcoma who had been enrolled in 24 open uncontrolled trials. The model indicated that female patients treated with docetaxel are at increased risk for severe neutropenia [12].

Reproductive health issues

Docetaxel, 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).

Updated: 2021-01-01

Date of litterature search: 2020-10-01

References

  1. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626-38. PubMed
  2. Vera Regitz-Zagrosek. Sex and Gender Differences in Pharmacology. Springer-Verlag Berlin Heidelberg; 2012.
  3. Socialstyrelsen. Cancer i siffror 2018. Socialstyrelsen [www]. [updated 2018-06-10, cited 2020-10-01]. länk
  4. Docetaxel Accord (docetaxel). Summary of Product Characteristics. European Medicines Agency (EMA) [updated 2020-10-01, cited 2020-10-01]
  5. Baker SD, Verweij J, Cusatis GA, van Schaik RH, Marsh S, Orwick SJ et al. Pharmacogenetic pathway analysis of docetaxel elimination. Clin Pharmacol Ther. 2009;85(2):155-63. PubMed
  6. Goh BC, Lee SC, Wang LZ, Fan L, Guo JY, Lamba J et al. Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies. J Clin Oncol. 2002;20(17):3683-90. PubMed
  7. de Graan AJ, Lancaster CS, Obaidat A, Hagenbuch B, Elens L, Friberg LE et al. Influence of polymorphic OATP1B-type carriers on the disposition of docetaxel. Clin Cancer Res. 2012;18(16):4433-40. PubMed
  8. Fajac A, Gligorov J, Rezai K, Lévy P, Lévy E, Selle F, Beerblock K, Avenin D, Saintigny P, Hugonin S, Bernaudin JF, Lokiec F. Effect of ABCB1 C3435T polymorphism on docetaxel pharmacokinetics according to menopausal status in breast cancer patients. Br J Cancer. 2010;103(4):560-6. länk
  9. Franke RM, Carducci MA, Rudek MA, Baker SD, Sparreboom A. Castration-dependent pharmacokinetics of docetaxel in patients with prostate cancer. J Clin Oncol. 2010;28(30):4562-7. PubMed
  10. Nieuweboer AJ, de Morrée ES, de Graan AJ, Sparreboom A, de Wit R, Mathijssen RH. Inter-patient variability in docetaxel pharmacokinetics: A review. Cancer Treat Rev. 2015;41(7):605-13. PubMed
  11. European Medicines Agency (EMA). Taxotere (docetaxel) - Scientific Discussion. [updated 2006-06-01, cited 2020-10-01]. länk
  12. Kloft C, Wallin J, Henningsson A, Chatelut E, Karlsson MO. Population pharmacokinetic-pharmacodynamic model for neutropenia with patient subgroup identification: comparison across anticancer drugs. Clin Cancer Res. 2006;12(18):5481-90. PubMed
  13. Concise (INSIKT). Kalmar: eHälsomyndigheten. 2018 [cited 2019-03-14.] länk

Authors: Alan Fotoohi

Reviewed by: Diana Rydberg, Carl-Olav Stiller

Approved by: Karin Schenck-Gustafsson