Skip to main content

Advertisement

SpringerLink
Log in

Prediction of neutrophil reduction using plasma paclitaxel concentration after administration in patients with uterine, ovarian, or cervical cancers in an outpatient clinic

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Plasma paclitaxel (PTX) concentration 24 h or later after PTX administration may predict myelosuppression. Here, we explored predictive markers for neutropenia induced by intravenous administration of PTX in an outpatient clinic.

Methods

Thirty women suffering from uterine, ovarian or cervical cancer were enrolled in this study. PTX (mean dose: 167 mg/m2) was intravenously infused and followed by carboplatin. Plasma samples were obtained 4 h after PTX administration. Genotyping was carried out for CYP3A5*3, ABCB1 1236 C>T, 2677 G>T/A, and 3435 C>T.

Results

There was no significant relationship between genotype and reduced neutrophil count. Neutrophil reduction rate correlated with the patient’s height, neutrophil count on the day of administration, and plasma PTX concentration. Multiple regression analysis with those three indices explained 47.7% of the interindividual variability of the neutrophil reduction rate. The model with plasma PTX concentration, patient’s height, and plasma 6-α-hydroxy-paclitaxel /PTX concentration ratio also explained 30.0% of the interindividual variability for the neutrophil nadir count after PTX administration.

Conclusions

These results indicate that neutrophil reduction after PTX administration can be partially predicted by multiple regression analysis involving plasma concentration data collected at outpatient clinics.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Spratlin J, Sawyer MB (2007) Pharmacogenetics of paclitaxel metabolism. Crit Rev Oncol Hematol 61(3):222–229. https://doi.org/10.1016/j.critrevonc.2006.09.006

    Article  PubMed  Google Scholar 

  2. Rodríguez-Antona C (2010) Pharmacogenomics of paclitaxel. Pharmacogenomics 11(5):621–623. https://doi.org/10.2217/pgs.10.32

    Article  PubMed  Google Scholar 

  3. Wiernik PH, Schwartz EL, Strauman JJ, Dutcher JP, Lipton RB, Paietta E (1987) Phase I clinical and pharmacokinetic study of taxol. Cancer Res 47(9):2486–2493

    CAS  PubMed  Google Scholar 

  4. Soyama A, Saito Y, Hanioka N et al (2001) Non-synonymous single nucleotide alterations found in the CYP2C8 gene result in reduced in vitro paclitaxel metabolism. Biol Pharm Bull 24(12):1427–1430. https://doi.org/10.1248/bpb.24.1427

    Article  CAS  PubMed  Google Scholar 

  5. Nakajima M, Fujiki Y, Noda K et al (2003) Genetic polymorphisms of CYP2C8 in Japanese population. Drug Metab Dispos 31(6):687–690. https://doi.org/10.1124/dmd.31.6.687

    Article  CAS  PubMed  Google Scholar 

  6. Wolking S, Schaeffeler E, Lerche H, Schwab M, Nies AT (2015) Impact of genetic polymorphisms of ABCB1 (MDR1, P-glycoprotein) on drug disposition and potential clinical implications: Update of the literature. Clin Pharmacokinet 54:709–735. https://doi.org/10.1007/s40262-015-0267-1

    Article  CAS  PubMed  Google Scholar 

  7. Iihara H, Fujii H, Yoshimi C, Yamada M, Suzuki A, Matsuhashi N, Takahashi T, Yoshida K, Itoh Y (2016) Control of chemotherapy-induced nausea in patients receiving outpatient cancer chemotherapy. 21(2), 409–418. https://doi.org/10.1007/s10147-015-0908-2

  8. Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA et al (2003) Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 21(17):3194–3200

    Article  CAS  PubMed  Google Scholar 

  9. Katsumata N, Yasuda M, Isonishi S, Takahashi F, Michimae H, Kimura E,et al (2013) Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol 14(10):1020–1026

    Article  CAS  PubMed  Google Scholar 

  10. Gianni L, Kearns CM, Giani A et al (1995) Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 13(1):180–190. https://doi.org/10.1200/JCO.1995.13.1.180

    Article  CAS  PubMed  Google Scholar 

  11. Ohtsu T, Sasaki Y, Tamura T, Miyata Y, Nakanomyo H, Nishiwaki Y, Saijo N (1995) Clinical pharmacokinetics and pharmacodynamics of paclitaxel: a 3-hour infusion versus a 24-hour infusion. Clin Cancer Res 1(6):599–606

    CAS  PubMed  Google Scholar 

  12. Joerger M, Huitema AD, Richel DJ et al (2007) Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients: a study by the European organization for research and treatment of cancer-pharmacology and molecular mechanisms group and new drug development group. Clin Cancer Res 13(21):6410–6418. https://doi.org/10.1158/1078-0432.CCR-07-0064

    Article  CAS  PubMed  Google Scholar 

  13. Basileo G, Breda M, Fonte G, Pisano R, James CA (2003) Quantitative determination of paclitaxel in human plasma using semi-automated liquid-liquid extraction in conjunction with liquid chromatography/tandem mass spectrometry. J Pharm Biomed Anal 32(4–5):591–600. https://doi.org/10.1016/S0731-7085(03)00166-3

    Article  CAS  PubMed  Google Scholar 

  14. Balram C, Zhou Q, Cheung YB, Lee EJ (2003) CYP3A5*3 and *6 single nucleotide polymorphisms in three distinct Asian populations. Eur J Clin Pharmacol 59(2):123–126. https://doi.org/10.1007/s00228-003-0594-2

    Article  CAS  PubMed  Google Scholar 

  15. Jelliffe RW, Jelliffe SM (1971) Estimation of creatinine clearance from changing serum-creatinine levels. Lancet 7726(2):710

    Article  Google Scholar 

  16. Panday VR, Huizing MT, van Warmerdam LJ et al (1998) Pharmacologic study of 3-hour 135 mg M-2 paclitaxel in platinum pretreated patients with advanced ovarian cancer. 3(38), 231–236. https://doi.org/10.1006/phrs.1998.0360

  17. Tanabe M, Ieiri I, Nagata N et al (2001) Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther 297(3):1137–1143

    CAS  PubMed  Google Scholar 

  18. Jiko M, Yano I, Sato E et al (2007) Pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine, and effects of CYP3A5 and MDR1 polymorphisms in patients with urogenital cancers. Int J Clin Oncol 12(4):284–290. https://doi.org/10.1007/s10147-007-0681-y

    Article  CAS  PubMed  Google Scholar 

  19. Pfeil AM, Vulsteke C, Paridaens R et al (2014) Multivariable regression analysis of febrile neutropenia occurrence in early breast cancer patients receiving chemotherapy assessing patient-related, chemotherapy-related and genetic risk factors. BMC Cancer, 201(14). https://doi.org/10.1186/1471-2407-14-201

  20. Henningsson A, Marsh S, Loos WJ et al (2005) Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel. Clin Cancer Res 11(22):8097–8104. https://doi.org/10.1158/1078-0432.CCR-05-1152

    Article  CAS  PubMed  Google Scholar 

  21. Rodriguez-Antona C, Niemi M, Backman JT, Kajosaari LI, Neuvonen PJ, Robledo M, Ingelman-Sundberg M (2008) Characterization of novel CYP2C8 haplotypes and their contribution to paclitaxel and repaglinide metabolism. Pharmacogenomics J 8(4):268–277. https://doi.org/10.1038/sj.tpj.6500482

    Article  CAS  PubMed  Google Scholar 

  22. Nakajima M, Fujiki Y, Kyo S et al (2005) Pharmacokinetics of paclitaxel in ovarian cancer patients and genetic polymorphisms of CYP2C8, CYP3A4, and MDR1. J Clin Pharmacol 45(6):674–682. https://doi.org/10.1177/0091270005276204

    Article  CAS  PubMed  Google Scholar 

  23. Gréen H, Söderkvist P, Rosenberg P, Mirghani RA, Rymark P, Lundqvist EA, Peterson C (2008) Pharmacogenetic studies of paclitaxel in the treatment of ovarian cancer. Basic Clin Pharmacol 104:130–137. https://doi.org/10.1111/j.1742-7843.2008.00351.x

    Article  Google Scholar 

  24. Marsh S, Paul J, King CR, Gifford G, McLeod HL, Brown R (2007) Pharmacogenetic assessment of toxicity and outcome after platinum plus taxane chemotherapy in ovarian cancer: the Scottish randomised trial in ovarian cancer. 25(29), 4528–4535. https://doi.org/10.1200/JCO.2006.10.4752

Download references

Acknowledgements

The genotyping assistance of Mrs. Ayami Sakakibara and Mr. Kiyoaki Ishino (Laboratory of Clinical Pharmaceutics) was greatly appreciated. This study was supported by JSPS KAKENHI Grant number JP22590138.

Author information

Authors and Affiliations

  1. Laboratory of Clinical Pharmaceutics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, Shizuoka, 420-0833, Japan

    Motoaki Ishikawa, Toshio Maeda & Yoshiyuki Kagawa

  2. Department of Pharmacy, Toyohashi Municipal Hospital, Toyohashi, 441-8570, Japan

    Motoaki Ishikawa & Michiyasu Kawai

  3. Department of Gynecology and Obstetrics, Toyohashi Municipal Hospital, Toyohashi, 441-8570, Japan

    Michiyasu Kawai

Authors
  1. Motoaki Ishikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michiyasu Kawai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshio Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshiyuki Kagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yoshiyuki Kagawa.

Ethics declarations

Conflict of interest

We have no conflicts of interest to declare in relationship to this study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ishikawa, M., Kawai, M., Maeda, T. et al. Prediction of neutrophil reduction using plasma paclitaxel concentration after administration in patients with uterine, ovarian, or cervical cancers in an outpatient clinic. Cancer Chemother Pharmacol 81, 399–411 (2018). https://doi.org/10.1007/s00280-017-3506-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-017-3506-3

Keywords

Search

Navigation