Prediction of neutrophil reduction using plasma paclitaxel concentration after administration in patients with uterine, ovarian, or cervical cancers in an outpatient clinic
- 197 Downloads
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.
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.
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.
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.
KeywordsPaclitaxel Outpatient clinic Neutrophil reduction 6-α-hydroxy-paclitaxel Ovarian cancer
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.
Compliance with ethical standards
Conflict of interest
We have no conflicts of interest to declare in relationship to this study.
- 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/s40262-015-0267-1CrossRefPubMedGoogle 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):3194–3200CrossRefPubMedGoogle 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):1020–1026CrossRefPubMedGoogle 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-07-0064CrossRefPubMedGoogle 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)00166-3CrossRefPubMedGoogle 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
- 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-yCrossRefPubMedGoogle 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
- 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.6500482CrossRefPubMedGoogle 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