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Systemic exposure of floxuridine after hepatic arterial infusion pump chemotherapy with floxuridine in patients with resected colorectal liver metastases - 29/04/23

Doi : 10.1016/j.biopha.2023.114625 
Nikki S. IJzerman a, b, 1, Wills F. Filipe c, 1, Peter de Bruijn a, Florian E. Buisman c, Leni van Doorn a, Pascal G. Doornebosch d, Jessica J. Holster a, Cecile Grootscholten b, Dirk J. Grünhagen c, Christian P.E. van Bommel e, Marjolein Y.V. Homs a, Niels F.M. Kok f, Cornelis Verhoef c, Bas Groot Koerkamp c, Koert F.D. Kuhlmann f, Ron H.J. Mathijssen a, Stijn L.W. Koolen a, e,
a Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands 
b Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands 
c Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands 
d Department of Surgery, IJsselland Hospital, Capelle aan den IJssel, the Netherlands 
e Department of Hospital Pharmacy, Erasmus MC, Rotterdam, the Netherlands 
f Department of Surgery, The Netherlands Cancer Institute, Amsterdam, the Netherlands 

Corresponding author at: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands.Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical CenterRotterdamthe Netherlands

Abstract

Background

Floxuridine’s high hepatic extraction ratio and short elimination half-life allows maximum liver exposure with minimal systemic side-effects. This study attempts to quantify the systemic exposure of floxuridine.

Methods

Patients undergoing continuous hepatic arterial infusion pump (HAIP) floxuridine after resection of colorectal liver metastases (CRLM) in two centres underwent six cycles of floxuridine at start dose 0.12 mg/kg/day. No concomitant systemic chemotherapy was administered. Peripheral venous blood samples were drawn during the first two cycles: pre-dose (only in the second cycle), 30 min, 1 h, 2 h, 7 h, and 15 days after floxuridine infusion. Foxuridine concentration in the residual pump reservoir was measured on day 15 of both cycles. A floxuridine assay with a lower boundary of detection of 0.250 ng/mL was developed.

Results

265 blood samples were collected in the 25 patient included in this study. Floxuridine was mostly measurable at day 7 and day 15 (86 % and 88 % of patients respectively). The median dose corrected concentrations were 0.607 ng/mL [IQR: 0.472–0.747] for cycle 1 day 7, 0.579 ng/mL [IQR: 0.470–0.693] for cycle 1 day 15, 0.646 ng/mL [IQR: 0.463–0.8546] for cycle 2 day 7, and 0.534 ng/mL [IQR: 0.4257–0.7075] for cycle 2 day 15. One patient had remarkably high floxuridine concentrations reaching up to 44 ng/mL during the second cycle, without a clear explanation.

The floxuridine concentration in the pump decreased by 14.7 % (range 0.5 %−37.8 %) over a period of 15 days (n = 18).

Conclusion

Overall, negligible systemic concentrations of floxuridine were detected. However, remarkably increased levels were detected in one patient. Floxuridine concentration in the pump decreases over time.

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Graphical Abstract




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Highlights

An assay was developed measuring serum floxuridine concentrations down to 0.25 ng/mL
Negligible serum floxuridine concentrations were measured during the HAIP cycles
Floxuridine concentration in the pump may gradually decline
No floxuridine-attributed extrahepatic toxicity were detected

Il testo completo di questo articolo è disponibile in PDF.

Abbreviations : 5-FU, AST, CRLM, CTCAE, DPYD, GDA, HAIP, IQR, IU, LC-MS/MS, LLQ, MAA, MRM, PK, SD, UPLC

Keywords : Pharmacokinetics, Hepatic arterial infusion pump chemotherapy, Floxuridine, Colorectal liver metastases


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© 2023  Pubblicato da Elsevier Masson SAS.
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