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Published in: Cancer Chemotherapy and Pharmacology 2/2019

01-02-2019 | Short Communication

Gemcitabine and metabolite pharmacokinetics in advanced NSCLC patients after bronchial artery infusion and intravenous infusion

Authors: Abeer F. Alharbi, Robert A. Kratzke, Jonathan D’Cunha, Michael Anthony Maddaus, Kinjal Sanghavi, Mark N. Kirstein

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2019

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Abstract

Purpose

We investigated the safety, pharmacokinetics, and efficacy of gemcitabine administered via bronchial artery infusion (BAI) and IV infusion in advanced NSCLC patients.

Methods

Patients were eligible if they had received at least two prior cytotoxic chemotherapy regimens. Gemcitabine was administered via BAI as 600 mg/m2 on day one of cycle one, followed by IV as 1000 mg/m2 on day eight of cycle one, and IV on days one and eight of all subsequent cycles. Pharmacokinetics for gemcitabine and dFdU metabolite in plasma, and dFdCTP active metabolite in peripheral blood mononuclear cells (PBMC) were evaluated. Intensive pharmacokinetic sampling was performed after BAI and IV infusions during cycle one.

Results

Three male patients (age range 59–68 years) were evaluated. All patients responded with stable disease or better. One PR was observed after cycle three, and the remaining had SD. Cmax (mean ± SD) following BAI for gemcitabine, dFdCTP, and dFdU were 7.71 ± 0.13, 66.5 ± 40.6, and 38 ± 6.27 µM and following IV infusion, 17 ± 2.36, 50.8 ± 3.61, and 83.2 ± 12.3 µM, respectively. The AUCinf (mean ± SD) following BAI for gemcitabine, dFdCTP, and dFdU were 6.89 ± 1.2, 791.1 ± 551.2, and 829.9 ± 217.8 µM h and following IV infusion, 12.5 ± 3.13, 584 ± 86.6, and 1394.64 ± 682.2 µM h, respectively. The AUC and Cmax of dFdCTP after BAI were higher than IV. The median OS was 6.27 months. No grade 3 or 4 toxicity was observed. The most common side effects were all grade ≤ 2 involving nausea, vomiting, rigor, thrombocytopenia, and anemia.

Conclusions

Systemic exposure to dFdCTP was higher after BAI than IV in two out of three patients.
Literature
1.
go back to reference de Sousa Cavalcante L, Monteiro G (2014) Gemcitabine: metabolism and molecular mechanisms of action, sensitivity and chemo resistance in pancreatic cancer. Eur J Pharmacol 741:8–16CrossRefPubMed de Sousa Cavalcante L, Monteiro G (2014) Gemcitabine: metabolism and molecular mechanisms of action, sensitivity and chemo resistance in pancreatic cancer. Eur J Pharmacol 741:8–16CrossRefPubMed
2.
go back to reference Zhu J, Zhang H, Jiang S, Ni J (2017) Neoadjuvant chemotherapy by bronchial arterial infusion in patients with unresectable stage III squamous cell lung cancer. Ther Adv Respir Dis 11(8):301–309CrossRefPubMedPubMedCentral Zhu J, Zhang H, Jiang S, Ni J (2017) Neoadjuvant chemotherapy by bronchial arterial infusion in patients with unresectable stage III squamous cell lung cancer. Ther Adv Respir Dis 11(8):301–309CrossRefPubMedPubMedCentral
3.
go back to reference Khatri A, Williams B, Fisher J, Brundage R, Gurvich V, Lis L et al (2014) SLC28A3 genotype and gemcitabine rate of infusion affect dFdCTP metabolite disposition in patients with solid tumours. Br J Cancer 110(2):304–312CrossRefPubMed Khatri A, Williams B, Fisher J, Brundage R, Gurvich V, Lis L et al (2014) SLC28A3 genotype and gemcitabine rate of infusion affect dFdCTP metabolite disposition in patients with solid tumours. Br J Cancer 110(2):304–312CrossRefPubMed
5.
go back to reference Ciccolini J, Serdjebi C, Peters G, Giovannetti E (2016) Pharmacokinetics and pharmacogenetics of gemcitabine as a mainstay in adult and pediatric oncology: an EORTC-PAMM perspective. Cancer Chemother Pharmacol 78(1):1–12CrossRefPubMedPubMedCentral Ciccolini J, Serdjebi C, Peters G, Giovannetti E (2016) Pharmacokinetics and pharmacogenetics of gemcitabine as a mainstay in adult and pediatric oncology: an EORTC-PAMM perspective. Cancer Chemother Pharmacol 78(1):1–12CrossRefPubMedPubMedCentral
6.
go back to reference Derissen E, Huitema A, Rosing H, Schellens J, Beijnen J (2018) Intracellular pharmacokinetics of gemcitabine, its deaminated metabolite 2′,2′-difluorodeoxyuridine and their nucleotides. Br J Clin Pharmacol 84(6):1279–1289CrossRefPubMedPubMedCentral Derissen E, Huitema A, Rosing H, Schellens J, Beijnen J (2018) Intracellular pharmacokinetics of gemcitabine, its deaminated metabolite 2′,2′-difluorodeoxyuridine and their nucleotides. Br J Clin Pharmacol 84(6):1279–1289CrossRefPubMedPubMedCentral
7.
go back to reference Tempero M, Plunkett W, Ruiz van Haperen V, Hainsworth J, Hochster H, Lenzi R et al (2003) Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 21(18):3402–3408CrossRefPubMed Tempero M, Plunkett W, Ruiz van Haperen V, Hainsworth J, Hochster H, Lenzi R et al (2003) Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 21(18):3402–3408CrossRefPubMed
8.
go back to reference Alvarellos M, Lamba J, Sangkuhl K, Thorn C, Wang L, Klein D et al (2014) PharmGKB summary pharmacogenetics. Genomics 24(11):564–574 Alvarellos M, Lamba J, Sangkuhl K, Thorn C, Wang L, Klein D et al (2014) PharmGKB summary pharmacogenetics. Genomics 24(11):564–574
9.
go back to reference Mitra A, Kirstein M, Khatri A, Skubitz K, Dudek A, Greeno E et al (2012) Pathway-based pharmacogenomics of gemcitabine pharmacokinetics in patients with solid tumors. Pharmacogenomics 13(9):1009–1021CrossRefPubMed Mitra A, Kirstein M, Khatri A, Skubitz K, Dudek A, Greeno E et al (2012) Pathway-based pharmacogenomics of gemcitabine pharmacokinetics in patients with solid tumors. Pharmacogenomics 13(9):1009–1021CrossRefPubMed
Metadata
Title
Gemcitabine and metabolite pharmacokinetics in advanced NSCLC patients after bronchial artery infusion and intravenous infusion
Authors
Abeer F. Alharbi
Robert A. Kratzke
Jonathan D’Cunha
Michael Anthony Maddaus
Kinjal Sanghavi
Mark N. Kirstein
Publication date
01-02-2019
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 2/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-018-3757-7

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