nach oben

Erschienen in:

17.07.2023 | Original Article

Effect of massive ascites on ramucirumab pharmacokinetics in patients with gastrointestinal cancers: a population pharmacokinetic analysis

verfasst von: Takuya Kaneko, Kosuke Doki, Takeshi Yamada, Yoshiyuki Yamamoto, Toshikazu Moriwaki, Yoshiharu Suzuki, Masato Homma

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2023

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Considerable amounts of injected immunoglobulin G-based therapeutic monoclonal antibodies, such as ramucirumab, are distributed into ascites. This study aimed to examine the effect of massive ascites on ramucirumab pharmacokinetics in patients with gastrointestinal cancers.

Methods

Population pharmacokinetic analysis of ramucirumab was performed using data on serum ramucirumab concentrations of 52 patients with gastrointestinal cancers, including 8 patients with massive ascites. The Bayesian method using the final population pharmacokinetic model was utilized to estimate trough ramucirumab concentrations after the first dose and at steady state.

Results

Population pharmacokinetic analysis revealed that massive ascites as well as body weight were influencing factors for ramucirumab clearance. The estimated ramucirumab clearance was significantly higher in patients with massive ascites than in those with no/mild ascites (0.020 ± 0.004 versus 0.013 ± 0.004 L/h, P < 0.001). The estimated trough ramucirumab concentrations were significantly lower in patients with massive ascites than in those with no/mild ascites after the first dose (26.4 ± 6.8 versus 36.1 ± 7.1 μg/mL, P < 0.001) and at steady state (41.4 ± 16.3 versus 65.9 ± 18.0 μg/mL, P < 0.001).

Conclusion

In the present study, the presence of massive ascites affected the pharmacokinetics of ramucirumab in patients with gastrointestinal cancers. Our results suggest that dose optimization of ramucirumab may be necessary in patients with massive ascites due to higher ramucirumab clearance.

Nur mit Berechtigung zugänglich

Fuchs CS, Tomasek J, Yong CJ et al (2014) Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383:31–39. https://doi.org/10.1016/S0140-6736(13)61719-5CrossRefPubMed

Wilke H, Muro K, Van Cutsem E et al (2014) Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 15:1224–1235. https://doi.org/10.1016/S1470-2045(14)70420-6CrossRefPubMed

Iwasa S, Bando H, Piao Y et al (2022) The clinical position of ramucirumab-containing regimens for advanced gastric cancer: a review of clinical trial data. Futur Oncol 18:2709–2721. https://doi.org/10.2217/fon-2022-0281CrossRef

European medicines agency (EMA) (2022) Cyramza-epar product information. http://www.ema.europa.eu. Accessed 4 Mar, 2023

Tabernero J, Ohtsu A, Muro K et al (2017) Exposure-response analyses of ramucirumab from two randomized, phase III trials of second-line treatment for advanced gastric or gastroesophageal junction cancer. Mol Cancer Ther 16:2215–2223. https://doi.org/10.1158/1535-7163.MCT-16-0895CrossRefPubMed

O’Brien L, Westwood P, Gao L, Heathman M (2017) Population pharmacokinetic meta-analysis of ramucirumab in cancer patients. Br J Clin Pharmacol 83:2741–2751. https://doi.org/10.1111/bcp.13403CrossRefPubMedPubMedCentral

Cavazzoni E, Bugiantella W, Graziosi L et al (2013) Malignant ascites: pathophysiology and treatment. Int J Clin Oncol 18:1–9. https://doi.org/10.1007/s10147-012-0396-6CrossRefPubMed

Becker G, Galandi D, Blum HE (2006) Malignant ascites: systematic review and guideline for treatment. Eur J Cancer 42:589–597. https://doi.org/10.1016/j.ejca.2005.11.018CrossRefPubMed

Kaneko T, Doki K, Yamada T et al (2021) Bevacizumab distribution into ascitic fluid decreases serum drug exposure. Ther Drug Monit 43:813–814. https://doi.org/10.1097/FTD.0000000000000926CrossRefPubMed

10.

Kaneko T, Doki K, Yamada T et al (2022) Distribution of therapeutic monoclonal antibodies into ascites in advanced gastric cancer patients with peritoneal metastasis: case reports and literature review. Cancer Chemother Pharmacol 90:421–426. https://doi.org/10.1007/s00280-022-04479-3CrossRefPubMed

11.

Matsumoto H, Kawazoe A, Shimada K et al (2018) A retrospective study of the safety and efficacy of paclitaxel plus ramucirumab in patients with advanced or recurrent gastric cancer with ascites. BMC Cancer 18:120. https://doi.org/10.1186/s12885-018-4057-7CrossRefPubMedPubMedCentral

12.

Nakajima TE, Yamaguchi K, Boku N et al (2020) Randomized phase II/III study of 5-fluorouracil/l-leucovorin versus 5-fluorouracil/l-leucovorin plus paclitaxel administered to patients with severe peritoneal metastases of gastric cancer (JCOG1108/WJOG7312G). Gastric Cancer 23:677–688. https://doi.org/10.1007/s10120-020-01043-xCrossRefPubMed

13.

Tabernero J, Ohtsu A, Muro K et al (2015) Exposure-response (E-R) relationship of ramucirumab (RAM) from two global, randomized, double-blind, phase 3 studies of patients (Pts) with advanced second-line gastric cancer. J Clin Oncol 33:abstr121. https://doi.org/10.1200/jco.2015.33.3_suppl.121CrossRef

14.

Kim TY, Yen CJ, Al-Batran SE et al (2018) Exposure–response relationship of ramucirumab in East Asian patients from RAINBOW: a randomized clinical trial in second-line treatment of gastric cancer. Gastric Cancer 21:276–284. https://doi.org/10.1007/s10120-017-0737-2CrossRefPubMed

15.

Cohn AL, Yoshino T, Heinemann V et al (2017) Exposure–response relationship of ramucirumab in patients with advanced second-line colorectal cancer: exploratory analysis of the RAISE trial. Cancer Chemother Pharmacol 80:599–608. https://doi.org/10.1007/s00280-017-3380-zCrossRefPubMedPubMedCentral

16.

de Wit R, Powles T, Castellano D et al (2022) Exposure-response relationship of ramucirumab in RANGE, a randomized phase III trial in advanced urothelial carcinoma refractory to platinum therapy. Br J Clin Pharmacol 88:3182–3192. https://doi.org/10.1111/bcp.15233CrossRefPubMed

17.

Smit EF, Garon EB, Reck M et al (2018) Exposure–response relationship for ramucirumab from the randomized, double-blind, phase 3 REVEL trial (docetaxel versus docetaxel plus ramucirumab) in second-line treatment of metastatic non-small cell lung cancer. Cancer Chemother Pharmacol 82:77–86. https://doi.org/10.1007/s00280-018-3560-5CrossRefPubMed

Titel: Effect of massive ascites on ramucirumab pharmacokinetics in patients with gastrointestinal cancers: a population pharmacokinetic analysis
verfasst von: Takuya Kaneko
Kosuke Doki
Takeshi Yamada
Yoshiyuki Yamamoto
Toshikazu Moriwaki
Yoshiharu Suzuki
Masato Homma
Publikationsdatum: 17.07.2023
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 4/2023
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-023-04568-x

Neu im Fachgebiet Onkologie

Umsetzung der POMGAT-Leitlinie läuft

03.05.2024 DCK 2024 Kongressbericht

Seit November 2023 gibt es evidenzbasierte Empfehlungen zum perioperativen Management bei gastrointestinalen Tumoren (POMGAT) auf S3-Niveau. Vieles wird schon entsprechend der Empfehlungen durchgeführt. Wo es im Alltag noch hapert, zeigt eine Umfrage in einem Klinikverbund.

Springer Medizin

Effect of massive ascites on ramucirumab pharmacokinetics in patients with gastrointestinal cancers: a population pharmacokinetic analysis