Sustained-Hepatic Arterial Infusion of oxaliplatin: pharmacokinetic advantages over Hepatic Arterial Infusion using a preclinical animal tumour model

Frederic Deschamps (1, 2) , Lambros Tselikas (3) , Masako Tasaki (4) , Shinji Motoyama (4) , Thomas Isoardo (3) , Michel Ducreux (5, 1, 6) , Dragica Paunovic (7) , Laurence Moine (8) , Thierry de Baere (5, 1, 2)

1 IGR - Institut Gustave Roussy
2 Imagerie thérapeutique (radiologie interventionnelle)
3 ITIC - Immunologie anti-tumorale et immunothérapie des cancers
4 Terumo Corporation Shonan Center
5 Université Paris-Saclay
6 Oncologie digestive
7 Terumo Corporation
8 IGPS - Institut Galien Paris-Saclay

Hepatic arterial infusion (HAI) of oxaliplatin allows greater liver tumour drug exposure compared to systemic infusion. However, the therapeutic index of HAI oxaliplatin remains poor. Using Pickering emulsion technology, we developed a platform able to provide sustained releases of oxaliplatin. The goal of this study was to evaluate the pharmacokinetic advantages of sustained-HAI oxaliplatin over HAI using a preclinical animal tumour model. Injections of 0.6 mg oxaliplatin in 20 min were selectively done in left hepatic arteries of 20 rabbits bearing a VX2 liver tumour in the middle left-lobe, using HAI (n = 10) or sustained-HAI (n = 10). In each group, half of the rabbits were sacrificed at 24 h and half at 72 h. Mass spectrometry was used to quantify drug pharmacokinetics in blood and oxaliplatin concentrations in tumour tissues, right- and middle left-liver lobes, spleen and lung. Compared to HAI, sustained-HAI of oxaliplatin resulted in lower plasmatic peak (Cmax: 275 ± 41 vs. 416 ± 133 ng/mL, p = 0.02) and higher concentration in the tumour at 24 h (2118 ± 2107 vs. 210 ± 93 ng/g, p = 0.008). After HAI, oxaliplatin concentration in tumours was significantly higher than in lung at 24 h (p = 0.03) but no other difference was found between oxaliplatin concentrations in tumours and in liver lobes, spleen or lung, neither at 24 h nor at 72 h. On the opposite, sustained-HAI resulted in higher concentrations of oxaliplatin in tumour compared to oxaliplatin concentrations in the middle left lobe (163 ± 86 ng/g at 24 h, p = 0.01, and 90 ± 15 ng/g at 72 h, p = 0.04), right lobe (174 ± 112 ng/g at 24 h, p = 0.01, and 112 ± 35 ng/g, p = 0.04 at 72 h), spleen (142 ± 21 ng/g at 24 h, p = 0.01, and 98 ± 12 ng/g at 72 h, p = 0.04), and lung (85 ± 11 ng/g at 24 h, p = 0.01, and 52 ± 4 ng/g at 72 h, p = 0.03). Sustained-HAI improves the therapeutic index of HAI oxaliplatin and offers a great potential for patients suffering from unresectable colorectal liver metastases or hepatocellular carcinoma.

Domaines: Pharmacologie; Cancer; Hépatologie et Gastroentérologie

Frederic Deschamps, Lambros Tselikas, Masako Tasaki, Shinji Motoyama, Thomas Isoardo, et al.. Sustained-Hepatic Arterial Infusion of oxaliplatin: pharmacokinetic advantages over Hepatic Arterial Infusion using a preclinical animal tumour model. Drug Delivery and Translational Research, In press, 11, pp.2144-2150. ⟨10.1007/s13346-020-00881-7⟩. ⟨hal-03324619⟩