Pharmacokinetic evaluation of oxaliplatin combined with S-1 (SOX) chemotherapy in a rat model of colorectal cancer with acute kidney injury: predictive renal biomarkers for dose optimisation
Creators: name: Tanaka, Takumi
name: Kobuchi, Shinji
name: Ito, Yukako
name: Sakaeda, Toshiyuki
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biochemistry
subject: Microbiology
subject: FOS: Biological sciences
subject: Cell Biology
subject: Pharmacology
subject: Biotechnology
subject: Chemical Sciences not elsewhere classified
subject: Mathematical Sciences not elsewhere classified
subject: Developmental Biology
subject: Marine Biology
subject: Cancer

description: Dose adjustment based on renal function is essential in S-1, which contains the 5‑fluorouracil prodrug tegafur, and platinum-based agent oxaliplatin (SOX) combination chemotherapy for colorectal cancer in patients with chronic kidney disease. However, limited evidence on dose adjustment in acute kidney injury (AKI) and challenges in determining dosing strategies. This study investigated the pharmacokinetics of SOX chemotherapy and renal biomarkers in rats.AKI was prepared by renal ischaemia-reperfusion injury in 1,2-dimethylhydrazine-induced colorectal cancer model rats. Serum creatinine (<i>sCr</i>) levels were determined as a renal biomarker. After administration of S-1 (2 mg/kg tegafur) and oxaliplatin (5 mg/kg), drug concentrations of tegafur, 5-FU, and platinum were measured in the plasma and tumours.No alterations in the area under the plasma concentration–time curve (<i>AUC<sub>0-24h</sub></i>) values of 5-fluorouracil were observed between control and AKI model rats. The tumour concentrations of 5-fluorouracil in the mild and severe AKI groups were significantly lower than control group. The <i>AUC<sub>0-24h</sub></i> for platinum increased with AKI severity. Notably, population pharmacokinetic analysis identified <i>sCr</i> as a covariate in platinum distribution after SOX chemotherapy.To optimise dose adjustment of SOX chemotherapy in patients with AKI, <i>sCr</i> may be a key factor in determining the appropriate dose. Dose adjustment based on renal function is essential in S-1, which contains the 5‑fluorouracil prodrug tegafur, and platinum-based agent oxaliplatin (SOX) combination chemotherapy for colorectal cancer in patients with chronic kidney disease. However, limited evidence on dose adjustment in acute kidney injury (AKI) and challenges in determining dosing strategies. This study investigated the pharmacokinetics of SOX chemotherapy and renal biomarkers in rats. AKI was prepared by renal ischaemia-reperfusion injury in 1,2-dimethylhydrazine-induced colorectal cancer model rats. Serum creatinine (<i>sCr</i>) levels were determined as a renal biomarker. After administration of S-1 (2 mg/kg tegafur) and oxaliplatin (5 mg/kg), drug concentrations of tegafur, 5-FU, and platinum were measured in the plasma and tumours. No alterations in the area under the plasma concentration–time curve (<i>AUC<sub>0-24h</sub></i>) values of 5-fluorouracil were observed between control and AKI model rats. The tumour concentrations of 5-fluorouracil in the mild and severe AKI groups were significantly lower than control group. The <i>AUC<sub>0-24h</sub></i> for platinum increased with AKI severity. Notably, population pharmacokinetic analysis identified <i>sCr</i> as a covariate in platinum distribution after SOX chemotherapy. To optimise dose adjustment of SOX chemotherapy in patients with AKI, <i>sCr</i> may be a key factor in determining the appropriate dose.