Association of Plasma Creatinine with Systemic Exposure to S-1 and Oxaliplatin in Two Types of Chronic Kidney Disease Animal Models.

Abstract

Chronic kidney disease (CKD) is a serious chemotherapy-associated clinical condition. CKD complicates the pharmacokinetics of anticancer drugs, requiring personalized dosing strategies to minimize toxicity. S-1 and oxaliplatin (the SOX regimen) are widely used for gastrointestinal cancer treatment. However, the specific association between systemic drug exposure and renal biomarker levels in CKD remains unclear. This study evaluated the pharmacokinetics of S-1 and oxaliplatin in 2 CKD model rats (5/6 nephrectomy and adenine-induced) and examined their relationships with renal biomarkers. S-1 (2 mg/kg as tegafur) and oxaliplatin (5 mg/kg) were administered separately, and plasma levels of tegafur, 5-fluorouracil (5-FU), 5-chloro-2,4-dihydropyridine, oxaliplatin, and platinum were measured by LC-tandem MS. Systemic exposure to S-1 and oxaliplatin was higher in the CKD model rats than in the normal group, with 5-FU levels being particularly higher in the adenine-induced model than in the 5/6 nephrectomy model. The area under the curve values of 5-FU and platinum were strongly correlated with plasma creatinine (P_Cr) levels (r = 0.79 and 0.88, respectively). Population pharmacokinetic analysis identified P_Cr as a significant covariate of 5-FU clearance. A nomogram constructed using P_Cr-based simulations demonstrated the feasibility of individualized S-1 dosing. Overall, our findings suggest that P_Cr is a practical biomarker to guide S-1 dose optimization and highlight the importance of pharmacokinetics-based strategies for patients with cancer and CKD.