Population Pharmacokinetic Model-Based Evaluation of Intact Oxaliplatin in Rats with Acute Kidney Injury

SIMPLE SUMMARY: Acute kidney injury (AKI) complicates the dose setting of oxaliplatin (L-OHP), making it difficult to continue treatment cycles and retain antitumor efficacies with minimum L-OHP-related toxicities. Our study aimed to assess the impact of AKI on the pharmacokinetics of intact L-OHP and simulate the relationship between the degree of renal function and intact L-OHP exposures using a population pharmacokinetic model. Mild and severe renal dysfunction model rats were used to determine plasma and urine intact L-OHP concentration–time profiles after L-OHP administration. No significant differences in intact L-OHP levels between rats with normal renal function and those with renal dysfunction were observed, whereas renal excretion of intact L-OHP was correlated with renal function. Results of population PK model simulation suggested that dose reduction is dispensable for patients with mild to moderate AKI. The population PK modeling and simulation approach can contribute to developing an appropriate dose regimen of L-OHP for AKI patients. ABSTRACT: Acute kidney injury (AKI) complicates the dosing strategies of oxaliplatin (L-OHP) and the requirement for L-OHP dose reduction in patients with renal failure remains controversial. The objective of this study is to assess the impact of AKI on the pharmacokinetics (PK) of intact L-OHP and simulate the relationship between the degree of renal function and intact L-OHP exposures using a population PK model. Intact L-OHP concentrations in plasma and urine after L-OHP administration were measured in mild and severe AKI models established in rats through renal ischemia-reperfusion. Population PK modeling and simulation were performed. There were no differences among rats in the area under the plasma concentration–time curve of intact L-OHP after intravenous L-OHP administrations. Nevertheless, the amount of L-OHP excretion after administration of 8 mg/kg L-OHP in mild and severe renal dysfunction rats was 63.5% and 37.7%, respectively, and strong correlations were observed between biochemical renal function markers and clearance of intact L-OHP. The population PK model simulated well the observed levels of intact L-OHP in AKI model rats. The population PK model-based simulation suggests that dose reduction is unnecessary for patients with mild to moderate AKI.