Abstract
Simple SummaryAcute 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.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.
Highlights
Acute kidney injury (AKI) is a common and critical complication in the treatments of cancer [1]
In a previous clinical study, decreased plasma ultrafiltrate Pt clearance and enhanced systemic exposure of Pt were observed in cancer patients treated with single-agent L-OHP, whereas a corresponding increase in L-OHP-related toxicities was not observed [19]. These observations and our results suggest that monitoring the level of intact L-OHP might help in predicting the degree of toxicodynamics of L-OHP in patients with renal dysfunction
We investigated the PK of intact L-OHP in mild and severe AKI model rats and developed a population PK model for simulating the quantitative relationship between renal function and intact L-OHP exposures
Summary
Acute kidney injury (AKI) is a common and critical complication in the treatments of cancer [1]. A series of pathological processes involved in AKI results in decreased glomerular filtration and renal excretion [3,4], leading to a decrease in renal clearance of drugs and toxins [5]. AKI affects the disposition and hepatic clearance of drugs and toxins [6,7,8], complicating our understanding of drug pharmacokinetics (PK). AKI, the risk of toxicity from chemotherapeutic agents is increased, leading to the discontinuation of cancer chemotherapy or the change to alternative treatments. AKI requires a dose setting for each patient and dose reduction in chemotherapy. Excessive dose reduction based on the physician’s experience may induce attenuation of antitumor effects. To continue the treatment cycle and retain the antitumor efficacy, the development of a rational dosing strategy based on renal function is needed but remains a challenge
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