Population Pharmacokinetic Model-Based Evaluation of Intact Oxaliplatin in Rats with Acute Kidney Injury
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 t...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-12-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/13/24/6382 |
| _version_ | 1797506293334802432 |
|---|---|
| author | Shinji Kobuchi Miyu Kai Yukako Ito |
| author_facet | Shinji Kobuchi Miyu Kai Yukako Ito |
| author_sort | Shinji Kobuchi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T04:31:34Z |
| format | Article |
| id | doaj.art-2fafb08dec754c1fbc5922303642422b |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T04:31:34Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2fafb08dec754c1fbc5922303642422b2023-11-23T04:08:05ZengMDPI AGCancers2072-66942021-12-011324638210.3390/cancers13246382Population Pharmacokinetic Model-Based Evaluation of Intact Oxaliplatin in Rats with Acute Kidney InjuryShinji Kobuchi0Miyu Kai1Yukako Ito2Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607-8414, JapanDepartment of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607-8414, JapanDepartment of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607-8414, JapanAcute 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.https://www.mdpi.com/2072-6694/13/24/6382renal dysfunctionpharmacokinetic modeling and simulationplatinum compoundscancer chemotherapy |
| spellingShingle | Shinji Kobuchi Miyu Kai Yukako Ito Population Pharmacokinetic Model-Based Evaluation of Intact Oxaliplatin in Rats with Acute Kidney Injury Cancers renal dysfunction pharmacokinetic modeling and simulation platinum compounds cancer chemotherapy |
| title | Population Pharmacokinetic Model-Based Evaluation of Intact Oxaliplatin in Rats with Acute Kidney Injury |
| title_full | Population Pharmacokinetic Model-Based Evaluation of Intact Oxaliplatin in Rats with Acute Kidney Injury |
| title_fullStr | Population Pharmacokinetic Model-Based Evaluation of Intact Oxaliplatin in Rats with Acute Kidney Injury |
| title_full_unstemmed | Population Pharmacokinetic Model-Based Evaluation of Intact Oxaliplatin in Rats with Acute Kidney Injury |
| title_short | Population Pharmacokinetic Model-Based Evaluation of Intact Oxaliplatin in Rats with Acute Kidney Injury |
| title_sort | population pharmacokinetic model based evaluation of intact oxaliplatin in rats with acute kidney injury |
| topic | renal dysfunction pharmacokinetic modeling and simulation platinum compounds cancer chemotherapy |
| url | https://www.mdpi.com/2072-6694/13/24/6382 |
| work_keys_str_mv | AT shinjikobuchi populationpharmacokineticmodelbasedevaluationofintactoxaliplatininratswithacutekidneyinjury AT miyukai populationpharmacokineticmodelbasedevaluationofintactoxaliplatininratswithacutekidneyinjury AT yukakoito populationpharmacokineticmodelbasedevaluationofintactoxaliplatininratswithacutekidneyinjury |