Population pharmacokinetics of raltitrexed in patients with advanced solid tumours

Blair, E.; Rivory, Laurent P.; Clarke, Stephen; McLachlan, Andrew J.

doi:10.1111/j.1365-2125.2003.02050.x

Cited by 12 publications

(8 citation statements)

References 38 publications

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“…Population pharmacokinetics of many anticancer agents are currently being investigated as a part of clinical development; ( 25–31 ) however, unfit patients, including those with organ dysfunction or poor performance status, are commonly excluded from clinical trials, resulting in a paucity of pharmacokinetic information for these groups. After drugs are approved, however, these patients are treated in medical practice, and dose reduction may be required at the discretion of attending physicians.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of docetaxel in patients with hepatic dysfunction treated in an oncology practice

et al. 2009

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To investigate the relationship between the degree of liver dysfunction and the pharmacokinetics of docetaxel, a population pharmacokinetic model was developed in an oncology practice without excluding patients with moderate to severe liver dysfunction. Two hundred patients were treated with docetaxel as a single agent or in combination chemotherapy. The plasma concentration-time course data were analyzed using a three-compartment open model with zero-order administration and first-order elimination on the NONMEM program. Sixty-one had elevated transaminase levels, and alkaline phosphatase was elevated in 40. Body surface area, albumin, a 1 -acid glycoprotein, and liver function were found to be significant covariates for the systemic clearance of docetaxel. Compared to patients with normal or minimal impairment of liver function, patients with grade 2 and 3 elevations of transaminases at baseline in conjunction with elevation of alkaline phosphatase had 22 and 38% lower clearances, respectively. Goodness-of-fit plots indicated that the model was fitted well with the observed data, and the bootstrap method guaranteed robustness of the model. We A nticancer drugs have a narrow therapeutic window, and interpatient variabilities in pharmacokinetics and pharmacodynamics may results in serious toxicities.(1) Elucidating the factors causing these interpatient variabilities is helpful for avoiding serious toxicities and augmenting antitumor activity. Population pharmacokinetics represent a means to investigate the effect of patients' variables on the pharmacokinetics of drugs.(2-4) In this approach, pharmacokinetics are analyzed in many patients with different backgrounds as a population, and the effect of these backgrounds on the pharmacokinetics are investigated. Pharmacokinetic information on patients with small numbers of drug concentration data can also be analyzed by population pharmacokinetic methodology.(2-5) Thus, it is a useful tool for investigating pharmacokinetics of drugs in a population including elderly patients or patients with organ dysfunctions.Docetaxel has been used widely to treat breast, non-small-cell lung, ovarian, head and neck, gastric, esophageal, and prostate cancers. (6)(7)(8)(9)(10)(11)(12)(13)(14)(15) The drug is eliminated from the body mainly by hepatic metabolism. Population pharmacokinetic models of docetaxel have been developed using data obtained from patients treated in clinical trials prior to its drug registration, (16)(17)(18) where body surface area, albumin, age, α 1 -acid glycoprotein, and liver function were found to be significant covariates for the systemic clearance of docetaxel. In clinical studies for the development of anticancer drugs, unfit patients including those with moderate to severe liver dysfunction or poor performance status are commonly excluded, and information on pharmacokinetics and pharmacodynamics for such patients is therefore lacking.Therefore, in the present study, we developed a population pharmacokinetic model of docetaxel in cancer patients treat...

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Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of docetaxel in patients with hepatic dysfunction treated in an oncology practice

et al. 2009

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“…Also, raltitrexed (Tomudex) PK parameters were similar to those of pralatrexate, and the disposition was found to be influenced by weight, CrCL, and albumin level. 15 Finally, the PKs of methotrexate were well described using a two-compartment model and are influenced by body weight. 16 Although CrCL was not identified in this evaluation, there is evidence that pralatrexate undergoes renal elimination through active transport.…”

Section: Discussionmentioning

confidence: 99%

A Population Pharmacokinetic and Pharmacodynamic Evaluation of Pralatrexate in Patients With Relapsed or Refractory Non-Hodgkin's or Hodgkin's Lymphoma

Mould

Sweeney

Duffull

et al. 2009

Clin Pharmacol Ther

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In a pralatrexate phase I study, patients displayed a high incidence of mucositis of grades 3 and 4. Preliminary evaluations of the pharmacokinetics of the drug and its association with mucositis suggested that pralatrexate exposure (area under the concentration-time curve (AUC)) could be controlled with body size (e.g., weight or body surface area)-based dosing and that pretreatment with folic acid and vitamin B(12) might diminish the incidence and severity of mucositis. The study was amended, with revised dosing and vitamin B(12) administration. Data from 47 patients were evaluated using NONMEM. Weight and methylmalonic acid (MMA) level were predictive of pharmacokinetic (PK) variability. AUC and MMA level were positively correlated with the risk of developing mucositis. A lower AUC schedule with vitamin B(12) pretreatment may control mucositis without compromising efficacy. The covariates identified in this study are comparable with other antifolate analogs. The application of modeling was a critical step in the development of pralatrexate, yielding important suggestions for dose, scheduling, and pretreatment modifications.

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“…As RTX displays a large pharmacokinetics (PK) variability, 11 we assumed that its adverse events occurrence may be linked to overexposure linked to its interindividual variability. To investigate this hypothesis, and to explore PK differences between the two previously mentioned regimens, we performed a randomized crossover PK comparative study between every 2 weeks TOMOX (RTX 2 mg/m 2 and oxaliplatin 85 mg/m 2 every 2 weeks) and every 3 weeks TOMOX (RTX 3 mg/m 2 and oxaliplatin 130 mg/m 2 every 3 weeks) in metastatic CRC patients.…”

Section: Introductionmentioning

confidence: 99%

Exposure‐response analysis of Raltitrexed assessing liver toxicity

Royer

Schmitt

Nguyen

et al. 2020

Brit J Clinical Pharma

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Aim Raltitrexed (RTX) is a thymidylate synthase inhibitor with large pharmacokinetics (PK) variability that can be administered in case of 5‐fluorouracil (5FU) intolerance or dihydropyrimidine dehydrogenase deficiency. While it is a more potent thymidylate synthase inhibitor than 5FU, RTX failed to replace this drug for colorectal cancer patients, mainly due to its toxicity at the recommended dose of 3 mg/m2 every 3 weeks. However, every 2 weeks administration at 2 mg/m2 demonstrated a favourable toxicity profile. Method We performed a randomized crossover comparative population PK study between every 2 weeks TOMOX (RTX 2 mg/m2) and every 3 weeks TOMOX (RTX 3 mg/m2). Results A three‐compartment model and a proportional error model best describe the data. Creatinine clearance and sex, but not body surface area (BSA), were covariates of RTX clearance leading to decrease of its interindividual variability of 28%. Weight and body surface area were covariates of central and peripheral volumes of distribution, respectively, leading to decreases of interindividual variability of 34.6% and 100%, respectively. In contrast to the dose, AUC was a good predictor of liver toxicity (P = 0.006, OR = 3.91, 95%CI = [1.48‐10.34]). Using covariates to compute individual clearance and a threshold AUC (1.639, determined in this study), a covariates‐based dose was calculated, leading to less variability in AUC than observed with the actual BSA‐based or fixed doses. Conclusion These results advocate for the use of creatinine clearance and sex to determine the RTX dose instead of BSA.

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Population pharmacokinetics of raltitrexed in patients with advanced solid tumours

Cited by 12 publications

References 38 publications

Population pharmacokinetics of docetaxel in patients with hepatic dysfunction treated in an oncology practice

Population pharmacokinetics of docetaxel in patients with hepatic dysfunction treated in an oncology practice

A Population Pharmacokinetic and Pharmacodynamic Evaluation of Pralatrexate in Patients With Relapsed or Refractory Non-Hodgkin's or Hodgkin's Lymphoma

Exposure‐response analysis of Raltitrexed assessing liver toxicity

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