A limited sampling schedule to estimate individual pharmacokinetics of pemetrexed in patients with varying renal functions

Purpose: Pemetrexed is a widely used cytostatic agent with an established exposure–response relationship. Although dosing is based on body surface area (BSA), large interindividual variability in pemetrexed plasma concentrations is observed. Therapeutic drug monitoring (TDM) can be a feasible strategy to reduce variability in specific cases leading to potentially optimized pemetrexed treatment. The aim of this study was to develop a limited sampling schedule (LSS) for the assessment of pemetrexed pharmacokinetics. Methods: Based on two real-life datasets, several limited sampling designs were evaluated on predicting clearance, using NONMEM, based on mean prediction error (MPE %) and normalized root mean squared error (NRMSE %). The predefined criteria for an acceptable LSS were: a maximum of four sampling time points within 8 h with an MPE and NRMSE ≤ 20%. Results: For an accurate estimation of clearance, only four samples in a convenient window of 8 h were required for accurate and precise prediction (MPE and NRMSE of 3.6% and 5.7% for dataset 1 and of 15.5% and 16.5% for dataset 2). A single sample at t = 24 h performed also within the criteria with MPE and NRMSE of 5.8% and 8.7% for dataset 1 and of 11.5% and 16.4% for dataset 2. Bias increased when patients had lower creatinine clearance. Conclusions: We presented two limited sampling designs for estimation of pemetrexed pharmacokinetics. Either one can be used based on preference and feasibility

Toxicity of pemetrexed during renal impairment explained-Implications for safe treatment

Item does not contain fulltextPemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: <45 mL/min) the approved dose of 500 mg/m(2) would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20 mg for patients (eGFR: 20 mL/min) is shown to be neutropenic-equivalent to the approved dose in patients with adequate renal function (eGFR: 90 mL/min), but would result in an approximately 13-fold lower area under the concentration-time curve. The pemetrexed exposure-toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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Prediction of the pharmacokinetics of pemetrexed with a low test dose: A proof-of-concept study.

PURPOSE: Pemetrexed is a cytotoxic drug used for the treatment of lung cancer and mesothelioma. The use of a low test dosing of cytotoxic drugs may aid in dose individualization without causing harm. The aim of this proof-of-concept study was to assess if the pharmacokinetics (PKs) of a test dose could predict the PKs of a therapeutic pemetrexed dose. METHODS: Ten patients received both a low test dose (100 μg) and a therapeutic dose of pemetrexed after which plasma concentrations pemetrexed were measured. PK analysis was performed by means of nonlinear mixed-effects modelling. The predictive performances of test dose clearance and renal function towards a therapeutic dose were assessed. RESULTS: The PKs of a pemetrexed test dose were best described by a one-compartment model with linear elimination. A high variability in the administered dose was observed for the test dose, but not for the therapeutic dose. A statistically significant correlation between test dose clearance and therapeutic dose clearance was observed (Spearman's rho: 0.758, P = 0.02). The predictive performance of test dose clearance was worse than renal function: mean predictive error (+95% confidence interval [CI]) 53.9% (50.1-57.6%) vs 19.4% (12.4-26.4%) and normalized root-mean square error (+95% CI) 57.8% (30.5-85.1%) vs 25.7% (20.3-31.0%). CONCLUSION: We show that test dosing of pemetrexed is feasible, but there seems no added value for a low test dosing in the dose individualization of pemetrexed

Year-to-year crop shifts promote weed diversity in tropical permanent rainfed cultivation

In the past decades, the expansion and modernisation of agriculture in the mountainous areas of Southeast Asia has had severe impacts on biodiversity, as the once species-rich forests were turned into homogeneous fields receiving ample external inputs. A common feature of permanent cropping with annual crops is the frequent change of crop choice, depending on market opportunities or other motives. However, the precise effect of crop shifts on weeds in tropical areas is largely unknown. In this study, we investigated the short-term effect of crop sequences on the diversity of weed communities in smallholder fields of Northern Thailand. Crop choices were upland rice, maize, fallow and young tree plantations with or without intercrop. We counted the number of crop shifts and the number of crops involved during a 3-years period preceding weed sampling. We showed that the number of crop shifts did not affect weed density and biomass. However, herbaceous species number and diversity (measured as Shannon index) increased by 36% and 46% respectively, while herbaceous species dominance decreased by 38%, in fields with yearly crop shifts compared to fields with no shifts in the previous three years. The effect of a particular crop on diversity, or the effect of intercropping with young trees, was weaker. It was likely due to the more variable resources (especially light) in fields with two crop shifts, allowing species with different niches to co-exist. Crop type and frequent crop shifts did not affect shrub and tree species number,diversity or dominance. Some species were strongly associated with fields with no crop shift in the sequence (e.g. the tree Antidesma velutinosum) or to fields with two crop shifts in the sequence (e.g. the herb Centella asiatica, the C4 grass Digitaria radicosa). Overall, this study showed that in this agronomical system, maintaining yearly crop shifts does not significantly affect weed abundance, but supports in-field plant species diversity, which is likely to impact the services provisioned by tropical mountainous agro-ecosystems

Year-to-year crop shifts promote weed diversity in tropical permanent rainfed cultivation [plus Supplementary information]

In the past decades, the expansion and modernisation of agriculture in the mountainous areas of Southeast Asia has had severe impacts on biodiversity, as the once species-rich forests were turned into homogeneous fields receiving ample external inputs. A common feature of permanent cropping with annual crops is the frequent change of crop choice, depending on market opportunities or other motives. However, the precise effect of crop shifts on weeds in tropical areas is largely unknown. In this study, we investigated the short-term effect of crop sequences on the diversity of weed communities in smallholder fields of Northern Thailand. Crop choices were upland rice, maize, fallow and young tree plantations with or without intercrop. We counted the number of crop shifts and the number of crops involved during a 3-years period preceding weed sampling. We showed that the number of crop shifts did not affect weed density and biomass. However, herbaceous species number and diversity (measured as Shannon index) increased by 36% and 46% respectively, while herbaceous species dominance decreased by 38%, in fields with yearly crop shifts compared to fields with no shifts in the previous three years. The effect of a particular crop on diversity, or the effect of intercropping with young trees, was weaker. It was likely due to the more variable resources (especially light) in fields with two crop shifts, allowing species with different niches to co-exist. Crop type and frequent crop shifts did not affect shrub and tree species number,diversity or dominance. Some species were strongly associated with fields with no crop shift in the sequence (e.g. the tree Antidesma velutinosum) or to fields with two crop shifts in the sequence (e.g. the herb Centella asiatica, the C4 grass Digitaria radicosa). Overall, this study showed that in this agronomical system, maintaining yearly crop shifts does not significantly affect weed abundance, but supports in-field plant species diversity, which is likely to impact the services provisioned by tropical mountainous agro-ecosystems

Mechanisms, Management and Prevention of Pemetrexed-Related Toxicity

Pemetrexed is a cytostatic antifolate drug and a cornerstone in the treatment of lung cancer. Although generally well tolerated, a substantial part of the patient population experiences dose-limiting or even treatment-limiting toxicities. These include mucositis, skin problems, fatigue, renal toxicity, and neutropenia. Several studies confirmed that pemetrexed pharmacokinetics can serve as a prognostic factor for the development of toxicity, especially for neutropenia. Preventing and managing toxicity of pemetrexed can help to ensure durable treatment. Several evidence-based strategies are already implemented in clinical care. With the introduction of standard vitamin supplementation and dexamethasone, the incidence of hematological toxicity and skin reactions substantially decreased. In the case of high risk for toxicity, granulocyte colony-stimulating factor can be used to prevent severe hematological toxicity. Moreover, high-dose folinic acid can resolve severe pemetrexed-induced toxicity. There are several experimental options to prevent or manage pemetrexed-related toxicity, such as the use of standard folinic acid, hemodialysis, antidotes such as thymidine, hypoxanthine, and glucarpidase, and the use of therapeutic drug monitoring. These strategies still need clinical evaluation before implementation, but could enable treatment with pemetrexed for patients who are at risk for toxicity, such as in renal impairment