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- Boosman, René J, et al.
(författare)
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Toxicity of pemetrexed during renal impairment explained-Implications for safe treatment
- 2021
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 149:8, s. 1576-1584
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Tidskriftsartikel (refereegranskat)abstract
- Pemetrexed 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/m2 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.
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| 3. |
- Sim, Thomas G., et al.
(författare)
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Regional variability in peatland burning at mid-to high-latitudes during the Holocene
- 2023
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Ingår i: Quaternary Science Reviews. - : Elsevier. - 0277-3791 .- 1873-457X. ; 305
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Tidskriftsartikel (refereegranskat)abstract
- Northern peatlands store globally-important amounts of carbon in the form of partly decomposed plant detritus. Drying associated with climate and land-use change may lead to increased fire frequency and severity in peatlands and the rapid loss of carbon to the atmosphere. However, our understanding of the patterns and drivers of peatland burning on an appropriate decadal to millennial timescale relies heavily on individual site-based reconstructions. For the first time, we synthesise peatland macrocharcoal re-cords from across North America, Europe, and Patagonia to reveal regional variation in peatland burning during the Holocene. We used an existing database of proximal sedimentary charcoal to represent regional burning trends in the wider landscape for each region. Long-term trends in peatland burning appear to be largely climate driven, with human activities likely having an increasing influence in the late Holocene. Warmer conditions during the Holocene Thermal Maximum (similar to 9e6 cal. ka BP) were associated with greater peatland burning in North America's Atlantic coast, southern Scandinavia and the Baltics, and Patagonia. Since the Little Ice Age, peatland burning has declined across North America and in some areas of Europe. This decline is mirrored by a decrease in wider landscape burning in some, but not all sub-regions, linked to fire-suppression policies, and landscape fragmentation caused by agricultural expansion. Peatlands demonstrate lower susceptibility to burning than the wider landscape in several instances, probably because of autogenic processes that maintain high levels of near-surface wetness even during drought. Nonetheless, widespread drying and degradation of peatlands, particularly in Europe, has likely increased their vulnerability to burning in recent centuries. Consequently, peatland restoration efforts are important to mitigate the risk of peatland fire under a changing climate. Finally, we make recommendations for future research to improve our understanding of the controls on peatland fires.(c) 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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- Yin, Anyue, et al.
(författare)
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Quantitative modeling of tumor dynamics and development of drug resistance in non-small cell lung cancer patients treated with erlotinib
- 2024
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Ingår i: CPT. - : John Wiley & Sons. - 2163-8306. ; 13:4, s. 612-623
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Tidskriftsartikel (refereegranskat)abstract
- Insight into the development of treatment resistance can support the optimization of anticancer treatments. This study aims to characterize the tumor dynamics and development of drug resistance in patients with non-small cell lung cancer treated with erlotinib, and investigate the relationship between baseline circulating tumor DNA (ctDNA) data and tumor dynamics. Data obtained for the analysis included (1) intensively sampled erlotinib concentrations from 29 patients from two previous pharmacokinetic (PK) studies, and (2) tumor sizes, ctDNA measurements, and sparsely sampled erlotinib concentrations from 18 patients from the START-TKI study. A two-compartment population PK model was first developed which well-described the PK data. The PK model was subsequently applied to investigate the exposure-tumor dynamics relationship. To characterize the tumor dynamics, models accounting for intra-tumor heterogeneity and acquired resistance with or without primary resistance were investigated. Eventually, the model assumed acquired resistance only resulted in an adequate fit. Additionally, models with or without exposure-dependent treatment effect were explored, and no significant exposure-response relationship for erlotinib was identified within the observed exposure range. Subsequently, the correlation of baseline ctDNA data on EGFR and TP53 variants with tumor dynamics' parameters was explored. The analysis indicated that higher baseline plasma EGFR mutation levels correlated with increased tumor growth rates, and the inclusion of ctDNA measurements improved model fit. This result suggests that quantitative ctDNA measurements at baseline have the potential to be a predictor of anticancer treatment response. The developed model can potentially be applied to design optimal treatment regimens that better overcome resistance.
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