Pemetrexed safety and pharmacokinetics in patients with third-space fluid

Nicolas J Dickgreber; Jens Benn Sørensen; Luis G Paz-Ares; Tine Kjestrup Schytte; Jane E Latz; Karen B Schneck; Yuan Zheng; José Miguel Sanchez-Torres

doi:10.1158/1078-0432.ccr-09-3324

Pemetrexed safety and pharmacokinetics in patients with third-space fluid

Nicolas J Dickgreber, Jens Benn Sørensen, Luis G Paz-Ares, Tine Kjestrup Schytte, Jane E Latz, Karen B Schneck, Yuan Zheng, José Miguel Sanchez-Torres

23 Citations (Scopus)

Abstract

Purpose: Pemetrexed is established as first-line treatment with cisplatin for malignant pleural mesothelioma and advanced nonsquamous non-small-cell lung cancer (NSCLC) and as single-agent second-line treatment for nonsquamous NSCLC. Because the structure and pharmacokinetics of pemetrexed are similar to those of methotrexate, and methotrexate is associated with severe toxicity in patients with third-space fluid (TSF), the safety of pemetrexed in patients with TSF was evaluated. Experimental Design: Patients with TSF (pleural effusions, ascites) and relapsed, stage III/IV NSCLC or malignant pleural/peritoneal mesothelioma were treated with pemetrexed (500 mg/m²) on day 1 of each 21-day cycle. TSF was drained at any time only if clinically indicated. Plasma samples were collected during cycles 1 and 2 to compare pemetrexed concentrations with reference data from patients without TSF. Results: Thirty-one patients with TSF received 123 pemetrexed doses (median, 4 cycles per patient; range, 1-11; mean dose intensity, 97.5%). Seven grade 3/4 drug-related toxicities, including four hematologic, were reported; there were no treatment-related deaths. There was no correlation between TSF amount and type, number, and sequelae of toxicities. Pemetrexed plasma concentrations were within the range of those in patients without TSF. Pemetrexed clearance and central volume of distribution were not statistically different between patients with and without TSF. Conclusions: No clinically relevant alterations of pemetrexed pharmacokinetics occurred in patients with TSF. Pemetrexed was well tolerated; toxicities were expected and manageable. The standard pemetrexed dose recommendations were adequate for patients with TSF in this study. These data suggest that draining TSF before administering pemetrexed is unnecessary.

Original language	English
Journal	Clinical Cancer Research
Volume	16
Issue number	10
Pages (from-to)	2872-80
Number of pages	9
ISSN	1078-0432
DOIs	https://doi.org/10.1158/1078-0432.ccr-09-3324
Publication status	Published - 15 May 2010

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10.1158/1078-0432.ccr-09-3324

https://aacrjournals.org/clincancerres/article-pdf/16/10/2872/1990569/2872.pdf

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@article{351b7a188a4a4e488b5661a3efeeb25e,

title = "Pemetrexed safety and pharmacokinetics in patients with third-space fluid",

abstract = "Purpose: Pemetrexed is established as first-line treatment with cisplatin for malignant pleural mesothelioma and advanced nonsquamous non-small-cell lung cancer (NSCLC) and as single-agent second-line treatment for nonsquamous NSCLC. Because the structure and pharmacokinetics of pemetrexed are similar to those of methotrexate, and methotrexate is associated with severe toxicity in patients with third-space fluid (TSF), the safety of pemetrexed in patients with TSF was evaluated. Experimental Design: Patients with TSF (pleural effusions, ascites) and relapsed, stage III/IV NSCLC or malignant pleural/peritoneal mesothelioma were treated with pemetrexed (500 mg/m2) on day 1 of each 21-day cycle. TSF was drained at any time only if clinically indicated. Plasma samples were collected during cycles 1 and 2 to compare pemetrexed concentrations with reference data from patients without TSF. Results: Thirty-one patients with TSF received 123 pemetrexed doses (median, 4 cycles per patient; range, 1-11; mean dose intensity, 97.5%). Seven grade 3/4 drug-related toxicities, including four hematologic, were reported; there were no treatment-related deaths. There was no correlation between TSF amount and type, number, and sequelae of toxicities. Pemetrexed plasma concentrations were within the range of those in patients without TSF. Pemetrexed clearance and central volume of distribution were not statistically different between patients with and without TSF. Conclusions: No clinically relevant alterations of pemetrexed pharmacokinetics occurred in patients with TSF. Pemetrexed was well tolerated; toxicities were expected and manageable. The standard pemetrexed dose recommendations were adequate for patients with TSF in this study. These data suggest that draining TSF before administering pemetrexed is unnecessary.",

author = "Dickgreber, {Nicolas J} and S{\o}rensen, {Jens Benn} and Paz-Ares, {Luis G} and Schytte, {Tine Kjestrup} and Latz, {Jane E} and Schneck, {Karen B} and Yuan Zheng and Sanchez-Torres, {Jos{\'e} Miguel}",

year = "2010",

month = may,

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doi = "10.1158/1078-0432.ccr-09-3324",

language = "English",

volume = "16",

pages = "2872--80",

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TY - JOUR

T1 - Pemetrexed safety and pharmacokinetics in patients with third-space fluid

AU - Dickgreber, Nicolas J

AU - Sørensen, Jens Benn

AU - Paz-Ares, Luis G

AU - Schytte, Tine Kjestrup

AU - Latz, Jane E

AU - Schneck, Karen B

AU - Zheng, Yuan

AU - Sanchez-Torres, José Miguel

PY - 2010/5/15

Y1 - 2010/5/15

N2 - Purpose: Pemetrexed is established as first-line treatment with cisplatin for malignant pleural mesothelioma and advanced nonsquamous non-small-cell lung cancer (NSCLC) and as single-agent second-line treatment for nonsquamous NSCLC. Because the structure and pharmacokinetics of pemetrexed are similar to those of methotrexate, and methotrexate is associated with severe toxicity in patients with third-space fluid (TSF), the safety of pemetrexed in patients with TSF was evaluated. Experimental Design: Patients with TSF (pleural effusions, ascites) and relapsed, stage III/IV NSCLC or malignant pleural/peritoneal mesothelioma were treated with pemetrexed (500 mg/m2) on day 1 of each 21-day cycle. TSF was drained at any time only if clinically indicated. Plasma samples were collected during cycles 1 and 2 to compare pemetrexed concentrations with reference data from patients without TSF. Results: Thirty-one patients with TSF received 123 pemetrexed doses (median, 4 cycles per patient; range, 1-11; mean dose intensity, 97.5%). Seven grade 3/4 drug-related toxicities, including four hematologic, were reported; there were no treatment-related deaths. There was no correlation between TSF amount and type, number, and sequelae of toxicities. Pemetrexed plasma concentrations were within the range of those in patients without TSF. Pemetrexed clearance and central volume of distribution were not statistically different between patients with and without TSF. Conclusions: No clinically relevant alterations of pemetrexed pharmacokinetics occurred in patients with TSF. Pemetrexed was well tolerated; toxicities were expected and manageable. The standard pemetrexed dose recommendations were adequate for patients with TSF in this study. These data suggest that draining TSF before administering pemetrexed is unnecessary.

AB - Purpose: Pemetrexed is established as first-line treatment with cisplatin for malignant pleural mesothelioma and advanced nonsquamous non-small-cell lung cancer (NSCLC) and as single-agent second-line treatment for nonsquamous NSCLC. Because the structure and pharmacokinetics of pemetrexed are similar to those of methotrexate, and methotrexate is associated with severe toxicity in patients with third-space fluid (TSF), the safety of pemetrexed in patients with TSF was evaluated. Experimental Design: Patients with TSF (pleural effusions, ascites) and relapsed, stage III/IV NSCLC or malignant pleural/peritoneal mesothelioma were treated with pemetrexed (500 mg/m2) on day 1 of each 21-day cycle. TSF was drained at any time only if clinically indicated. Plasma samples were collected during cycles 1 and 2 to compare pemetrexed concentrations with reference data from patients without TSF. Results: Thirty-one patients with TSF received 123 pemetrexed doses (median, 4 cycles per patient; range, 1-11; mean dose intensity, 97.5%). Seven grade 3/4 drug-related toxicities, including four hematologic, were reported; there were no treatment-related deaths. There was no correlation between TSF amount and type, number, and sequelae of toxicities. Pemetrexed plasma concentrations were within the range of those in patients without TSF. Pemetrexed clearance and central volume of distribution were not statistically different between patients with and without TSF. Conclusions: No clinically relevant alterations of pemetrexed pharmacokinetics occurred in patients with TSF. Pemetrexed was well tolerated; toxicities were expected and manageable. The standard pemetrexed dose recommendations were adequate for patients with TSF in this study. These data suggest that draining TSF before administering pemetrexed is unnecessary.

U2 - 10.1158/1078-0432.ccr-09-3324

DO - 10.1158/1078-0432.ccr-09-3324

M3 - Journal article

SN - 1078-0432

VL - 16

SP - 2872

EP - 2880

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 10

ER -

Pemetrexed safety and pharmacokinetics in patients with third-space fluid

Abstract

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