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Irinotecan pharmacokinetics-pharmacodynamics: the clinical relevance of prolonged exposure to SN-38.

Mathijssen RH, Verweij J, Loos WJ, de Bruijn P, Nooter K, Sparreboom A - Br. J. Cancer (2002)

Bottom Line: Here, we found that SN-38 concentrations present in human plasma for up to 3 weeks after a single irinotecan infusion induce significant cytotoxicity in vitro.The time course of SN-38 concentrations (AUC(500 h)) was significantly related to this AOC (P<0.001).Based on these findings, a new limited-sampling model was developed for SN-38 AUC(500 h) using only two timed samples: AUC(500 h)=(6.588 x C(2.5 h))+(146.4 x C(49.5 h))+15.53, where C(2.5 h) and C(49.5 h) are plasma concentrations at 2.5 and 49.5 h after start of infusion, respectively.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Erasmus MC-Daniel den Hoed, PO Box 5201, 3008 AE Rotterdam, The Netherlands.

ABSTRACT
We have shown previously that the terminal disposition half-life of SN-38, the active metabolite of irinotecan, is much longer than earlier thought. Currently, it is not known whether this prolonged exposure has any relevance toward SN-38-induced toxicity. Here, we found that SN-38 concentrations present in human plasma for up to 3 weeks after a single irinotecan infusion induce significant cytotoxicity in vitro. Using pharmacokinetic data from 26 patients, with sampling up to 500 h, relationships were evaluated between systemic exposure (AUC) to SN-38 and the per cent decrease in absolute neutrophil count (ANC) at nadir, or by taking the entire time course of ANC into account (AOC). The time course of SN-38 concentrations (AUC(500 h)) was significantly related to this AOC (P<0.001). Based on these findings, a new limited-sampling model was developed for SN-38 AUC(500 h) using only two timed samples: AUC(500 h)=(6.588 x C(2.5 h))+(146.4 x C(49.5 h))+15.53, where C(2.5 h) and C(49.5 h) are plasma concentrations at 2.5 and 49.5 h after start of infusion, respectively. The use of this limited-sampling model may open up historic databases to retrospectively obtain information about SN-38-induced toxicity in patients treated with irinotecan.

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Correlation between the observed AUC from a linear three-compartment model and the predicted AUC from the LSM for SN-38 total. Closed symbols represent training set data; open symbols represent validation set data. The solid line represents the line of identity (y=x).
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fig6: Correlation between the observed AUC from a linear three-compartment model and the predicted AUC from the LSM for SN-38 total. Closed symbols represent training set data; open symbols represent validation set data. The solid line represents the line of identity (y=x).

Mentions: where C2.5 h and C49.5 h represent plasma concentrations of SN-38 (in ng ml−1) at 2.5 h after the start of infusion (1 h post-infusion) and 49.5 h (48 h post-infusion), respectively. In both the training set and validation sets, this model showed little bias (MPE, 0.33% and 0.76%) and excellent precision (RMSE, 4.9% and 9.1%), with correlation coefficients of 0.99 and 0.96, respectively (Figure 6Figure 6


Irinotecan pharmacokinetics-pharmacodynamics: the clinical relevance of prolonged exposure to SN-38.

Mathijssen RH, Verweij J, Loos WJ, de Bruijn P, Nooter K, Sparreboom A - Br. J. Cancer (2002)

Correlation between the observed AUC from a linear three-compartment model and the predicted AUC from the LSM for SN-38 total. Closed symbols represent training set data; open symbols represent validation set data. The solid line represents the line of identity (y=x).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2376117&req=5

fig6: Correlation between the observed AUC from a linear three-compartment model and the predicted AUC from the LSM for SN-38 total. Closed symbols represent training set data; open symbols represent validation set data. The solid line represents the line of identity (y=x).
Mentions: where C2.5 h and C49.5 h represent plasma concentrations of SN-38 (in ng ml−1) at 2.5 h after the start of infusion (1 h post-infusion) and 49.5 h (48 h post-infusion), respectively. In both the training set and validation sets, this model showed little bias (MPE, 0.33% and 0.76%) and excellent precision (RMSE, 4.9% and 9.1%), with correlation coefficients of 0.99 and 0.96, respectively (Figure 6Figure 6

Bottom Line: Here, we found that SN-38 concentrations present in human plasma for up to 3 weeks after a single irinotecan infusion induce significant cytotoxicity in vitro.The time course of SN-38 concentrations (AUC(500 h)) was significantly related to this AOC (P<0.001).Based on these findings, a new limited-sampling model was developed for SN-38 AUC(500 h) using only two timed samples: AUC(500 h)=(6.588 x C(2.5 h))+(146.4 x C(49.5 h))+15.53, where C(2.5 h) and C(49.5 h) are plasma concentrations at 2.5 and 49.5 h after start of infusion, respectively.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Erasmus MC-Daniel den Hoed, PO Box 5201, 3008 AE Rotterdam, The Netherlands.

ABSTRACT
We have shown previously that the terminal disposition half-life of SN-38, the active metabolite of irinotecan, is much longer than earlier thought. Currently, it is not known whether this prolonged exposure has any relevance toward SN-38-induced toxicity. Here, we found that SN-38 concentrations present in human plasma for up to 3 weeks after a single irinotecan infusion induce significant cytotoxicity in vitro. Using pharmacokinetic data from 26 patients, with sampling up to 500 h, relationships were evaluated between systemic exposure (AUC) to SN-38 and the per cent decrease in absolute neutrophil count (ANC) at nadir, or by taking the entire time course of ANC into account (AOC). The time course of SN-38 concentrations (AUC(500 h)) was significantly related to this AOC (P<0.001). Based on these findings, a new limited-sampling model was developed for SN-38 AUC(500 h) using only two timed samples: AUC(500 h)=(6.588 x C(2.5 h))+(146.4 x C(49.5 h))+15.53, where C(2.5 h) and C(49.5 h) are plasma concentrations at 2.5 and 49.5 h after start of infusion, respectively. The use of this limited-sampling model may open up historic databases to retrospectively obtain information about SN-38-induced toxicity in patients treated with irinotecan.

Show MeSH
Related in: MedlinePlus