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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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Cell-growth vs time curves for the IGROV (A), Caco-2 (B), and H226 (C) cell lines, incubated with medium containing 100 pM, 1.00 nM or 10.0 nM of SN-38 or medium without SN-38 (reference) for a 500-h incubation time period. Data indicate mean values (symbol) with SD (error bars), which are shown when larger than symbol.
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fig3: Cell-growth vs time curves for the IGROV (A), Caco-2 (B), and H226 (C) cell lines, incubated with medium containing 100 pM, 1.00 nM or 10.0 nM of SN-38 or medium without SN-38 (reference) for a 500-h incubation time period. Data indicate mean values (symbol) with SD (error bars), which are shown when larger than symbol.

Mentions: The growth-inhibitory potential of low SN-38 concentrations was evaluated in vitro against several cell lines using a 3-week continuous-exposure period. Clear manifestation of growth-inhibiting effects were seen at SN-38 concentrations of 100 pM, 1.00 nM and 10.0 nM in the IGROV cell lines, with the number of remaining viable cells being reduced by 46±8.7%, 77±10.4%, and >99.9%, respectively, as compared to untreated controls (Figure 3Figure 3


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)

Cell-growth vs time curves for the IGROV (A), Caco-2 (B), and H226 (C) cell lines, incubated with medium containing 100 pM, 1.00 nM or 10.0 nM of SN-38 or medium without SN-38 (reference) for a 500-h incubation time period. Data indicate mean values (symbol) with SD (error bars), which are shown when larger than symbol.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Cell-growth vs time curves for the IGROV (A), Caco-2 (B), and H226 (C) cell lines, incubated with medium containing 100 pM, 1.00 nM or 10.0 nM of SN-38 or medium without SN-38 (reference) for a 500-h incubation time period. Data indicate mean values (symbol) with SD (error bars), which are shown when larger than symbol.
Mentions: The growth-inhibitory potential of low SN-38 concentrations was evaluated in vitro against several cell lines using a 3-week continuous-exposure period. Clear manifestation of growth-inhibiting effects were seen at SN-38 concentrations of 100 pM, 1.00 nM and 10.0 nM in the IGROV cell lines, with the number of remaining viable cells being reduced by 46±8.7%, 77±10.4%, and >99.9%, respectively, as compared to untreated controls (Figure 3Figure 3

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