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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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Related in: MedlinePlus

Plasma concentration-time profiles of SN-38 in patients treated with a 90-min i.v. infusion of CPT-11 (dose level 350 mg m−2).
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fig1: Plasma concentration-time profiles of SN-38 in patients treated with a 90-min i.v. infusion of CPT-11 (dose level 350 mg m−2).

Mentions: Exponentially growing cells obtained from the IGROV (ovarian cancer), Caco-2 (colon cancer) and H226 (lung cancer) cell lines were cultured in 4 ml of RPMI-1640 medium, and plated in 25 cm2 T-flasks (Corning Costar), at a density of 10 000 cells/flask. Hereafter, plates were incubated in a controlled environment at 37°C and 95% air per 5% CO2, and 24 h after the start of incubation, the medium was replaced by medium containing SN-38 at final concentrations of 100 pM (39.2 pg ml−1), 1.00 nM (392 pg ml−1), or 10.0 nM (3920 pg ml−1). These concentrations were chosen because they adequately simulated the median SN-38 plasma concentrations circulating in patients after 3 weeks, 10 days and 2 days, respectively, after infusion of the standard dose of CPT-11 (350 mg m−2, given as a 90-min infusion once every 3 weeks; see Figure 1Figure 1


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)

Plasma concentration-time profiles of SN-38 in patients treated with a 90-min i.v. infusion of CPT-11 (dose level 350 mg m−2).
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Plasma concentration-time profiles of SN-38 in patients treated with a 90-min i.v. infusion of CPT-11 (dose level 350 mg m−2).
Mentions: Exponentially growing cells obtained from the IGROV (ovarian cancer), Caco-2 (colon cancer) and H226 (lung cancer) cell lines were cultured in 4 ml of RPMI-1640 medium, and plated in 25 cm2 T-flasks (Corning Costar), at a density of 10 000 cells/flask. Hereafter, plates were incubated in a controlled environment at 37°C and 95% air per 5% CO2, and 24 h after the start of incubation, the medium was replaced by medium containing SN-38 at final concentrations of 100 pM (39.2 pg ml−1), 1.00 nM (392 pg ml−1), or 10.0 nM (3920 pg ml−1). These concentrations were chosen because they adequately simulated the median SN-38 plasma concentrations circulating in patients after 3 weeks, 10 days and 2 days, respectively, after infusion of the standard dose of CPT-11 (350 mg m−2, given as a 90-min infusion once every 3 weeks; see Figure 1Figure 1

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