Clinical Pharmacokinetics of Irinotecan

Chabot, Guy G.

doi:10.2165/00003088-199733040-00001

Cited by 237 publications

(169 citation statements)

References 69 publications

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“…Intratumoral SN-38 was only measurable at concentrations 50 times lower than CPT-11. It is known that only a limited amount of CPT-11 is transformed into SN-38 (Chabot, 1997), which agrees with plasma levels being about 12 times lower than CPT-11 in our study (data not shown). Intratumoral SN-38 levels were somewhat higher after anti-VEGF therapy, but not significantly.…”

Section: Anti-vegf Mab Does Not Impair Intratumoral Cpt-11 Deliverysupporting

confidence: 92%

Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11

Wildiers¹,

Guetens²,

Boeck³

et al. 2003

Br J Cancer

302

150

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Promising preclinical activity with agents blocking the function of vascular endothelial growth factor (VEGF) has been observed in various cancer types, especially with combination therapy. However, these drugs decrease microvessel density, and it is not known whether this reduced vessel density (VD) results in decreased delivery of concomitantly administered classical anticancer drugs. We designed an in vivo study to investigate the relation between VEGF-blocking therapy, tumoral blood vessels, and intratumoral uptake of anticancer drugs. Nude NMRI mice bearing colon adenocarcinoma (HT29) were treated with the anti-VEGFmAb A4.6.1 or placebo. After 1 week, CPT-11 was administered 1 h prior to killing the animals. In A4.6.1 treated tumours, there was a significant decrease in VD, more pronounced with potentially functional large vessels than endothelial cords. Interestingly, a trend to increased intratumoral CPT-11 concentration was observed (P ¼ 0.09). In parallel, we measured an increase in tumour perfusion, as estimated by high-performance liquid chromatography determination of intratumoural Hoechst 33342 concentration. In the growth delay study, CPT-11 was at least equally effective with or without pretreatment with A4.6.1. These data suggest that tumour vascular function and tumour uptake of anticancer drugs improve with VEGF-blocking therapy, and indicate the relevance for further investigations.

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Section: Anti-vegf Mab Does Not Impair Intratumoral Cpt-11 Deliverysupporting

confidence: 92%

Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11

Wildiers¹,

Guetens²,

Boeck³

et al. 2003

Br J Cancer

302

150

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“…The liposomal payload, irinotecan, is a member of the camptothecin class of topoisomerase I (TOP1) inhibitors and causes cell death through DNA damage after replication-fork collisions with transiently trapped drug-TOP1-DNA cleavage complexes, thus highlighting length of drug exposure as an important driver for cytotoxicity (13). Compared with pharmacokinetic data of nonliposomal irinotecan (14), nal-IRI is characterized by a higher exposure, lower clearance, and smaller volume of distribution.…”

Section: Introductionmentioning

confidence: 99%

Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study

Ramanathan

Korn

Raghunand

et al. 2017

Clinical Cancer Research

153

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Purpose: To determine whether deposition characteristics of ferumoxytol (FMX) iron nanoparticles in tumors, identified by quantitative MRI, may predict tumor lesion response to nanoliposomal irinotecan (nal-IRI).Experimental Design: Eligible patients with previously treated solid tumors had FMX-MRI scans before and following (1, 24, and 72 hours) FMX injection. After MRI acquisition, R2 Ã signal was used to calculate FMX levels in plasma, reference tissue, and tumor lesions by comparison with a phantom-based standard curve. Patients then received nal-IRI (70 mg/m 2 free base strength) biweekly until progression. Two percutaneous core biopsies were collected from selected tumor lesions 72 hours after FMX or nal-IRI.Results: Iron particle levels were quantified by FMX-MRI in plasma, reference tissues, and tumor lesions in 13 of 15 eligible patients. On the basis of a mechanistic pharmacokinetic model, tissue permeability to FMX correlated with early FMX-MRI signals at 1 and 24 hours, while FMX tissue binding contributed at 72 hours. Higher FMX levels (ranked relative to median value of multiple evaluable lesions from 9 patients) were significantly associated with reduction in lesion size by RECIST v1.1 at early time points (P < 0.001 at 1 hour and P < 0.003 at 24 hours FMX-MRI, one-way ANOVA). No association was observed with post-FMX levels at 72 hours. Irinotecan drug levels in lesions correlated with patient's time on treatment (Spearman r ¼ 0.7824; P ¼ 0.0016).Conclusions: Correlation between FMX levels in tumor lesions and nal-IRI activity suggests that lesion permeability to FMX and subsequent tumor uptake may be a useful noninvasive and predictive biomarker for nal-IRI response in patients with solid tumors.

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“…Irinotecan serves as the water-soluble precursor of the lipophilic metabolite SN-38, which is formed by carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperdino side chain (4). SN-38 is glucuronidated to the non-toxic SN-38 glucuronide (SN-38G) in the liver via the uridine-diphospho-glucuronosyl transferase (UGT1A) enzyme family, which then releases SN-38G into the intestine for elimination (4).…”

Section: Introductionmentioning

confidence: 99%

“…SN-38 is glucuronidated to the non-toxic SN-38 glucuronide (SN-38G) in the liver via the uridine-diphospho-glucuronosyl transferase (UGT1A) enzyme family, which then releases SN-38G into the intestine for elimination (4). However, in the intestinal lumen, bacterial -glucuronidases regenerate SN-38 from SN-38G (5).…”

Section: Introductionmentioning

confidence: 99%

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms

Wardill

Gibson

Sebille

et al. 2016

Molecular Cancer Therapeutics

122

124

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Strong epidemiological data indicate that chemotherapy-induced gut toxicity and pain occur in parallel, indicating common underlying mechanisms. We have recently outlined evidence suggesting that TLR4 signaling may contribute to both side effects. We therefore aimed to determine if genetic deletion of TLR4 improves chemotherapy-induced gut toxicity and pain. Forty-two female wild-type (WT) and 42 Tlr4 null (−/−) BALB/c mice weighing between 18 and 25 g (10–13 weeks) received a single 270 mg/kg (i.p.) dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72, and 96 hours. Bacterial sequencing was conducted on cecal samples of control animals to determine the gut microbiome profile. Gut toxicity was assessed using validated clinical and histopathologic markers, permeability assays, and inflammatory markers. Chemotherapy-induced pain was assessed using the validated rodent facial grimace criteria, as well as immunologic markers of glial activation in the lumbar spinal cord. TLR4 deletion attenuated irinotecan-induced gut toxicity, with improvements in weight loss (P = 0.0003) and diarrhea (P < 0.0001). Crypt apoptosis was significantly decreased in BALB/c-Tlr4−/−billy mice (P < 0.0001), correlating with lower mucosal injury scores (P < 0.005). Intestinal permeability to FITC-dextran (4 kDa) and LPS translocation was greater in WT mice than in BALB/c-Tlr4−/−billy (P = 0.01 and P < 0.0001, respectively). GFAP staining in the lumbar spinal cord, indicative of astrocytic activation, was increased at 6 and 72 hours in WT mice compared with BALB/c-Tlr4−/−billy mice (P = 0.008, P = 0.01). These data indicate that TLR4 is uniquely positioned to mediate irinotecan-induced gut toxicity and pain, highlighting the possibility of a targetable gut/CNS axis for improved toxicity outcomes. Mol Cancer Ther; 15(6); 1376–86. ©2016 AACR.

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Clinical Pharmacokinetics of Irinotecan

Cited by 237 publications

References 69 publications

Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11

Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11

Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms

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