Pharmacokinetic analysis of irinotecan plus bevacizumab in patients with advanced solid tumors

Denlinger, Crystal S.; Blanchard, Rebecca; Xu, Lu; Bernaards, Coen A.; Litwin, Samuel; Spittle, Cindy; Berg, Daniel J.; McLaughlin, Susan; Redlinger, Maryann; Dorr, Andrew; Hambleton, Julie; Holden, Scott N.; Kearns, A.; Kenkare-Mitra, Sara R.; Lum, Bert L.; Meropol, Neal J.; O’Dwyer, Peter J.

doi:10.1007/s00280-009-1008-7

Cited by 31 publications

(20 citation statements)

References 28 publications

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“…The mean plasma concentration–time profiles of irinotecan with and without panitumumab coadministration are presented in Figure . The pharmacokinetic parameter values for irinotecan with and without panitumumab coadministration (cycle 2 vs. cycle 1) were similar (Table ) and are consistent with those reported in the literature . The ratios of geometric means were 98.0% for C max and 89.8% for AUC 0‐inf , and the 90% CIs of the ratios of geometric means for C max (89.4–107%) and AUC 0‐inf (81.9–98.5%) were inside the 80–125% interval, demonstrating that with or without concomitant panitumumab administration, the pharmacokinetics of irinotecan were similar.…”

Section: Resultssupporting

confidence: 85%

Pharmacokinetics of Irinotecan With and Without Panitumumab Coadministration in Patients With Metastatic Colorectal Cancer

Yang

Chen

et al. 2013

Clinical Pharm in Drug Dev

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This study examined the effects of panitumumab, a human monoclonal antibody against epidermal growth factor receptor (EGFR), on irinotecan pharmacokinetics. This phase I, open-label, multicenter, single-arm study enrolled patients with metastatic colorectal cancer (mCRC) without prior exposure to an EGFR inhibitor. In cycle 1, patients received irinotecan (180 mg/m(2) intravenously [IV]) on day 1 and panitumumab (6 mg/kg IV) on Day 4. In cycle 2 (2 weeks after cycle 1 panitumumab administration) and subsequent every-2-week cycles, patients received panitumumab followed immediately by irinotecan until disease progression or intolerability. Primary and secondary endpoints included Cmax and AUC of irinotecan after irinotecan infusion in cycles 1 and 2, and adverse events, respectively. Nineteen of 27 treated patients were eligible for pharmacokinetic analysis. Pharmacokinetic profiles of irinotecan with or without panitumumab coadministration were nearly identical. The 90% confidence intervals for ratios of geometric means for irinotecan Cmax and AUC with or without panitumumab were within the 80-125% interval, indicating that panitumumab had no apparent effects on irinotecan pharmacokinetics. Adverse events were as expected for irinotecan plus panitumumab combination therapy.

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Section: Resultssupporting

confidence: 85%

Pharmacokinetics of Irinotecan With and Without Panitumumab Coadministration in Patients With Metastatic Colorectal Cancer

Yang

Chen

et al. 2013

Clinical Pharm in Drug Dev

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“…The inhibition of hOCT2 (C max,unbound /IC 50 :12.55) by irinotecan was more potent than that of OCT1 (C max port, unbound /IC 50 : 2.87), suggesting that the effect of irinotecan on morphine renal clearance could be even greater in humans. Moreover, given the relatively long half-life of irinotecan (more than 10 h) (41) and the high ratio of C max,unbound /IC 50 for both OCT1 and OCT2, it is likely that irinotecan has a sustained inhibition on these transporters in humans, i.e., not only at its C max but also at a trough concentration in the plasma. We have to point out that the levels of morphine and its metabolites were measured in total as we dosed the radiolabeled morphine in mice in the present study.…”

Section: Discussionmentioning

confidence: 99%

Irinotecan Alters the Disposition of Morphine Via Inhibition of Organic Cation Transporter 1 (OCT1) and 2 (OCT2)

et al. 2018

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Purpose The organic cation transporters (OCTs) and multi-drug and toxin extrusions (MATEs) together are regarded as an organic cation transport system critical to the disposition and response of many organic cationic drugs. Patient response to the analgesic morphine, a characterized substrate for human OCT1, is highly variable. This study was aimed to examine whether there is any organic cation transporter-mediated drug and drug interaction (DDI) between morphine and commonly co-administrated drugs. Methods The uptake of morphine and its inhibition by six drugs which are commonly co-administered with morphine in the clinic were assessed in human embryonic kidney 293 (HEK293) cells stably expressing OCT1, OCT2 and MATE1. The in vivo interaction between morphine and the select irinotecan was determined by comparing the disposition of morphine in the absence versus presence of irinotecan treatment in mice. Results The uptake of morphine in the stable HEK293 cells expressing human OCT1 and OCT2 was significantly increased by 3.56 and 3.04 fold, respectively, than that in the control cells, with no significant uptake increase in the cells expressing human MATE1. All of the six drugs examined, including amitriptyline, fluoxetine, imipramine, irinotecan, ondansetron, and verapamil, were inhibitors of OCT1/2-mediated morphine uptake. The select irinotecan significantly increased the plasma concentrations and decreased hepatic and renal accumulation of morphine in mice. Conclusions Morphine is a substrate of OCT1 and OCT2. Clinician should be aware that the disposition of and thus the response to morphine may be altered by co-administration of an OCT1/2 inhibitor, such as irinotecan.

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“…11 This difference has not been confirmed in three formal drug-drug interaction studies, including ours. 17, 18…”

Section: Discussionmentioning

confidence: 99%

Genotype-Guided Dosing Study of FOLFIRI plus Bevacizumab in Patients with Metastatic Colorectal Cancer

Toffoli

Sharma

Marangon

et al. 2017

Clinical Cancer Research

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confers a higher risk of toxicity in patients treated with irinotecan. Patients with and genotypes might tolerate higher than standard doses of irinotecan. We aimed to identify the MTD of irinotecan in patients with metastatic colorectal cancer (mCRC) with and genotypes treated with FOLFIRI plus bevacizumab, and to determine whether bevacizumab alters irinotecan pharmacokinetics. Previously untreated patients with mCRC (25 ; 23) were given FOLFIRI plus bevacizumab every 2 weeks. The irinotecan dose was escalated using a 3 + 3 design in each genotype group as follows: 260, 310, and 370 mg/m The MTD was the highest dose at which <4/10 patients had a dose-limiting toxicity (DLT). Pharmacokinetics of irinotecan and SN-38 were measured on days 1 to 3 (without bevacizumab) and 15 to 17 (with bevacizumab). For patients, 2 DLTs were observed among 10 patients at 310 mg/m, while 370 mg/m was not tolerated (2 DLTs in 4 patients). For patients, 2 DLTs were observed among 10 patients at 260 mg/m, while 310 mg/m was not tolerated (4 DLTs in 10 patients). Neutropenia and diarrhea were the most common DLTs. Changes in the AUCs of irinotecan and SN-38 associated with bevacizumab treatment were marginal. The MTD of irinotecan in FOLFIRI plus bevacizumab is 310 mg/m for patients and 260 mg/m for patients. Bevacizumab does not alter the pharmacokinetics of irinotecan. The antitumor efficacy of these genotype-guided doses should be tested in future studies of patients with mCRC treated with FOLFIRI plus bevacizumab..

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Pharmacokinetic analysis of irinotecan plus bevacizumab in patients with advanced solid tumors

Cited by 31 publications

References 28 publications

Pharmacokinetics of Irinotecan With and Without Panitumumab Coadministration in Patients With Metastatic Colorectal Cancer

Pharmacokinetics of Irinotecan With and Without Panitumumab Coadministration in Patients With Metastatic Colorectal Cancer

Irinotecan Alters the Disposition of Morphine Via Inhibition of Organic Cation Transporter 1 (OCT1) and 2 (OCT2)

Genotype-Guided Dosing Study of FOLFIRI plus Bevacizumab in Patients with Metastatic Colorectal Cancer

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