A phase I clinical and pharmacological study of oral 9-nitrocamptothecin, a novel water-insoluble topoisomerase I inhibitor

Verschraegen, Claire F.; Natelson, Ethan A.; Giovanella, Beppino C.; Kavanagh, John J.; Kudelka, Andrzej P.; Freedman, Ralph S.; Edwards, Creighton L.; Ende, K.M. Van Vliet-van den; Stehlin, John S.

doi:10.1097/00001813-199801000-00004

Cited by 86 publications

(59 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the low (Ͻ20%) and variable (50% variation in area under the curve) bioavailability significantly diminishes its potential for oral delivery. Since low and variable oral bioavailability occurs among all CPT analogs and their physicochemical properties vary widely, these factors are less likely to play a crucial role in the oral absorption of CPT-11 (Gupta et al, 1998;Verschraegen et al, 1998). Instead, physiological factors, such as intestinal absorption/secretion and first pass metabolism, are more likely to account for the low and variable oral absorption of CPT-11.…”

Section: Discussionmentioning

confidence: 99%

Intestinal Transport of Irinotecan in Caco-2 Cells and MDCK II Cells Overexpressing Efflux Transporters Pgp, cMOAT, and MRP1

et al. 2002

View full text Add to dashboard Cite

ABSTRACT:Irinotecan (CPT-11) is a water-soluble camptothecin (CPT) derivative that has been recently approved in the United States for patients as a first-line therapy in advanced colorectal cancer. Phase I clinical trials using oral CPT-11 have shown poor and variable oral bioavailability. The present study was designed to investigate the intestinal absorption and efflux mechanisms of CPT-11 using in vitro cell culture models, Caco-2 cells, and engineered MadineDarby canine kidney (MDCK) II cells overexpressing P-glycoprotein (Pgp), canalicular multispecific organic anion transporter (cMOAT), and multidrug resistance-associated protein (MRP1). The intestinal absorptive and secretory transport of CPT-11 was investigated using Caco-2 cell monolayers. Secretory transport was concentration-dependent and saturable. The secretory efflux permeability

show abstract

Section: Discussionmentioning

confidence: 99%

Intestinal Transport of Irinotecan in Caco-2 Cells and MDCK II Cells Overexpressing Efflux Transporters Pgp, cMOAT, and MRP1

et al. 2002

View full text Add to dashboard Cite

show abstract

“…Observed in conjunction with the prolonged terminal t 1/2 of pegamotecan, this may explain the similar overall incidence of genitourinary toxicity observed when pegamotecan was dosed weekly at lower administered doses when compared with as opposed to another phase 1 study in which pegamotecan was administered every 3 weeks but generally at higher doses (22). Patients currently receiving pegamotecan are encouraged to increase their fluid intake up to 3 L/d, an intervention that has been noted to decrease genitourinary toxicity with another camptothecin analogue (23). Prolongation of partial thromboplastin time is of questionable significance, and studies are ongoing to further evaluate its cause.…”

Section: Discussionmentioning

confidence: 99%

Phase 1 Study of Weekly Polyethylene Glycol-Camptothecin in Patients with Advanced Solid Tumors and Lymphomas

Posey

Saif

Carlisle

et al. 2005

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose:To determine the maximal tolerated dose and dose-limiting toxicities (DLT) of pegamotecan (polyethylene glycol-camptothecin) in patients with advanced malignancies when administered in cycles of once weekly for 3 of 4 weeks. Experimental Design: Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, including also the following criteria: measurable disease, Eastern Cooperative Oncology Group performance status of V2, and acceptable organ function. Pegamotecan was administered as a 60-minute infusion, with successive patient cohorts receiving escalating doses from 800 to 4,300 mg/m 2 . The primary end point was to determine the maximal tolerated dose. Other end points were toxicity, pharmacokinetics, pharmacodynamics, and efficacy. Pharmacokinetic analysis measured free camptothecin. Pharmacodynamic analysis correlated drug effects with pegamotecan dose and pharmacokinetic variables. Results: Twenty-seven patients were enrolled. The maximal tolerated dose was 3,240 mg/m 2 . Grade 4 neutropenia, the DLT, was noted in two of four patients treated at 4,300 mg/m 2 . Other grade 3 and 4 toxicities were anemia, thrombocytopenia, fatigue, prolonged partial thromboplastin time, hemorrhagic cystitis, dysuria, and urinary frequency. Pharmacokinetic analysis showed the apparent terminal elimination half-life to be 46 F 12.8 hours. Pharmacodynamic analysis showed that hematuria occurred in 8 of 15 patients with an area under the curve extrapolated to infinity (AUC 0-1 ) > 20 ng h/mL and 0 of10 patients with an AUC 0-1 V 20 ng h/mL. Unconfirmed partial responses were observed in two patients, one with metastatic small bowel adenocarcinoma and the other with metastatic esophageal cancer. Conclusions: The maximal tolerated dose of pegamotecan when administered weekly for 3 of 4 weeks is 3,240 mg/m 2 . The DLT was neutropenia. Among nonhematologic toxicities, the incidence of gastrointestinal toxicity was low, but genitourinary toxicity seems to occur in the same effective dose range as noted with native camptothecin in earlier trials (27-43 mg/m 2 ). The observed antitumor activity suggests that pegamotecan has single-agent activity and merits further investigation in phase 2 studies.

show abstract

“…Diarrhoea is a well-known side effect of camptothecin and its derivatives. Oral administration of irinotecan (Soepenberg et al, 2002), 20-S-camptothecin (Natelson et al, 1996), 9-nitrocamptothecin (Verschraegen et al, 1998), topotecan (Creemers et al, 1997;Gerrits et al, 1998) and 9-AC (Mani et al, 1998;De Jonge et al, 1999) induced diarrhoea in 24 -54% of administered cycles. Prolonged oral administration (21 days) of topotecan resulted in severe diarrhoea in 22%, which could not be controlled with loperamide (Creemers et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Phase I and pharmacokinetic study of XR11576, an oral topoisomerase I and II inhibitor, administered on days 1–5 of a 3-weekly cycle in patients with advanced solid tumours

Jonge¹,

Kaye

Verweij³

et al. 2004

Br J Cancer

View full text Add to dashboard Cite

XR11576 is an oral topoisomerase I and II inhibitor. The objectives of this phase I study were to assess the dose-limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD) and to describe the pharmacokinetics (PKs) of XR11576 when administered orally on days 1 -5 every 3 weeks to patients with advanced solid tumours. Patients were treated with escalating doses of XR11576 at doses ranging from 30 to 180 mg day À1 . For PK analysis, plasma sampling was performed during the first and second courses of treatment and XR11576 concentrations were assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection. In all, 21 patients received a total of 47 courses. The MTD was reached at 180 mg day À1 , with diarrhoea and fatigue as DLT. Nausea and vomiting, although not qualifying for DLT, was ubiquitous. Only in combination with an extensive prophylactic antiemetic regimen consisting of a combination of both dexamethasone and a 5HT3 antagonist was treatment with XR11576 at 120 mg day À1 tolerable. The systemic exposure of XR11576 increased more than proportionally with increasing dose, with a large interpatient variability. No objective responses were seen; four patients experienced stable disease for periods of 12 -30 weeks. In this study, the DLTs of XR11576 were diarrhoea and fatigue. The recommended dose for phase II studies of XR11576 is 120 mg administered orally, on days 1 -5 every 21 days. Alternative regimens are currently being explored.

show abstract

A phase I clinical and pharmacological study of oral 9-nitrocamptothecin, a novel water-insoluble topoisomerase I inhibitor

Cited by 86 publications

References 0 publications

Intestinal Transport of Irinotecan in Caco-2 Cells and MDCK II Cells Overexpressing Efflux Transporters Pgp, cMOAT, and MRP1

Intestinal Transport of Irinotecan in Caco-2 Cells and MDCK II Cells Overexpressing Efflux Transporters Pgp, cMOAT, and MRP1

Phase 1 Study of Weekly Polyethylene Glycol-Camptothecin in Patients with Advanced Solid Tumors and Lymphomas

Phase I and pharmacokinetic study of XR11576, an oral topoisomerase I and II inhibitor, administered on days 1–5 of a 3-weekly cycle in patients with advanced solid tumours

Contact Info

Product

Resources

About