Five days of oral topotecan (hycamtin®), a phase I and pharmacological study in adult patients with solid tumours

Gerrits, C. J. H.; Burris, Howard A.; Schellens, Jan H.M.; Planting, A. S. T.; Burg, Matthias; Rodriguez, G. I.; Beurden, Vera van; Loos, Walter J.; Hudson, I.; Fields, Scott Z.; Verweij, Jaap; Hoff, Daniel D. Von

doi:10.1016/s0959-8049(97)10173-3

Cited by 52 publications

(25 citation statements)

References 22 publications

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“…formulation of topotecan administered orally was 30-44% with moderate interpatient variability (Eckardt et al, 1995;Schellens et al, 1996). A phase I study of a gelatin capsule formulation of topotecan has determined the MTD to be 2.3 mg m -2 for the daily times five dosing schedule (Gerrits et al, 1998). Dose-limiting toxicity (DLT) was NCI CTC grade 4 neutropenia, which is consistent with that of the i.v.…”

Section: Discussionmentioning

confidence: 68%

“…topotecan administered as daily 30-min infusions for 5 days has recently received marketing approval for the treatment of patients with ovarian cancer after failure of initial or subsequent platinum-based chemotherapy. An oral gelatin capsule formulation has now been developed (Creemers et al, 1997;Gerrits et al 1998). A phase I study has determined the maximum tolerated dose (MTD) for oral topotecan to be 2.3 mg m -2 for the daily times five dosing schedule (Gerrits et al, 1998).…”

mentioning

confidence: 99%

“…An oral gelatin capsule formulation has now been developed (Creemers et al, 1997;Gerrits et al 1998). A phase I study has determined the maximum tolerated dose (MTD) for oral topotecan to be 2.3 mg m -2 for the daily times five dosing schedule (Gerrits et al, 1998).…”

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confidence: 99%

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Oral topotecan: bioavailability and effect of food co-administration

et al. 1999

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SummaryThe aims of the study were twofold: (1) to evaluate the effect of food on the relative oral bioavailability of topotecan gelatin capsules in patients with solid tumours, and (2) to determine the absolute bioavailability of oral topotecan with reference to the intravenous (i.v.) formulation. The study had a randomized two-period cross-over design. On day 1 of the first treatment course patients were administered 2.3 mg m -2 day -1 of oral topotecan with or without a high-fat breakfast. They crossed over to receive the alternate regimen on day 2. In the second course (3 weeks later) fasted patients received topotecan orally (2.3 mg m -2 day -1 ) or i.v. (1.5 mg m -3 day). They crossed over to receive the alternate regimen on day 2. On days 3-5 of both treatment courses patients received oral topotecan. Plasma pharmacokinetics were performed on days 1 and 2 of the first and second course using a high-performance liquid chromatographic assay. Eighteen patients were enrolled in the study. The ratio of the area under the curve to infinity during fasted and high-fat treatment was 0.93 ± 0.23 (90% confidence interval (CI) 0.83-1.03). Maximal plasma concentrations of topotecan were similar after ingestion of the capsules with (10.6 ± 4.4 ng ml -1 ) or without food (9.2 ± 4.1 ng ml -1 ) (P = 0.130). The time needed to reach maximal plasma levels was significantly prolonged after food intake (median 3.1 h, range 2.8-6.1) compared to fasted conditions (2.0 h, range 1.1-8.1) (P = 0.013). The absolute bioavailability of topotecan averaged 42 ± 13% (90% CI 37-47%). The apparent terminal half-life was significantly longer after administration of oral topotecan (3.9 ± 1.0 h) than after i.v. administration (2.7 ± 0.4 h) (P < 0.001). Topotecan demonstrates suitable bioavailability for oral treatment. Co-administration of the topotecan gelatin capsules with a high-fat breakfast leads to a small decrease in absorption rate but does not affect the extent of absorption.Keywords: topotecan; oral; bioavailability; food 1380British Journal of Cancer (1999) 80(9), 1380-1386 © 1999 Cancer Research Campaign Article no. bjoc.1999 Received 10 June 1998 Revised 8 December 1998 Accepted 21 January 1999Correspondence to: VMM Herben, Slotervaart Hospital/The Netherlands Cancer Institute, Department of Pharmacy and Pharmacology, Louwesweg 6, 1066 EC Amsterdam, The Netherlands Oral topotecan: bioavailability and effect of food 1381

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Section: Discussionmentioning

confidence: 68%

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Oral topotecan: bioavailability and effect of food co-administration

et al. 1999

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“…Phase I studies evaluating the pharmacokinetics and early safety data of single-agent oral topotecan have been completed (Table 1) [23][24][25][26][27][28][29][30][31]. Single-dose studies determined that the absolute bioavailability of the oral formulation is 30%-44% [23][24][25] and is not affected by food intake [23].…”

Section: Development Of Oral Topotecanmentioning

confidence: 99%

“…Together these studies suggested the following recommended dosing schema: 14 mg/m 2 on day 1 every 21 days [25], 0.5 mg/m 2 twice daily for 21 days every 28 days [28], 2.3 mg/m 2 per day or 4 mg/day for 5 days every 21 days [29], and 1.4 mg/m 2 per day or 0.7 mg/mcytopenia) with the shorter schedule (dosing for 1 or 5 days). Both diarrhea and granulocytopenia occurred with the 10-day schedules.…”

Section: Development Of Oral Topotecanmentioning

confidence: 99%

Recent Advances with Topotecan in the Treatment of Lung Cancer

O’Brien

Eckardt²,

Ramlau

2007

The Oncologist

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After completing this course, the reader will be able to:1. Describe phase I studies evaluating the pharmacokinetics and early safety data of single-agent oral topotecan. Discuss the results and implications of clinical trials evaluating oral topotecan for small cell lung cancer (SCLC)and non-small cell lung cancer (NSCLC).3. Explain why topotecan is a good candidate for combination with other novel anticancer agents.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME Further, an oral formulation of topotecan is currently under investigation and may provide added convenience for patients. Oral topotecan has been studied in the first-and second-line settings for both SCLC and non-small cell lung cancer (NSCLC). Three recent phase III trials have demonstrated the activity of oral topotecan. In the first study of chemotherapy-naïve patients with extensivedisease SCLC, oral topotecan plus cisplatin provided efficacy and safety similar to those of etoposide plus cisplatin. In a second study of patients with relapsed SCLC, treatment with oral topotecan showed a statistically significant and clinically meaningful longer overall survival time and improvement in dyspnea and quality of life compared with best supportive care alone in all prognostic groups. Finally, in previously treated patients with NSCLC, single-agent oral topotecan was shown to be noninferior in 1-year survival rate relative to the current standard of i.v. docetaxel. In future studies, oral topotecan will represent a good candidate for combination therapy with other i.v. or oral chemotherapy agents, monoclonal antibodies, and small molecule tyrosine kinase inhibitors. ABSTRACT

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Development and validation of a liquid chromatography–tandem mass spectrometry method for topotecan determination in beagle dog plasma and its application in a bioequivalence study

Shi

Wan

et al. 2013

Biomedical Chromatography

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Topotecan (TPT) is an important anti-cancer drug that inhibits topoisomerase I. A sensitive and robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method that potentially determines TPT in beagle dog plasma is needed for a bioequivalence study of TPT formulations. We developed and validated LC-MS/MS to evaluate TPT in beagle dog plasma in terms of specificity, linearity, precision, accuracy, stability, extraction recovery and matrix effect. Plasma samples were treated with an Ostro(TM) sorbent plate (a robust and effective tool) to eliminate phospholipids and proteins before analysis. TPT and camptothecin (internal standard) were separated on an Acquity UPLC BEH C18 column (1.7 µm, 2.1 × 50 mm) with 0.1% formic acid and methanol as the mobile phase at a flow rate of 0.25 mL/min. TPT was analyzed using positive ion electrospray ionization in multiple-reaction monitoring mode. The obtained lower limit of quantitation was 1 ng/mL (signal-to-noise ratio > 10). The standard calibration curve for TPT was linear (correlation coefficient > 0.99) at the concentration range of 1-400 ng/mL. The intra-day and inter-day precision, accuracy, stability, extraction recovery and matrix effect of TPT were within the acceptable limits. The validated method was successfully applied in a bioequivalence study of TPT in healthy beagle dogs.

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Five days of oral topotecan (hycamtin®), a phase I and pharmacological study in adult patients with solid tumours

Cited by 52 publications

References 22 publications

Oral topotecan: bioavailability and effect of food co-administration

Oral topotecan: bioavailability and effect of food co-administration

Recent Advances with Topotecan in the Treatment of Lung Cancer

Development and validation of a liquid chromatography–tandem mass spectrometry method for topotecan determination in beagle dog plasma and its application in a bioequivalence study

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