Bioavailability and pharmacokinetics of oral topotecan: a new topoisomerase I inhibitor

Schellens, Jan H.M.; Creemers, Geert-Jan; Beijnen, Jos H.; Rosing, Hilde; Boer-Dennert, M. de; McDonald, Mirna; Davies, Brian E.; Verweij, Jaap

doi:10.1038/bjc.1996.243

Cited by 114 publications

(56 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The absolute bioavailability of topotecan averaged 42%, which is in good agreement with previous reports (Eckardt et al, 1995;Schellens et al, 1996). The bioavailability of topotecan calculated using only the lactone data was 38%.…”

Section: Discussionsupporting

confidence: 81%

“…In previous studies, bioavailability of the i.v. 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).…”

Section: Discussionmentioning

confidence: 99%

“…formulation of topotecan administered orally was 30-44% with moderate interpatient variability (Eckardt et al, 1995;Schellens et al, 1996). In these studies, bioavailability was tested in fasted patients.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Oral topotecan: bioavailability and effect of food co-administration

et al. 1999

Self Cite

View full text Add to dashboard Cite

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

show abstract

Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Oral topotecan: bioavailability and effect of food co-administration

et al. 1999

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the present study, in humans the absolute bioavailability averaged 11.3 ± 5.2%. In comparison, bioavailability studies of topotecan showed a variable systemic exposure of 32% and 44%, which is higher than the bioavailability of oral GI147211 (Kuhn et al, 1995;Schellens et al, 1996). The bioavailability after oral administration of GI14721 1 showed wide interpatient variability ranging from 4.8% to 24.3%.…”

Section: Discussionmentioning

confidence: 97%

The bioavailability of oral GI147211 (GG211), a new topoisomerase I inhibitor

Gerrits

Schellens²,

Creemers³

et al. 1997

Br J Cancer

Self Cite

View full text Add to dashboard Cite

Summary Topoisomerase I inhibitors are new compounds of interest for cancer chemotherapy. We performed a study with Gl147211, a new semisynthetic camptothecin analogue, to determine the absolute bioavailability of the drug given orally. Patients with a histologically confirmed diagnosis of a solid tumour refractory to standard forms of therapy were eligible for the study. Gi147211 was given orally on day 1 and as a 30-min infusion daily on days 2-5. The treatment course was repeated every 3 weeks. In subsequent patient cohorts, the dose of the oral formulation was escalated from 1.5 mg m-2 to 6.0 mg m-2; the dose for i.v. administration was fixed at 1.2 mg m-2. Plasma pharmacokinetics was performed on day 1 and 2 of the first course and on day 1 of the second course using a validated high-performance liquid chromatographic assay. Nineteen patients were entered into the study; one patient was not evaluable because the treatment course was stopped prematurely. Eighteen patients received a total of 47 treatment courses. The absolute bioavailability of G1147211 averaged 1.3 ± 5.2%. Drug appeared quickly in plasma with a median Tma, at 0.5 h. Fasting or fed state had no significant influence on the bioavailability of G1147211. The terminal half-life after administration of oral G1147211 was 6.85 ± 3.13 h, similar to the half-life after intravenous administration. The major toxicities were neutropenia and thrombocytopenia. Nadirs for neutropenia and thrombocytopenia occurred on day 8 and day 15 respectively. Other toxicities predominantly consisted of mild and infrequent nausea and vomiting, and fatigue. The oral administration of the drug is well tolerated. Oral administration of topoisomerase I inhibitor G1147211 results in a low bioavailability with relatively wide interpatient variation. The intravenous route of administration is advised for further development of this promising topoisomerase I inhibitor.

show abstract

“…The bioavailability of oral TPT varies from 32% to 44% with relatively limited intrapatient variation (Kuhn et al, 1995;Schellens et al, 1996). Oral TPT was studied in paediatric patients with solid tumours in a phase I study with two different dose schedules.…”

Section: Prolonged Exposurementioning

confidence: 99%

Topoisomerase I inhibitors: the relevance of prolonged exposure for present clinical development

Gerrits

Jonge²,

Schellens³

et al. 1997

Br J Cancer

Self Cite

113

View full text Add to dashboard Cite

Summary Topoisomerase inhibitors constitute a new class of anti-cancer agents. Recently, topotecan and irinotecan were registered for clinical use in ovarian cancer and colorectal cancer respectively. Cytotoxicity of topoisomerase inhibitors is S-phase specific, and in vitro and in vivo studies have suggested that, for efficacy, prolonged exposure might be more important than short-term exposure to high concentration. Clinical development of those topoisomerase inhibitors that have reached this stage is also focused on schedules aiming to achieve prolonged exposure. In this review, we summarize all published preclinical studies on this topic for topoisomerase inhibitors in clinical development, namely 20-S-camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin, topotecan, irinotecan and G1147211. In addition, preliminary data on clinical studies concerning this topic are also reviewed. The data suggest that prolonged exposure may indeed be relevant for anti-tumour activity. However, the optimal schedule is yet to be determined. Finally, clinical data are yet too immature to draw definitive conclusions.

show abstract

Bioavailability and pharmacokinetics of oral topotecan: a new topoisomerase I inhibitor

Cited by 114 publications

References 14 publications

Oral topotecan: bioavailability and effect of food co-administration

Oral topotecan: bioavailability and effect of food co-administration

The bioavailability of oral GI147211 (GG211), a new topoisomerase I inhibitor

Topoisomerase I inhibitors: the relevance of prolonged exposure for present clinical development

Contact Info

Product

Resources

About