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Jan H.m. Schellens - One of the best experts on this subject based on the ideXlab platform.

  • a phase i randomized open label parallel cohort dose finding study of elacridar gf120918 and oral Topotecan in cancer patients
    Clinical Cancer Research, 2007
    Co-Authors: Isa E L M Kuppens, R C Jewell, Elaine M Paul, S G Mangum, S. A. Radema, Els Witteveen, Emile E Voest, Jos H. Beijnen, Jan H.m. Schellens
    Abstract:

    Purpose: Breast cancer resistance protein (ABCG2) substantially limits the oral bioavailability of Topotecan. Coadministration with elacridar, an inhibitor of breast cancer resistance protein–mediated drug transport, increases the bioavailability of Topotecan. The aim of this study was to establish the lowest effective dose of elacridar to obtain maximum oral bioavailability of Topotecan and to determine the optimal schedule of coadministration of oral Topotecan and elacridar. In the second part of this study, dose-limiting toxicities and maximum tolerated dose of oral Topotecan coadministered with elacridar, at a daily times five regimen administered every 21 days, were established. Experimental Design: In part I, 20 patients were randomized to receive 100, 300, 500, 700, or 1,000 mg of elacridar on days 1 and 8 1 h before or simultaneously with 2.0 mg oral Topotecan, which was also randomized. On day 15, all patients were treated with 1.5 mg/m 2 i.v. Topotecan. In part II of the study, patients were treated daily with oral Topotecan and with the lowest effective dose of elacridar following from part I. The maximum tolerated dose and dose-limiting toxicity were determined in cohorts of three patients. Blood samples were taken on days 1, 8, and 15 of part I and on day 1 of cycles 1 and 2 of part II. Results: Complete apparent oral bioavailability of Topotecan (102 ± 7%) for all treatment arms with elacridar in both schedules was seen in part I. In the Topotecan dose escalation part, two dose-limiting toxicities were seen at the 2.5 mg Topotecan dose level. Conclusion: The recommended schedule is 2.0 mg oral Topotecan plus 100 mg elacridar administered concomitantly daily times five every 21 days.

  • phase i and pharmacological study of oral Topotecan and the bcrp and p gp inhibitor elacridar
    Journal of Clinical Oncology, 2004
    Co-Authors: Jan H.m. Schellens, Isa E L M Kuppens, R C Jewell, Elaine M Paul, S G Mangum, Hilde Rosing, S. A. Radema, Els Witteveen, Jos H. Beijnen, Emile E Voest
    Abstract:

    2003 Background: Oral Topotecan has a moderate (∼ 40%) and variable bioavailability (F). Complete apparent F can be obtained by combining Topotecan with elacridar which inhibits BCRP and P-gp in the gut wall. The OBJECTIVES were 1] to determine the lowest effective dose (LED) of elacridar resulting in complete apparent F of Topotecan and the optimal schedule of elacridar and Topotecan and 2] to determine the maximal tolerated dose (MTD) and dose-limiting toxicity (DLT) of Topotecan in combination with the LED of elacridar at a dailyx5 schedule every 21 days. Methods of part 1: Patients (pts) were randomized to receive 1000, 700, 500, 300 or 100 mg of elacridar (tablets) plus 2 mg Topotecan (capsules) after a standard breakfast. Elacridar was administered 60 minutes prior to Topotecan or simultaneously with Topotecan on day 1 and 8, which was randomized within patients. I.V. Topotecan was given on day 15. Pharmacokinetics (PK) of Topotecan (total and lactone form) and elacridar were obtained by validated L...

  • increased oral bioavailability of Topotecan in combination with the breast cancer resistance protein and p glycoprotein inhibitor gf120918
    Journal of Clinical Oncology, 2002
    Co-Authors: C M F Kruijtzer, R C Jewell, Elaine M Paul, Hilde Rosing, Jos H. Beijnen, W Ten Bokkel W Huinink, Margaret Schot, Jan H.m. Schellens
    Abstract:

    PURPOSE: We discovered that breast cancer resistance protein (BCRP), a recently identified adenosine triphosphate–binding cassette drug transporter, substantially limits the oral bioavailability of Topotecan in mdr1a/1b(−/−) P-glycoprotein (P-gp) knockout and wild-type mice. GF120918 is a potent inhibitor of BCRP and P-gp. The aim was to increase the bioavailability of Topotecan by GF120918. PATIENTS AND METHODS: In cohort A, eight patients received 1.0 mg/m2 oral Topotecan with or without coadministration of one single oral dose of 1,000 mg GF120918 (day 1 or day 8). In cohort B, eight other patients received 1.0 mg/m2 intravenous Topotecan with or without 1,000 mg oral GF120918 to study the effect of GF120918 on the systemic clearance of Topotecan. RESULTS: After oral Topotecan, the mean area under the plasma concentration-time curve (AUC) of total Topotecan increased significantly from 32.4 ± 9.6 μg·h/L without GF120918 to 78.7 ± 20.6 μg·h/L when GF120918 was coadministered (P = .008). The mean maximum...

  • Urinary and fecal excretion of Topotecan in patients with malignant solid tumours.
    Cancer chemotherapy and pharmacology, 2002
    Co-Authors: V. M. M. Herben, Hilde Rosing, Jan H.m. Schellens, Nadja E. Schoemaker, Desiree M. Van Zomeren, Wim W. Ten Bokkel Huinink, R. Dubbelman, Solange Hearn, Jos H. Beijnen
    Abstract:

    Abstract Purpose. The objectives of the study were to determine the pharmacokinetics and routes of excretion of Topotecan following intravenous or oral administration to patients with refractory solid tumours. Methods. Patients were randomized to receive either oral (2.3 mg/m2) or intravenous (1.5 mg/m2) Topotecan once daily for 5 days in course 1. Patients who received in course 1 oral Topotecan received in course 2 intravenous Topotecan on day 1 followed by oral Topotecan on days 2 to 5. Patients who received in course 1 intravenous Topotecan received in course 2 oral Topotecan once daily for 5 days. Plasma pharmacokinetics were performed on day 1 of course 1 (all patients) and course 2 (only patients receiving intravenous Topotecan on that day). In course 1, urine and feces were collected for up to 9 days after the first dosage. The amounts of Topotecan and N-desmethyl Topotecan in plasma, urine and feces were determined by validated high-performance liquid chromatographic assays. Results. A total of 11 patients were enrolled in the study. Nine patients were evaluable for pharmacokinetics. Plasma pharmacokinetics were similar to those previously reported. The principal route of excretion was the urine, with approximately 49% of the intravenously administered Topotecan dose and 20% of the oral dose collected in the urine as parent drug. Approximately 18% and 33% of the intravenous and oral dose, respectively, were recovered unchanged in the feces. Only small amounts of N-desmethyl Topotecan were found in the excreta. Conclusions. Fecal and urinary excretion of unchanged Topotecan were the major routes of Topotecan elimination. Approximately 28% of the intravenous dose and 43% of the oral dose of Topotecan were unaccounted for and eliminated through other routes.

  • overexpression of the bcrp mxr abcp gene in a Topotecan selected ovarian tumor cell line
    Cancer Research, 1999
    Co-Authors: Marc Maliepaard, M A Van Gastelen, L A De Jong, Dick Pluim, R C A M Van Waardenburg, M C Ruevekamphelmers, B G J Floot, Jan H.m. Schellens
    Abstract:

    Topotecan- or mitoxantrone-selected cell lines (T8 and MX3, respectively), derived from the human IGROV1 ovarian cancer cell line, were resistant to the topoisomerase I inhibitors Topotecan, SN-38 (the active metabolite of irinotecan), and 9-aminocamptothecin, as well as to the topoisomerase II drug mitoxantrone. In both resistant cell lines, decreased accumulation of Topotecan and mitoxantrone was observed, caused by enhanced energy-dependent efflux of the drugs involved. In both cell lines, we found that the breast cancer resistance protein/mitoxantrone resistance/placenta-specific ATP binding cassette ( BCRP/MXR/ABCP ) gene was overexpressed. Furthermore, BCRP/MXR/ABCP expression levels in various partially revertant T8 cells correlated with the levels of resistance to Topotecan, SN-38, and mitoxantrone, strongly suggesting BCRP/MXR/ABCP to be the transporter responsible for the enhanced efflux. Pharmacodynamic analysis demonstrated that BCRP/MXR/ABCP is a very efficient transporter of Topotecan; in vitro , 70% of the intracellular Topotecan pool was transported out of the T8 or MX3 cells within 30 s. In conclusion, we report for the first time that BCRP/MXR/ABCP can also be up-regulated upon exposure of tumor cells to the clinically important drug Topotecan, and that BCRP-mediated efflux of Topotecan is very efficient. This highly efficient efflux of Topotecan by BCRP/MXR/ABCP may have clinical relevance for patients being treated with Topotecan.

Clinton F. Stewart - One of the best experts on this subject based on the ideXlab platform.

  • Tyrosine Kinase Inhibitor Gefitinib Enhances Topotecan Penetration of Gliomas
    Cancer research, 2010
    Co-Authors: Angel M. Carcaboso, Mohamed A. Elmeliegy, Jun Shen, Stephen Juel, Ziwei M. Zhang, Christopher Calabrese, Lorraine Tracey, Christopher M. Waters, Clinton F. Stewart
    Abstract:

    Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, increases brain parenchymal extracellular fluid (ECF) accumulation of Topotecan, a substrate of the ATP-binding cassette (ABC) transporters P-glycoprotein (Pgp/MDR-1) and breast cancer resistance protein (BCRP/ABCG2). The effect of modulating these transporters on Topotecan penetration in gliomas has not been thoroughly studied. Thus, we performed intracerebral microdialysis on mice bearing orthotopic human gliomas (U87 and MT330) and assessed Topotecan tumor ECF (tECF) penetration and the effect of gefitinib on Topotecan tECF penetration and intratumor Topotecan distribution. We found that Topotecan penetration (Ptumor) of U87 was 0.96 ± 0.25 (n = 7) compared with that of contralateral brain (Pcontralateral, 0.42 ± 0.11, n = 5; P = 0.001). In MT330 tumors, Ptumor (0.78 ± 0.26, n = 6) and Pcontralateral (0.42 ± 0.11, n = 5) also differed significantly (P = 0.013). Because both tumor models had disrupted blood-brain barriers and similar Ptumor values, we used U87 and a steady-state drug administration approach to characterize the effect of gefitinib on Topotecan Ptumor. At equivalent plasma Topotecan exposures, we found that Ptumor after gefitinib administration was lower. In a separate cohort of animals, we determined the volume of distribution of unbound Topotecan in tumor (Vu,tumor) and found that it was significantly higher in groups receiving gefitinib, implying that gefitinib administration leads to a greater proportion of intracellular Topotecan. Our results provide crucial insights into the role that transporters play in central nervous system drug penetration and provide a better understanding of the effect of coadministration of transporter modulators on anticancer drug distribution within a tumor. Cancer Res; 70(11); 4499–508. ©2010 AACR.

  • Population Pharmacokinetic Analysis of Topotecan in Pediatric Cancer Patients
    Clinical Cancer Research, 2007
    Co-Authors: Paula Schaiquevich, John C Panetta, Lisa C Iacono, Victor M Santana, Amar Gajjar, B. Freeman, Clinton F. Stewart
    Abstract:

    Purpose: To characterize the population pharmacokinetics of Topotecan lactone in children with cancer and identify covariates related to Topotecan disposition. Patients and Methods: The study population consisted of 162 children in seven clinical trials receiving single agent Topotecan as a 30-min infusion. A population approach via nonlinear mixed effects modeling was used to conduct the analysis. Results: A two-compartment model was fit to Topotecan lactone plasma concentrations ( n = 1874), and large pharmacokinetic variability was observed among studies, among individuals, and within individuals. We conducted a covariate analysis using demographics, biochemical data, trial effects, and concomitant drugs. The most significant covariate was body surface area, which explained 54% of the interindividual variability for Topotecan systemic clearance. Interoccasion variability was considerable in both clearance and volume (20% and 22%, respectively), but was less than interindividual variability in both variables. Other covariates related to clearance were concomitant phenytoin, calculated glomerular filtration rate, and age ( Conclusions: We developed a descriptive and robust population pharmacokinetic model which identified patient covariates that account for Topotecan disposition in pediatric patients. Additionally, dosing Topotecan based on the covariate model led to a more accurate and precise estimation Topotecan systemic exposure compared with a fixed dosing approach, and could be a tool to assist clinicians to individualize Topotecan dosing.

  • Population pharmacokinetic analysis of Topotecan in pediatric cancer patients.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2007
    Co-Authors: Paula Schaiquevich, John C Panetta, Lisa C Iacono, Burgess B Freeman, Victor M Santana, Amar Gajjar, Clinton F. Stewart
    Abstract:

    To characterize the population pharmacokinetics of Topotecan lactone in children with cancer and identify covariates related to Topotecan disposition. The study population consisted of 162 children in seven clinical trials receiving single agent Topotecan as a 30-min infusion. A population approach via nonlinear mixed effects modeling was used to conduct the analysis. A two-compartment model was fit to Topotecan lactone plasma concentrations (n = 1874), and large pharmacokinetic variability was observed among studies, among individuals, and within individuals. We conducted a covariate analysis using demographics, biochemical data, trial effects, and concomitant drugs. The most significant covariate was body surface area, which explained 54% of the interindividual variability for Topotecan systemic clearance. Interoccasion variability was considerable in both clearance and volume (20% and 22%, respectively), but was less than interindividual variability in both variables. Other covariates related to clearance were concomitant phenytoin, calculated glomerular filtration rate, and age (<0.5 years). Including them in the model reduced the interindividual variability for Topotecan clearance by an additional 48% relative to the body surface area-normalized model. The full covariate model explained 76% and 50% of interindividual variability in Topotecan clearance and volume, respectively. We developed a descriptive and robust population pharmacokinetic model which identified patient covariates that account for Topotecan disposition in pediatric patients. Additionally, dosing Topotecan based on the covariate model led to a more accurate and precise estimation Topotecan systemic exposure compared with a fixed dosing approach, and could be a tool to assist clinicians to individualize Topotecan dosing.

  • Topotecan disposition in an anephric child.
    Journal of pediatric hematology oncology, 2004
    Co-Authors: Lisa C Iacono, Denise M. Adams, Alan Homans, Ann Guillot, Jeannine S. Mccune, Clinton F. Stewart
    Abstract:

    Although limited data are available about Topotecan disposition in patients with renal insufficiency, nothing has been reported in anephric patients. The objective of this report is to characterize Topotecan disposition in an anephric child with Wilms tumor, both on and off hemodialysis. The patient received Topotecan and cyclophosphamide for four cycles; Topotecan was administered daily for 5 days, with hemodialysis on the second and fourth day. Therapy was well tolerated, with grade 3 thrombocytopenia and grade 2 neutropenia noted after cycle four. The median Topotecan lactone clearance was 15.5 L/h/m off hemodialysis and 18.7 L/h/m on hemodialysis. Topotecan clearance was minimally affected by hemodialysis and was similar to that observed in children without renal failure.

  • Effect of hemodialysis on Topotecan disposition in a patient with severe renal dysfunction.
    Cancer chemotherapy and pharmacology, 2000
    Co-Authors: Jon D. Herrington, William C. Zamboni, Jose A. Figueroa, Mark N. Kirstein, Clinton F. Stewart
    Abstract:

    The pharmacokinetics of Topotecan have been extensively studied in patients with normal renal function and there is one study of patients with mild to moderate renal insufficiency. However, the effect of hemodialysis on Topotecan disposition has not been reported. The objective of this study was to characterize the disposition of Topotecan in a patient with severe renal insufficiency receiving hemodialysis. Topotecan lactone disposition was characterized in a patient on and off hemodialysis. The Topotecan lactone clearance determined after administration of Topotecan alone and with hemodialysis was 5.3 l/h per m2 vs 20.1 l/h per m2, respectively. At 30 min after the completion of hemodialysis, the Topotecan plasma concentration obtained was greater than that measured at the end of hemodialysis (i.e. 8.0 ng/ml vs 4.9 ng/ml), suggesting a rebound effect. The Topotecan terminal half-life off dialysis was 13.6 h, compared with an apparent half-life determined during hemodialysis of 3.0 h. These results demonstrate that Topotecan plasma clearance while on hemodialysis increased approximately fourfold. Hemodialysis may be an effective systemic clearance process for Topotecan and should be considered in selected clinical situations (e.g. inadvertent overdose, severe renal dysfunction).

Jos H. Beijnen - One of the best experts on this subject based on the ideXlab platform.

  • a phase i randomized open label parallel cohort dose finding study of elacridar gf120918 and oral Topotecan in cancer patients
    Clinical Cancer Research, 2007
    Co-Authors: Isa E L M Kuppens, R C Jewell, Elaine M Paul, S G Mangum, S. A. Radema, Els Witteveen, Emile E Voest, Jos H. Beijnen, Jan H.m. Schellens
    Abstract:

    Purpose: Breast cancer resistance protein (ABCG2) substantially limits the oral bioavailability of Topotecan. Coadministration with elacridar, an inhibitor of breast cancer resistance protein–mediated drug transport, increases the bioavailability of Topotecan. The aim of this study was to establish the lowest effective dose of elacridar to obtain maximum oral bioavailability of Topotecan and to determine the optimal schedule of coadministration of oral Topotecan and elacridar. In the second part of this study, dose-limiting toxicities and maximum tolerated dose of oral Topotecan coadministered with elacridar, at a daily times five regimen administered every 21 days, were established. Experimental Design: In part I, 20 patients were randomized to receive 100, 300, 500, 700, or 1,000 mg of elacridar on days 1 and 8 1 h before or simultaneously with 2.0 mg oral Topotecan, which was also randomized. On day 15, all patients were treated with 1.5 mg/m 2 i.v. Topotecan. In part II of the study, patients were treated daily with oral Topotecan and with the lowest effective dose of elacridar following from part I. The maximum tolerated dose and dose-limiting toxicity were determined in cohorts of three patients. Blood samples were taken on days 1, 8, and 15 of part I and on day 1 of cycles 1 and 2 of part II. Results: Complete apparent oral bioavailability of Topotecan (102 ± 7%) for all treatment arms with elacridar in both schedules was seen in part I. In the Topotecan dose escalation part, two dose-limiting toxicities were seen at the 2.5 mg Topotecan dose level. Conclusion: The recommended schedule is 2.0 mg oral Topotecan plus 100 mg elacridar administered concomitantly daily times five every 21 days.

  • phase i and pharmacological study of oral Topotecan and the bcrp and p gp inhibitor elacridar
    Journal of Clinical Oncology, 2004
    Co-Authors: Jan H.m. Schellens, Isa E L M Kuppens, R C Jewell, Elaine M Paul, S G Mangum, Hilde Rosing, S. A. Radema, Els Witteveen, Jos H. Beijnen, Emile E Voest
    Abstract:

    2003 Background: Oral Topotecan has a moderate (∼ 40%) and variable bioavailability (F). Complete apparent F can be obtained by combining Topotecan with elacridar which inhibits BCRP and P-gp in the gut wall. The OBJECTIVES were 1] to determine the lowest effective dose (LED) of elacridar resulting in complete apparent F of Topotecan and the optimal schedule of elacridar and Topotecan and 2] to determine the maximal tolerated dose (MTD) and dose-limiting toxicity (DLT) of Topotecan in combination with the LED of elacridar at a dailyx5 schedule every 21 days. Methods of part 1: Patients (pts) were randomized to receive 1000, 700, 500, 300 or 100 mg of elacridar (tablets) plus 2 mg Topotecan (capsules) after a standard breakfast. Elacridar was administered 60 minutes prior to Topotecan or simultaneously with Topotecan on day 1 and 8, which was randomized within patients. I.V. Topotecan was given on day 15. Pharmacokinetics (PK) of Topotecan (total and lactone form) and elacridar were obtained by validated L...

  • increased oral bioavailability of Topotecan in combination with the breast cancer resistance protein and p glycoprotein inhibitor gf120918
    Journal of Clinical Oncology, 2002
    Co-Authors: C M F Kruijtzer, R C Jewell, Elaine M Paul, Hilde Rosing, Jos H. Beijnen, W Ten Bokkel W Huinink, Margaret Schot, Jan H.m. Schellens
    Abstract:

    PURPOSE: We discovered that breast cancer resistance protein (BCRP), a recently identified adenosine triphosphate–binding cassette drug transporter, substantially limits the oral bioavailability of Topotecan in mdr1a/1b(−/−) P-glycoprotein (P-gp) knockout and wild-type mice. GF120918 is a potent inhibitor of BCRP and P-gp. The aim was to increase the bioavailability of Topotecan by GF120918. PATIENTS AND METHODS: In cohort A, eight patients received 1.0 mg/m2 oral Topotecan with or without coadministration of one single oral dose of 1,000 mg GF120918 (day 1 or day 8). In cohort B, eight other patients received 1.0 mg/m2 intravenous Topotecan with or without 1,000 mg oral GF120918 to study the effect of GF120918 on the systemic clearance of Topotecan. RESULTS: After oral Topotecan, the mean area under the plasma concentration-time curve (AUC) of total Topotecan increased significantly from 32.4 ± 9.6 μg·h/L without GF120918 to 78.7 ± 20.6 μg·h/L when GF120918 was coadministered (P = .008). The mean maximum...

  • Urinary and fecal excretion of Topotecan in patients with malignant solid tumours.
    Cancer chemotherapy and pharmacology, 2002
    Co-Authors: V. M. M. Herben, Hilde Rosing, Jan H.m. Schellens, Nadja E. Schoemaker, Desiree M. Van Zomeren, Wim W. Ten Bokkel Huinink, R. Dubbelman, Solange Hearn, Jos H. Beijnen
    Abstract:

    Abstract Purpose. The objectives of the study were to determine the pharmacokinetics and routes of excretion of Topotecan following intravenous or oral administration to patients with refractory solid tumours. Methods. Patients were randomized to receive either oral (2.3 mg/m2) or intravenous (1.5 mg/m2) Topotecan once daily for 5 days in course 1. Patients who received in course 1 oral Topotecan received in course 2 intravenous Topotecan on day 1 followed by oral Topotecan on days 2 to 5. Patients who received in course 1 intravenous Topotecan received in course 2 oral Topotecan once daily for 5 days. Plasma pharmacokinetics were performed on day 1 of course 1 (all patients) and course 2 (only patients receiving intravenous Topotecan on that day). In course 1, urine and feces were collected for up to 9 days after the first dosage. The amounts of Topotecan and N-desmethyl Topotecan in plasma, urine and feces were determined by validated high-performance liquid chromatographic assays. Results. A total of 11 patients were enrolled in the study. Nine patients were evaluable for pharmacokinetics. Plasma pharmacokinetics were similar to those previously reported. The principal route of excretion was the urine, with approximately 49% of the intravenously administered Topotecan dose and 20% of the oral dose collected in the urine as parent drug. Approximately 18% and 33% of the intravenous and oral dose, respectively, were recovered unchanged in the feces. Only small amounts of N-desmethyl Topotecan were found in the excreta. Conclusions. Fecal and urinary excretion of unchanged Topotecan were the major routes of Topotecan elimination. Approximately 28% of the intravenous dose and 43% of the oral dose of Topotecan were unaccounted for and eliminated through other routes.

  • A phase I and pharmacokinetic study of intraperitoneal Topotecan
    British journal of cancer, 2001
    Co-Authors: Ls Hofstra, Hilde Rosing, Jos H. Beijnen, A.m.e. Bos, E.g.e. De Vries, A.g.j. Van Der Zee, Nh Mulder, J.g. Aalders, Phb Willemse
    Abstract:

    Purpose: To evaluate the feasibility and pharmacology of intraperitoneal (IP) Topotecan. Patients and methods: Fifteen patients with recurrent ovarian cancer in a phase I trial were treated with escalating IP Topotecan doses (5–30 mg/m2) for pharmacokinetic analysis. Results: Dose limiting toxicity (DLT) was acute hypotension, chills and fever at the 30 mg/m2 dose level. Haematological toxicity and abdominal pain were mild for all dose levels studied. Pharmacokinetics: Peak plasma levels of total Topotecan were reached at 2.7 ± 1.1 h after IP instillation. The apparent V ss was 69.9 ± 25.4 L/m2, plasma clearance 13.4 ± 2.5 L/h/m2 and plasma T1/2 3.7 ± 1.3 h. The plasma AUC was correlated with the dose (R = 0.95, P < 0.01). The plasma AUC ratio of lactone versus total Topotecan (lactone + carboxy-forms) increased with the dose from 16% to 55%, (R = 0.84, P < 0.01). Peritoneal total Topotecan was cleared from the peritoneal cavity at 0.4 ± 0.3 L/h.m2 with a T1/2 = 2.7 ± 1.7 h. The mean peritoneal/plasma AUC ratio for total Topotecan was 54 ± 34. Conclusion: A substantial dose of Topotecan can be delivered by the IP route, achieving cytotoxic plasma levels of Topotecan, with acceptable toxicity. The recommended dose for further phase II trials is 20 mg/m2 IP, which enables combination with active doses of other cytotoxic drugs, in view of its limited myelotoxicity when given by this route. © 2001 Cancer Research Campaign http://www.bjcancer.com

Graham Ross - One of the best experts on this subject based on the ideXlab platform.

  • phase iii study of oral compared with intravenous Topotecan as second line therapy in small cell lung cancer
    Journal of Clinical Oncology, 2007
    Co-Authors: John R Eckardt, Jeanlouis Pujol, Joachim Von Pawel, Z Papai, Elisabeth Quoix, Andrea Ardizzoni, Ruth Poulin, A Preston, Graham Dane, Graham Ross
    Abstract:

    PURPOSE: Single-agent intravenous (IV) Topotecan is an effective treatment for small-cell lung cancer (SCLC) after failure of first-line chemotherapy. This open-label, randomized, phase III study compared oral and IV Topotecan in patients with SCLC sensitive to initial chemotherapy. PATIENTS AND METHODS: Patients with limited- or extensive-disease SCLC, documented complete or partial response to first-line therapy, Eastern Cooperative Oncology Group performance status or = 90 days were assigned to treatment with either oral Topotecan 2.3 mg/m2/d on days 1 through 5 or IV Topotecan 1.5 mg/m2/d on days 1 through 5 every 21 days. Primary end point was response rate as confirmed by an external reviewer blinded to treatment. RESULTS: A total of 309 patients were randomly assigned. In intent-to-treat analysis, response rates were 18.3% with oral Topotecan (n = 153) and 21.9% with IV Topotecan (n = 151), with a difference (oral -IV) of -3.6% (95% CI, -12.6% to 5.5%). Median survival time was 33.0 weeks for oral and 35.0 weeks for IV Topotecan; 1- and 2-year survival rates were 32.6% and 12.4% for oral Topotecan, respectively, and 29.2% and 7.1% for IV Topotecan, respectively. Third-line chemotherapy was similar for both groups (33% for oral; 35% for IV). Incidence of grade 4 toxicity in patients who received oral and IV Topotecan was as follows: neutropenia in 47% and 64%, thrombocytopenia in 29% and 18%, grade 3 or 4 anemia in 23% and 31%, and sepsis in 3% and 3%, respectively. The most frequent nonhematologic adverse events (all grades) included nausea (43% oral; 42% IV), alopecia (26% oral; 30% IV), fatigue (31% oral; 36% IV), and diarrhea (36% oral; 20% IV). CONCLUSION: Oral Topotecan demonstrates activity and tolerability similar to IV Topotecan in chemotherapy-sensitive SCLC patients and offers patients a convenient alternative to IV therapy.

  • phase iii study of oral compared with intravenous Topotecan as second line therapy in small cell lung cancer
    Journal of Clinical Oncology, 2007
    Co-Authors: John R Eckardt, Joachim Von Pawel, Jeanlouis Pujol, Z Papai, Elisabeth Quoix, Andrea Ardizzoni, Ruth Poulin, A Preston, Graham Dane, Graham Ross
    Abstract:

    Purpose Single-agent intravenous (IV) Topotecan is an effective treatment for small-cell lung cancer (SCLC) after failure of first-line chemotherapy. This open-label, randomized, phase III study compared oral and IV Topotecan in patients with SCLC sensitive to initial chemotherapy. Patients and Methods Patients with limited- or extensive-disease SCLC, documented complete or partial response to first-line therapy, Eastern Cooperative Oncology Group performance status ≤ 2, and measurable recurrent disease (WHO criteria) with a treatment-free interval of ≥ 90 days were assigned to treatment with either oral Topotecan 2.3 mg/m2/d on days 1 through 5 or IV Topotecan 1.5 mg/m2/d on days 1 through 5 every 21 days. Primary end point was response rate as confirmed by an external reviewer blinded to treatment. Results A total of 309 patients were randomly assigned. In intent-to-treat analysis, response rates were 18.3% with oral Topotecan (n = 153) and 21.9% with IV Topotecan (n = 151), with a difference (oral –IV)...

  • phase iii trial comparing supportive care alone with supportive care with oral Topotecan in patients with relapsed small cell lung cancer
    Journal of Clinical Oncology, 2006
    Co-Authors: Mary Obrien, Graham Dane, Graham Ross, Tudoreliade Ciuleanu, Hristo Tsekov, Yaroslav Shparyk, Branka Cucevia, Gabor Juhasz, Nick Thatcher, T Crofts
    Abstract:

    Purpose For patients with small-cell lung cancer (SCLC), further chemotherapy is routinely considered at relapse after first-line therapy. However, proof of clinical benefit has not been documented. Patients and Methods This study randomly assigned patients with relapsed SCLC not considered as candidates for standard intravenous therapy to best supportive care (BSC) alone (n = 70) or oral Topotecan (2.3 mg/m2/d, days 1 through 5, every 21 days) plus BSC (Topotecan; n = 71). Results In the intent-to-treat population, survival (primary end point) was prolonged in the Topotecan group (log-rank P = .0104). Median survival with BSC was 13.9 weeks (95% CI, 11.1 to 18.6) and with Topotecan, 25.9 weeks (95% CI, 18.3 to 31.6). Statistical significance for survival was maintained in a subgroup of patients with a short treatment-free interval (≤ 60 days). Response to Topotecan was 7% partial and 44% stable disease. Patients on Topotecan had slower quality of life deterioration and greater symptom control. Principal ...

Etienne Chatelut - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacokinetic-pharmacodynamic models for Topotecan-induced neutropenia
    Journal of Clinical Oncology, 2004
    Co-Authors: Etienne Chatelut, Walter J. Loos, F. Leger, Pierre Canal, Roland Bugat, Jaap Verweij, Alex Sparreboom
    Abstract:

    2054 Background: A semi-physiological pharmacokinetic-pharmacodynamic model derived from Friberg et al [J Clin Oncol, 2002, 20:4713] was applied to describe Topotecan-induced neutropenia, to quantify the inter-individual pharmacodynamic variability, and to study effect of covariates on the model Methods: The modeling was performed using the NONMEM program. The analysis was based on retrospective data from patients treated with Topotecan given either orally (118 patients) or intravenously (71 patients). The drug was given in various schedules, either in combination with cisplatin or as single agent. The model mimics the maturation chain of neutrophils. Topotecan concentration-time profiles affected the proliferation of neutrophils precursors (sensitive cells) through an inhibitory linear model; Topotecan is assumed to induce cell loss by a function, Edrug, proportional to the Topotecan concentration in the central compartment: Edrug=Slope.Conc. The Topotecan plasma concentrations versus time profile was ge...

  • Mechanism-based models for Topotecan-induced neutropenia.
    Clinical pharmacology and therapeutics, 2004
    Co-Authors: F. Leger, Walter J. Loos, Roland Bugat, Jaap Verweij, Alex Sparreboom, Ron H.j. Mathijssen, Marine Goffinet, Etienne Chatelut
    Abstract:

    Objective A semiphysiologic pharmacokinetic-pharmacodynamic model was applied to describe Topotecan-induced neutropenia, to quantify interindividual and intraindividual pharmacodynamic variability, and to study the effect of covariates on the model. Methods Data were obtained from patients treated with Topotecan given either orally (118 patients) or intravenously (71 patients), according to different schedules (5 to 21 consecutive days), with or without cisplatin. The model mimics the maturation chain of neutrophils. Topotecan concentration-time profiles affected the proliferation of neutrophil precursors (sensitive cells) through an inhibitory linear model (Topotecan is assumed to induce cell loss by a function, Edrug, proportional to the Topotecan concentration in the central compartment: Edrug = Slope · Concentration). The Topotecan plasma concentration versus time profile was generated for each patient by modeling the data according to a 2-compartment pharmacokinetic model and first-order absorption for oral administration by use of NONMEM. Results The model described the time course of neutrophil values well. Topotecan neutropenic effect exhibited a large interpatient variability (coefficient of variation of 82% for the slope values). The oral route was associated with a 43% lower value for slope, corresponding to a lower toxicity. The combination with cisplatin increased the neutropenic effect compared with Topotecan alone by a factor 3.5. The intrapatient variability between cycle 1 and cycle 2 on slope was lower for the intravenous administration than for the oral administration. By application of the model to a new weekly schedule of Topotecan, neutrophil values at the nadir were consistent with those observed during a phase I study of this regimen. Conclusion This model can be used to describe both the duration and intensity of neutropenia; the area between the curve of neutrophil count versus time and a critical neutrophil count (such as 0.500 × 103/mm3) would be a better toxic endpoint than the unique observed value of neutrophil at nadir. The model may be used to predict neutropenia corresponding to regimens of Topotecan not yet explored. Clinical Pharmacology & Therapeutics (2004) 76, 567–578; doi: 10.1016/j.clpt.2004.08.008