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Journal of Clinical Oncology, Vol 22, No 5 (March 1), 2004: pp. 829-837 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.07.110 Phase I and Pharmacokinetic Study of Topotecan Administered Orally Once Daily for 5 Days for 2 Consecutive Weeks to Pediatric Patients With Refractory Solid TumorsFrom the Departments of Hematology-Oncology, Molecular Pharmacology, and Pharmaceutical Sciences, St Jude Children's Research Hospital; and the University of Tennessee Health Science Center, Memphis, TN. Address reprint requests to Najat C. Daw, MD, Department of Hematology-Oncology, Mail Stop 260, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; e-mail: najat.daw{at}stjude.org
PURPOSE: We conducted a phase I trial of the injectable formulation of topotecan given orally once daily for 5 days for 2 consecutive weeks (qd x 5 x 2) in pediatric patients with refractory solid tumors. PATIENTS AND METHODS: Cohorts of two to six patients received oral topotecan at 0.8, 1.1, 1.4, 1.8, and 2.3 mg/m2/d every 28 days for a maximum of six courses. Twenty patients (median age, 10.6 years) received a total of 51 courses. Eight patients received topotecan capsules during course 2 only. RESULTS: Dose-limiting toxicity occurred at 2.3 mg/m2/d and consisted of prolonged grade 4 neutropenia (n = 2), grade 3 stomatitis as a result of radiation recall (n = 1), grade 3 hemorrhage (epistaxis) in the presence of grade 4 thrombocytopenia (n = 1), and grade 3 diarrhea in the presence of Clostridium difficile infection (n = 1). Dose-limiting, prolonged grade 4 neutropenia and thrombocytopenia occurred in one patient at 1.4 mg/m2/d. Infrequent toxicities were mild nausea, vomiting, elevated liver ALT or AST, and rash. The maximum-tolerated dosage was 1.8 mg/m2/d; the mean (± standard deviation) area under the plasma concentration-time curve for topotecan lactone at this dosage was 20.9 ± 8.4 ng/mL · h. The population mean (± standard error) oral bioavailability of the injectable formulation was 0.27 ± 0.03; that of capsules was 0.36 ± 0.06 (P = .16). Disease stabilized in nine of 19 assessable patients for 1.5 to 6 months. CONCLUSION: Oral topotecan (1.8 mg/m2/d) on a qd x 5 x 2 schedule is well tolerated and warrants additional testing in pediatric patients.
Topotecan has antitumor activity against a variety of pediatric solid tumors and acute leukemia, and has a limited toxicity profile [1-5]. A water-soluble semisynthetic analog of camptothecin, topotecan stabilizes the topoisomerase I-DNA complex, thereby interfering with the breakage-reunion process mediated by topoisomerase; this ultimately leads to DNA strand breaks and apoptosis [6-8]. The cytotoxicity of topotecan is specific to the S phase of the cell cycle [9]; thus, protracted administration has been associated with increased cytotoxicity [10]. In mice bearing xenografts of human tumors, protracted administration of topotecan enhanced efficacy and decreased toxicity [11-13]. However, continuous infusion may not be the optimal form of administration, because it downregulates free topoisomerase I, and such downregulation might constitute a mechanism of resistance to this drug [13-16]. Therefore, protracted, repeated administration of topotecan is the preferred dosing regimen for clinical development. In general, orally administered anticancer therapy is desirable because of its convenience and ease of administration. It can be delivered in the outpatient setting and does not require intravenous (IV) access; thus, patient control is enhanced and quality of life is maintained. Clearly, orally administered therapy offers a distinct advantage for drug administration on protracted schedules. In the mouse xenograft model, orally administered topotecan showed significant antitumor activity [11,12,17]. For these reasons, we sought to evaluate the safety profile and pharmacokinetics of topotecan administered orally on protracted schedules to pediatric patients with refractory solid tumors. In our previous phase I trial [18], dose-limiting myelosuppression and diarrhea prevented the dose escalation of topotecan given as the injectable formulation orally once daily for 21 consecutive days (total of 21 doses) or once daily for 5 days for 3 consecutive weeks (total of 15 doses). An adult phase I study suggested that a 10-day schedule allows an increase in dosage of and systemic exposure (SE) to oral topotecan [19]. In this report, we present the results of a pediatric phase I trial of oral topotecan given daily for 5 days for 2 consecutive weeks (qd x 5 x 2), a schedule found to be optimal in pediatric tumor models (P.J. Houghton, unpublished data). The primary objective of this trial was to determine the toxicity and maximum-tolerated dose (MTD) of the injectable formulation of topotecan given orally on the qd x 5 x 2 schedule in pediatric patients with recurrent or refractory solid tumors. In addition, we sought to estimate the bioavailability of topotecan given orally as the injectable formulation or as gelatin capsules, and to note any antitumor activity within the confines of a phase I study.
Study Design The injectable formulation of topotecan was administered orally once daily for 5 consecutive days followed by a 2-day rest and then by another 5 consecutive days of treatment (10 doses over 12 days) without hematopoietic growth factor support. Courses were repeated every 28 days. During course 2 only, topotecan gelatin capsules were given to children who were able to swallow capsules as determined by the parent or treating physician. Course 1 was used to determine the MTD and dose-limiting toxicity (DLT) of the injectable formulation of topotecan administered orally on the above-described schedule. The starting topotecan dosage was 0.8 mg/m2/d. In the absence of DLT, the dosage was escalated to 1.1, 1.4, 1.8, and 2.3 mg/m2/d and administered to cohorts of three patients. No intrapatient dose escalation was allowed. Unacceptable toxicity or DLT was defined as grade 4 neutropenia (absolute neutrophil count [ANC] < 500/µL) or grade 4 thrombocytopenia (platelet count < 25,000/µL) lasting longer than 10 days after the last topotecan dose, or grade 3 or higher nonhematologic toxicity in two of a cohort of three to six patients. Only the first course was considered in the evaluation of DLT. The MTD was defined as the dose level at which no more than one patient in a cohort of three to six experienced DLT. In the absence of disease progression, patients who experienced DLT during a course received topotecan at the next lower dosage during subsequent courses, if all nonhematologic toxicities resolved to baseline, the ANC recovered to more than 1,000/µL, and the platelet count recovered to more than 50,000/µL. In the absence of disease progression or irreversible toxicity, topotecan therapy was continued for a maximum of six courses. Patients were removed from the study for disease progression, irreversible life-threatening nonhematologic toxicity, patient noncompliance, patient or parent request, or patient death.
Patient Eligibility After initiation of the study, the protocol was amended to permit enrollment of eligible patients who had received prior craniospinal irradiation because topotecan is active against pediatric brain tumors and a significant number of patients with brain tumors receive craniospinal irradiation as part of their first-line therapy. In addition, the amendment allowed the enrollment of eligible patients who were receiving histamine H2 antagonists after a study conducted in adults showed that administration of ranitidine before the oral administration topotecan does not alter the extent of topotecan absorption [20].
Drug Formulation and Administration Topotecan capsules were supplied by GlaxoSmithKline. Two strengths of capsules were available (0.25 and 1.0 mg). The 0.25-mg hard gelatin capsule, the color of which ranged from white to pale yellow, was sealed with a clear gelatin band, and contained topotecan HCl that is equivalent to 0.25 mg of the anhydrous free base, 5% glyceryl monostearate, and hydrogenated vegetable oil. The 1.0-mg hard gelatin capsule was yellow and sealed with a clear gelatin band, and contained topotecan HCl that is equivalent to 1.0 mg of the anhydrous free base, 5% glyceryl monostearate, and hydrogenated vegetable oil. The calculated dose of topotecan capsules was based on the body-surface area and rounded to the nearest 0.25 mg.
Patient Evaluation
Toxicity was assessed by the National Cancer Institute Common Toxicity Criteria (version 1.0). For antitumor effect, a complete response was defined as complete regression of apparent tumor masses, including lesions noted on imaging, and clearing of bone marrow or CSF from tumor cells. A partial response was defined as greater than 50% and less than 100% regression of all tumor masses in the absence of any new lesions. Stable disease was defined as the absence of complete response, partial response, and progressive disease. Progressive disease was defined as
Pharmacokinetic Evaluation
Pharmacokinetic Analysis
To determine whether the capsule formulation significantly affected the parameter estimates (eg, ke, V, or F), we used the following covariate model:
where X was equal to 0 for the IV formulation and 1 for the capsule formulation,
Pharmacodynamic Analysis
where the pretreatment value (pre) was measured before topotecan therapy began and the nadir value was defined as the lowest count after the first day of topotecan therapy.
The sigmoid Emax model was chosen as the empirical mathematical function to describe the shape of the concentration-effect (neutropenia or thrombocytopenia) curve as follows:
where Emax, the maximal effect (% decrease in ANC or platelet count), is fixed at 100%. SE is measured as the AUC0
Patient Characteristics and Treatment Twenty patients were enrolled in this phase I study between August 1998 and July 2002. Relevant characteristics of the 20 patients are listed in Table 1. The patients had been extensively pretreated: 10 had received two or more multiagent chemotherapy regimens, and four had received autologous stem-cell transplant (one received a stem-cell transplant twice). Six patients had previously received intravenously administered topotecan, and two of these six patients also had received high-dose topotecan in combination with cyclophosphamide as a preparative regimen before stem-cell transplantation. Six patients, including three patients who had previously received topotecan administered intravenously, also had received irinotecan. None of the enrolled patients had renal insufficiency or abnormal serum creatinine at study entry.
The patients received a total of 51 assessable courses of topotecan administered orally at five dosages: 0.8 mg/m2/d (three patients), 1.1 mg/m2/d (three patients), 1.4 mg/m2/d (six patients), 1.8 mg/m2/d (six patients), and 2.3 mg/m2/d (two patients). Although only five of the 10 doses of topotecan were administered to one patient because of hospitalization for febrile neutropenia and grade 3 stomatitis after the fifth dose of topotecan had been given during course 1; this course was still considered assessable for toxicity. The median number of courses administered per patient was two (range, one to six).
Toxicity of Oral Topotecan
Three patients experienced DLT. One patient treated with topotecan at a dosage of 1.4 mg/m2/d had grade 4 neutropenia that lasted 22 days and grade 4 thrombocytopenia that lasted 12 days. A patient treated with the dosage of 2.3 mg/m2/d had grade 4 neutropenia that lasted 31 days, grade 3 diarrhea in the presence of a positive stool test for Clostridium difficile, and grade 3 hemorrhage (epistaxis) in the presence of grade 4 thrombocytopenia. Another patient treated with the dosage of 2.3 mg/m2/d experienced grade 4 neutropenia for 11 days and grade 3 stomatitis at a previously irradiated site. During course 1, a total of four patients had grade 4 neutropenia that lasted 7, 11, 22, or 31 days; only the three patients mentioned above met the definition of DLT. In addition, a total of three patients developed grade 4 thrombocytopenia for 1, 2, or 12 days; only the patient mentioned above met the definition of DLT. Patients with tumors of the CNS were not routinely transfused to maintain a minimum platelet count, and only one patient with a brain tumor had grade 4 thrombocytopenia (the patient with DLT at 1.4 mg/m2/d). No DLT was observed in patients treated with topotecan at a dosage of 1.8 mg/m2/d; therefore, the dose of 1.8 mg/m2 was determined to be the MTD. The eligibility criteria for this study did not restrict entry of patients receiving drugs that may potentially alter topotecan clearance, such as enzyme-inducing anticonvulsants or dexamethasone. However, only three patients (with brain tumors) received such medications: two treated with 1.1 mg/m2/d and one treated with 1.4 mg/m2/d.
Antitumor Activity
Pharmacokinetics
Pharmacodynamics Oral topotecan lactone SE (AUC) was plotted against the percent decrease of ANC or platelet count during course 1 for the 20 patients. The relationship between oral topotecan SE and percent decrease of ANC or platelet count was adequately fitted by a sigmoid Emax model. The pharmacodynamic relationships between measured topotecan lactone SE (AUC) and percent decrease in ANC (r = 0.72; P < .05; Fig 2A) or percent decrease in platelet count (r = 0.61; P < .05; Fig 2B) were statistically significant. The SE50 for the percent decrease in ANC and platelet count was 7.99 and 11.15 ng/mL · h, respectively.
We also evaluated the relation between oral topotecan lactone SE (AUC) and nonhematologic toxicity. All nonhematologic toxicities were graded and placed into three groups: grade 0, grades 1 and 2, and grades 3 and 4. The occurrence of nonhematologic toxicity during course 1 increased as the median topotecan lactone AUC increased (Fig 3).
Although previous studies in adults [25-27] have evaluated the safety and disposition of oral topotecan, our article is the first report of the safety of oral topotecan given on a protracted schedule to pediatric patients. In this trial conducted in pediatric patients with recurrent or refractory solid tumors, the toxicity of oral topotecan was primarily myelosuppression and diarrhea, a finding similar to that observed in adult patients. Topotecan SE increased linearly with the dosage and was positively correlated with pharmacodynamic parameters, including the percent decrease in ANC and platelet count and the occurrence of nonhematologic toxicity. The bioavailability of the orally administered injectable formulation did not differ significantly from that of the gelatin capsules (0.27 for the injectable formulation v 0.36 for the capsules; P = .16). The recommended dosage for phase II pediatric studies is 1.8 mg/m2/d on the qd x 5 x 2 schedule. The DLTs of oral topotecan in our study were prolonged neutropenia (n = 3) and thrombocytopenia (n = 1), hemorrhage (epistaxis) in the presence of grade 4 thrombocytopenia (n = 1), diarrhea in the presence of Clostridium difficile colitis (n = 1), and stomatitis caused by radiation recall (n = 1). When topotecan was administered intravenously, hematologic toxicity was dose-limiting in pediatric and adult patients [28-32]. In a study of orally administered topotecan in adult patients, the DLT after twice daily administration for 21 days was diarrhea (at 0.6 mg/m2 per dose), which started at a median of 15 days and resolved after a median of 8 days and did not improve with loperamide treatment [26]. In another study of adult patients, the DLT after topotecan given orally once or twice daily for 10 days was a combination of myelosuppression and diarrhea [27]. In the latter study, diarrhea appeared to have a shorter duration (median of 4 days). In our study, diarrhea was the most common nonhematologic toxicity. We suspect that topotecan administration contributed to the development of the dose-limiting diarrhea in our patient who had a positive stool test for Clostridium difficile. The median duration of the diarrhea in our study was 2 days, and the use of loperamide was not particularly beneficial. The mechanism of diarrhea caused by topotecan is not well understood, but it is speculated to result from a local effect of topotecan on the intestinal mucosa [26]. In our study, the MTD of topotecan given orally each day for 5 days for 2 consecutive weeks was 1.8 mg/m2. This dosage is higher than the MTD for adults treated with oral topotecan for 10 days and repeated every 21 days (1.4 mg/m2 for the once daily schedule or 0.7 mg/m2 for the twice daily schedule) [27]. In our study, treatment courses were repeated every 28 days; however, it is possible that our schedule will be tolerated every 21 days in chemotherapy-naive or minimally pretreated pediatric patients. As in our previous study [21] of the pharmacokinetics of the injectable formulation of topotecan administered orally to children, we noted a wide interpatient variability in the pharmacokinetic parameters for topotecan. For example, we observed approximately a five-fold range in the parameters associated with disposition of orally administered drug (eg, ka and F). The average oral bioavailability of the injectable topotecan formulation in this study (0.27) is similar to that previously reported for children (0.34) [21] and for adults (0.30) [33]. Our study is the first report of the absolute bioavailability of topotecan gelatin capsules in children. This bioavailability (0.36) was similar to that reported by Herben et al in adults (0.38) [34]. The addition of topotecan gelatin capsules as a covariate significantly improved the performance of our population pharmacokinetic model; however, the absolute oral bioavailability of the capsules was not significantly different from that of the injectable topotecan solution when given orally. The results of our pharmacodynamic studies showed a significant relation between topotecan lactone SE and the percent decrease in ANC and between topotecan lactone SE and the percent decrease in platelet count. As with other studies of topotecan pharmacodynamics, the empirical Emax model provided an adequate fit to topotecan lactone SE and the percent decrease in ANC or platelet count. Creemers et al [26] reported a significant correlation between oral topotecan AUC and the percent decrease in WBC count. Although they used WBC rather than ANC, their parameter estimates (eg, SE50 values) were similar to those observed in our study. We have conducted extensive pharmacokinetic studies to define topotecan lactone SEs that are associated with response after oral and IV topotecan administration in xenograft models of pediatric solid tumors [11]. These studies show that for the same tumor model, a lower oral topotecan dosage than IV dosage is associated with antitumor effects. The dosage associated with an objective response after oral administration ranges from 0.5 to 1.0 mg/kg, corresponding to a single-day topotecan lactone SE (expressed as AUC) of 17.5 to 35 ng/mL · h (P.J. Houghton and C.F. Stewart, unpublished data). Thus, the results from our study show that at MTDs of oral topotecan, children can achieve topotecan SEs similar to those required to induce tumor responses in the xenograft model. We intend to extend this promising finding to future clinical trials of orally administered topotecan in children. Strategies can be used to alter the low and variable oral bioavailability of anticancer agents by taking advantage of an interaction between anticancer agents and drugs that modulate active intestinal transporters or intestinal enzymes [35]. These modulators will increase topotecan absorption from the gut and potentially reduce the untoward effects on the gut mucosa and, more importantly, reduce the interpatient variability in SE. For example, coadministration of the breast cancer resistance protein and the P-glycoprotein inhibitor GF120918 significantly increased the SE and apparent oral bioavailability of topotecan in adults [36]. In addition, preclinical studies have shown that the human epidermal growth factor receptor tyrosine kinase inhibitors such as gefitinib (ZD1839, Iressa, AstraZeneca, Wilmington, DE) enhance topotecan cytotoxicity by inhibiting breast cancer resistance protein–mediated drug efflux [37-40]. Therefore, these agents may potentially enhance topotecan cytotoxicity, and effectively modulate its bioavailability after oral administration. Our study forms the basis for the rational and safe usage of oral topotecan in children with cancer. Oral topotecan administration on the qd x 5 x 2 schedule provides a convenient method for protracted topotecan administration, which was found to be effective in xenograft models. The antitumor efficacy of this schedule warrants additional evaluation in clinical trials. The significant antitumor activity of topotecan observed in the xenograft model coupled with the clear advantages of oral drug administration make oral topotecan therapy an attractive component to incorporate in maintenance therapy against multiple types of childhood malignancy.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Victor M. Santana, GlaxoSmithKline. Acted as a consultant within the last 2 years: Clinton F. Stewart, GlaxoSmithKline; Peter J. Houghton, GlaxoSmithKline. Received more than $2,000 a year from a company for either of the last 2 years: Clinton F. Stewart, GlaxoSmithKline.
We thank the medical nursing team and Lisa Walters, Terri Kuehner, Sheri Ring, Margaret Edwards, and Paula Condy for their assistance; Brad Johnston for his invaluable technical support in the laboratory; Marion Strom for data management; and Julia Cay Jones for editing the manuscript.
Supported in part by Cancer Center Support (CORE) grant CA21765 and grant CA23099 from the National Cancer Institute, by the American Lebanese Syrian Associated Charities (ALSAC), and by GlaxoSmithKline. Presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, May 12-15, 2001, San Francisco, CA, and the 39th Annual Meeting, May 31-June 3, 2003, Chicago, IL. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Furman WL, Baker SD, Pratt CB, et al: Escalating systemic exposure of continuous infusion topotecan in children with recurrent acute leukemia. J Clin Oncol 14:1504-1511, 1996 2. Stewart CF, Zamboni WC, Crom WR, et al: Topoisomerase I interactive drugs in children with cancer. Invest New Drugs 14:37-47, 1996[CrossRef][Medline] 3. Pratt CB, Stewart C, Santana VM, et al: Phase I study of topotecan for pediatric patients with malignant solid tumors. J Clin Oncol 12:539-543, 1994[Abstract]
4. Furman WL, Stewart CF, Kirstein M, et al: Protracted intermittent schedule of topotecan in children with refractory acute leukemia: A pediatric oncology group study. J Clin Oncol 20:1617-1624, 2002
5. Santana VM, Zamboni WC, Kirstein MN, et al: A pilot study of protracted topotecan dosing using a pharmacokinetically guided dosing approach in children with solid tumors. Clin Cancer Res 9:633-640, 2003 6. Kingsbury WD, Boehm JC, Jakas DR, et al: Synthesis of water-soluble (aminoalkyl)camptothecin analogues: Inhibition of topoisomerase I and antitumor activity. J Med Chem 34:98-107, 1991[CrossRef][Medline]
7. Hsiang YH, Liu LF: Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 48:1722-1726, 1988 8. Taudou G, Portemer C, Jaxel C, et al: Inhibition of DNA synthesis and DNA fragmentation in stimulated splenocytes by the concerted action of topoisomerase I and II poisons. Biochem Pharmacol 45:331-337, 1993[CrossRef][Medline] 9. Del Bino G, Lassota P, Darzynkiewicz Z: The S-phase cytotoxicity of camptothecin. Exp Cell Res 193:27-35, 1991[CrossRef][Medline] 10. Houghton PJ, Stewart CF, Zamboni WC, et al: Schedule-dependent efficacy of camptothecins in models of human cancer. Ann N Y Acad Sci 803:188-201, 1996[Medline] 11. Houghton PJ, Cheshire PJ, Myers L, et al: Evaluation of 9-dimethylaminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors. Cancer Chemother Pharmacol 31:229-239, 1992[CrossRef][Medline] 12. Houghton PJ, Cheshire PJ, Hallman JD II, et al: Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol 36:393-403, 1995[Medline]
13. Guichard S, Montazeri A, Chatelut E, et al: Schedule-dependent activity of topotecan in OVCAR-3 ovarian carcinoma xenograft: Pharmacokinetic and pharmacodynamic evaluation. Clin Cancer Res 7:3222-3228, 2001
14. Hochster H, Wadler S, Runowicz C, et al: Activity and pharmacodynamics of 21-day topotecan infusion in patients with ovarian cancer previously treated with platinum-based chemotherapy: New York Gynecologic Oncology Group. J Clin Oncol 17:2553-2561, 1999
15. Desai SD, Li TK, Rodriguez-Bauman A, et al: Ubiquitin/26S proteasome-mediated degradation of topoisomerase I as a resistance mechanism to camptothecin in tumor cells. Cancer Res 61:5926-5932, 2001 16. Saleem A, Edwards TK, Rasheed Z, et al: Mechanisms of resistance to camptothecins. Ann N Y Acad Sci 922:46-55, 2000[CrossRef][Medline] 17. McCabe FL, Johnson RK: Comparative activity of oral and parenteral topotecan in murine tumor models: Efficacy of oral topotecan. Cancer Invest 12:308-313, 1994[Medline] 18. Bowman LC, Stewart CF, Zamboni WC, et al: Toxicity and pharmacodynamics of oral topotecan (POTOPO) in pediatric patients with relapsed solid tumors. Proc Am Soc Clin Oncol 15:462, 1996 (abstr 1453) 19. Burris H, Gerrits C, Schellens J, et al: Oral topotecan for 10 days once daily and twice daily every 3 weeks: A phase I and pharmacologic study in adults. Ann Oncol 7:126, 1996 (abstr 605P) 20. Akhtar S, Beckman RA, Mould DR, et al: Pretreatment with ranitidine does not reduce the bioavailability of orally administered topotecan. Cancer Chemother Pharmacol 46:204-210, 2000[CrossRef][Medline] 21. Zamboni WC, Bowman LC, Tan M, et al: Interpatient variability in bioavailability of the intravenous formulation of topotecan given orally to children with recurrent solid tumors. Cancer Chemother Pharmacol 43:454-460, 1999[CrossRef][Medline] 22. Derendorf H, Lesko LJ, Chaikin P, et al: Pharmacokinetic/pharmacodynamic modeling in drug research and development. J Clin Pharmacol 40:1399-1418, 2000[Abstract] 23. Holford NH, Sheiner LB: Pharmacokinetic and pharmacodynamic modeling in vivo. CRC Crit Rev Bioeng 5:273-322, 1981[Medline] 24. Aikaike H: An information criterion. Math Sci 14:5-9, 1976 25. Gerrits CJ, Burris H, Schellens JH, et al: Five days of oral topotecan (Hycamtin), a phase I and pharmacological study in adult patients with solid tumours. Eur J Cancer 34:1030-1035, 1998
26. Creemers GJ, Gerrits CJ, Eckardt JR, et al: Phase I and pharmacologic study of oral topotecan administered twice daily for 21 days to adult patients with solid tumors. J Clin Oncol 15:1087-1093, 1997 27. Gerrits CJ, Burris H, Schellens JH, et al: Oral topotecan given once or twice daily for ten days: A phase I pharmacology study in adult patients with solid tumors. Clin Cancer Res 4:1153-1158, 1998[Abstract]
28. Blaney SM, Balis FM, Cole DE, et al: Pediatric phase I trial and pharmacokinetic study of topotecan administered as a 24-hour continuous infusion. Cancer Res 53:1032-1036, 1993
29. Rowinsky EK, Grochow LB, Hendricks CB, et al: Phase I and pharmacologic study of topotecan: A novel topoisomerase I inhibitor. J Clin Oncol 10:647-656, 1992 30. Hochster H, Liebes L, Speyer J, et al: Phase I trial of low-dose continuous topotecan infusion in patients with cancer: An active and well-tolerated regimen. J Clin Oncol 12:553-559, 1994[Abstract] 31. Creemers GJ, Lund B, Verweij J: Topoisomerase I inhibitors: Topotecan and irinotecan. Cancer Treat Rev 20:73-96, 1994[CrossRef][Medline]
32. Verweij J, Lund B, Beijnen J, et al: Phase I and pharmacokinetics study of topotecan, a new topoisomerase I inhibitor. Ann Oncol 4:673-678, 1993 33. Schellens JH, Creemers GJ, Beijnen JH, et al: Bioavailability and pharmacokinetics of oral topotecan: A new topoisomerase I inhibitor. Br J Cancer 73:1268-1271, 1996[Medline] 34. Herben VM, Rosing H, ten Bokkel Huinink WW, et al: Oral topotecan: Bioavailability and effect of food co-administration. Br J Cancer 80:1380-1386, 1999[CrossRef][Medline] 35. Sparreboom A, de Jonge MJ, Verweij J: The use of oral cytotoxic and cytostatic drugs in cancer treatment. Eur J Cancer 38:18-22, 2002
36. Kruijtzer CM, Beijnen JH, Rosing H, et al: Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J Clin Oncol 20:2943-2950, 2002
37. Erlichman C, Boerner SA, Hallgren CG, et al: The HER tyrosine kinase inhibitor CI1033 enhances cytotoxicity of 7-ethyl-10-hydroxycamptothecin and topotecan by inhibiting breast cancer resistance protein-mediated drug efflux. Cancer Res 61:739-748, 2001
38. Ciardiello F, Caputo R, Bianco R, et al: Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 6:2053-2063, 2000 39. Schuetz J, Leggas M, Sampath J, et al: Potent BCRP inhibition by the ErbB1 inhibitor ZD1839 (Iressa) dramatically enhances oral bioavailability of topotecan and irinotecan in mice. Proc Am Soc Clin Oncol 43:272, 2002 (abstr 1351) 40. Houghton P, Germain G, Schuetz J, et al: Imatinib mesylate (STI571, Gleevec) is a potent inhibitor of BCRP (ABCG2) and reverses topotecan resistance in vitro. Proc Am Assoc Cancer Res 44:446-447, 2003 (abstr 1959) Submitted July 22, 2003; accepted December 15, 2003.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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TOP
ABSTRACT
INTRODUCTION
2; a baseline WBC count more than 2,000/µL, an ANC more than 1,000/µL, and a platelet count more than 100,000/µL (without transfusion support), irrespective of bone marrow involvement by the tumor; adequate liver function (bilirubin concentration < 1.5 x the normal values, ALT concentration 
25% increase in the sum of the products of the greatest length and maximum width of indicator lesions or the appearance of tumor in a previously uninvolved site. 
, where parpop was the population estimate of the parameter and 
i
N(0,
) described the variation of individual i from the population average. The residual error of the model was described by y = f(1 + 
1) + 
1) described the relative error, and 
) was determined by the linear trapezoid method using the model-estimated curve. 
2 was the change due to the capsule formulation, and 
described the variation of individual i from the population average change due to capsule formulation. The statistical significance of the addition of this covariate was evaluated by determining the change in the -2 x log likelihood (eg, a decrease of 3.84 indicates a significant difference [P < .05] as calculated by the 
2 test). In addition, we tested whether the parameter 
) Values from individual patients; (
) value that was not included in the analysis.
