Abstract
Objective. To determine the maximum tolerated dose and pharmacokinetics of topotecan when administered by the intraperitoneal route. Methods. A dose-escalating Phase I trial was conducted in which fifteen % of the total dose was given as an intraperitoneal bolus in two litres of D5W and the remainder was given as a continuous intraperitoneal infusion over 24 hours. Treatments were given every 21 days. Pharmacokinetic analyses were performed at the recommended phase II dose. Results. Seventeen patients received a total of 43 cycles at 21-day intervals. The maximum tolerated dose was 4 mg/m2 and acute dose-limiting toxicity was neutropenia. Other toxicities included leukopenia, anemia, emesis, fever, and abdominal pain. Although no objective responses were achieved, five of ten patients with ascites had a decrease in fluid accumulation with administration of intraperitoneal topotecan. The recommended phase II dose is 3 mg/m2. Pharmacokinetic analysis performed at a dose of 3 mg/m2 demonstrated that elimination from the peritoneal cavity followed second-order kinetics with k1 = 1.6 hr-1, k2 = 0.3 hr-1 and first and second-phase half-lives of 0.49 and 2.7 hours, respectively. Plasma pharmacokinetic behavior was best described by first-order kinetics with k = 0.5 hr-1 and a half-life of 3.9 hours. The pharmacologic advantage, expressed as the peritoneal to plasma AUC ratio was 31.2. Conclusions. Intraperitoneal administration of topotecan at 3 mg/m2 results in a substantial increase in drug exposure for the peritoneal cavity without compromising systemic exposure; this may be beneficial for the treatment of patients with ovarian cancer or intraperitoneal carcinomatosis.
Similar content being viewed by others
References
Swisher EM, Mutch DG, Rader JS, Elbanedary A, Herzorg TJ: Topotecan in platinum-and paclitaxel-resistant ovarian cancer. Gynegologic Oncol 66: 480–486, 1997
Ten Bokkel Huinink W, Gore M, Carmichael J, Gordan A, Malfetano J, Hudson I, Broom C, Scarabelli C, Davidson N, Spanczynski M, Bolis G, Malmstrom H, Coleman R, Fields SC, Heron JF: Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 15: 2183–2193, 1997
Creemers GJ, Bolis G, Gore M, Scarfone G, Lacave AJ, Guastalla JP, Despax R, Favalli G, Kreinberg R, Van Belle S et al.: Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: results of a large European phase II study. J Clin Oncol 14: 3056–3061, 1996
Rowinsky E, Grochow L, Hendricks C, Sartonus S, Ettinger D, McGuire W, Forastiere A, Hurowitz L, Easter V, Doehower R: Phase I and pharmacologic study of topotecan (SK & F 104864): a novel topoisomerase I inhibitor. Proc ASCO 10: 93, 1992
Sirott MN, Saltz L, Young C, Tong W, Trochanowski B, Niedzwiecki D, Toomasi F, Kelsen D: Phase I and clinical pharmacologic study of intravenous topotecan (T). Proc ASCO 10: 104, 1991
Kudelka AP, Tresukosol D, Edwards CL, Freedman RS, Levenback C, Chantarawiroj P, Gonzalez de Leon C, Kim EE, Madden T, Wallin B, Hord M, Verschragen C, Raber M, Kavanagh J: Phase II study of intravenous topotecan as a 5–day infusion for refractory ovarian carcinoma. J Clin Oncol 14: 1552–1557, 1996
Alberts DS, Liu PY, Hannigan EV, O'Toole R, Williams SD, Young JA, Franklin EW, Clarke-Pearson DL, Malviya VK, DuBeshter B, Adelson MD, Hoskins WJ: Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 335: 1950–1955, 1996
Myers CE, Collins JM: Pharmacology of intraperitoneal chemotherapy. Cancer Invest 1(5): 395–407, 1983
Herben VMM, Ten Bokkel Huinink WW, Beijnen JH: Clinical pharmacokinetics of topotecan. Clin Pharmacokinet 31: 85– 102, 1996
Wall J, Havlin K, Burris H, Weiss G, Brown T, Brown J, Kuhn J, Johnson R, Mann W, Webb D, Von Hoff D: Phase I study of SK & F 104864: a novel topoisomerase inhibitor. Proc ASCO 9: 86, 1990
O'Quigley J, Chevret SS: Methods for dose finding studies in cancer clinical trials. Statistics in Medicine 10: 1647–1664, 1991
O'Quigley J, Pepe M, Fisher L: Continual reassessment method: a practical design for phase I clinical trials in cancer. Biometrics 46: 33–48, 1990
O'Quigley J: Estimating the probability of toxicity at the recommended dose following a phase I clinical study in cancer. Biometrics (in press)
Markman M, Howell SB, Lucas WE, Pfeifle CE, Green M: Combination intraperitoneal chemotherapy with cisplatin, cytarabine and doxorubicin for refractory ovarian carcinoma and other malignancies principally confined to the peritoneal cavity. J Clin Oncol 2: 1321–1326, 1984
Beijnen JH, Smith BR, Keijer WJ, Van Gijn R, Ten Bokkel Huinink WW, Vlasveld LT, Rodenhuis S, Underberg WJM: High-performance liquid chromatographic of the new antitumor drug SKF104864–A (NSC 606699) in plasma. J Pharmacol Biomed Anal 8: 789–794, 1990
Van Warmerdam LJC, Ten Bokkel Huinink WW, Rodenhuis S et al.: Phase I clinical and pharmacokinetic study of topotecan administered by a 24–hour continuous infusion (published erratum appears in J Clin Oncol 14: 689, 1996). J Clin Oncol 13: 1768–1776, 1995
O'Reilly S, Fleming GF, Baker SD, Walczak JR, Bookman MA, McGuire III WP, Schilder RJ, Alvarez RD, Armstrong DK, Horowitz IR, Ozols RF, Rowinsky EK: Phase I trial and pharmacologic trial of sequences of paclitaxel and topotecan in previously treated ovarian epithelial malignancies: a gynecologic oncology group study. J Clin Oncol 15: 177–186, 1997
Rowinsky E, Grochow L, Kaufmann S et al.: Sequence-dependent effects of topotecan and cisplatin in a phase I and pharmacokinetic study. Proc ASCO 13: 142, 1994
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Plaxe, S.C., Christen, R.D., O'Quigley, J. et al. Phase I and pharmacokinetic study of intraperitoneal topotecan. Invest New Drugs 16, 147–153 (1998). https://doi.org/10.1023/A:1006045125018
Issue Date:
DOI: https://doi.org/10.1023/A:1006045125018