{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T15:40:02Z","timestamp":1790005202169,"version":"4.0.1"},"reference-count":33,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCO"],"published-print":{"date-parts":[[2000,6,12]]},"abstract":"<jats:p>PURPOSE: To investigate dose escalation of oral paclitaxel in combination with dose increment and scheduling of cyclosporine (CsA) to improve the systemic exposure to paclitaxel and to explore the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT).<\/jats:p><jats:p>PATIENTS AND METHODS: A total of 53 patients received, on one occasion, oral paclitaxel in combination with CsA, coadministered to enhance the absorption of paclitaxel, and, on another occasion, intravenous paclitaxel at a dose of 175 mg\/m<jats:sup>2<\/jats:sup>as a 3-hour infusion.<\/jats:p><jats:p>RESULTS: The main toxicities observed after oral intake of paclitaxel were acute nausea and vomiting, which reached DLT at the dose level of 360 mg\/m<jats:sup>2<\/jats:sup>. Dose escalation of oral paclitaxel from 60 to 300 mg\/m<jats:sup>2<\/jats:sup>resulted in significant but less than proportional increases in the plasma area under the concentration-time curve (AUC) of paclitaxel. The mean AUC values \u00b1 SD after 60, 180, and 300 mg\/m<jats:sup>2<\/jats:sup>of oral paclitaxel were 1.65 \u00b1 0.93, 3.33 \u00b1 2.39, and 3.46 \u00b1 1.37 \u03bcmol\/L\u00b7h, respectively. Dose increment and scheduling of CsA did not result in a further increase in the AUC of paclitaxel. The AUC of intravenous paclitaxel was 15.39 \u00b1 3.26 \u03bcmol\/L\u00b7h.<\/jats:p><jats:p>CONCLUSION: The MTD of oral paclitaxel was 300 mg\/m<jats:sup>2<\/jats:sup>. However, because the pharmacokinetic data of oral paclitaxel, in particular at the highest doses applied, revealed nonlinear pharmacokinetics with only a moderate further increase of the AUC with doses up to 300 mg\/m<jats:sup>2<\/jats:sup>, the oral paclitaxel dose of 180 mg\/m<jats:sup>2<\/jats:sup>in combination with 15 mg\/kg oral CsA is considered most appropriate for further investigation. The safety of the oral combination at this dose level was good.<\/jats:p>","DOI":"10.1200\/jco.2000.18.12.2468","type":"journal-article","created":{"date-parts":[[2017,2,24]],"date-time":"2017-02-24T09:09:58Z","timestamp":1487927398000},"page":"2468-2475","source":"Crossref","is-referenced-by-count":74,"title":["Phase I and Pharmacokinetic Study of Oral Paclitaxel"],"prefix":"10.1200","volume":"18","author":[{"given":"Mirte M.","family":"Malingr\u00e9","sequence":"first","affiliation":[{"name":"From the Department of Medical OncologyThe Netherlands Cancer Institute\/Antoni van Leeuwenhoek Hospital, and Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute\/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, the Netherlands; and Baker Norton Pharmaceuticals, Miami, FL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jetske M. Meerum","family":"Terwogt","sequence":"additional","affiliation":[{"name":"From the Department of Medical OncologyThe Netherlands Cancer Institute\/Antoni van Leeuwenhoek Hospital, and Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute\/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, the Netherlands; and Baker Norton Pharmaceuticals, Miami, FL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos H.","family":"Beijnen","sequence":"additional","affiliation":[{"name":"From the Department of Medical OncologyThe Netherlands Cancer Institute\/Antoni van Leeuwenhoek Hospital, and Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute\/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, the Netherlands; and Baker Norton Pharmaceuticals, Miami, FL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilde","family":"Rosing","sequence":"additional","affiliation":[{"name":"From the Department of Medical OncologyThe Netherlands Cancer Institute\/Antoni van Leeuwenhoek Hospital, and Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute\/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, the Netherlands; and Baker Norton Pharmaceuticals, Miami, FL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franciska J.","family":"Koopman","sequence":"additional","affiliation":[{"name":"From the Department of Medical OncologyThe Netherlands Cancer Institute\/Antoni van Leeuwenhoek Hospital, and Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute\/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, the Netherlands; and Baker Norton Pharmaceuticals, Miami, FL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"van Tellingen","sequence":"additional","affiliation":[{"name":"From the Department of Medical OncologyThe Netherlands Cancer Institute\/Antoni van Leeuwenhoek Hospital, and Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute\/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, the Netherlands; and Baker Norton Pharmaceuticals, Miami, FL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Duchin","sequence":"additional","affiliation":[{"name":"From the Department of Medical OncologyThe Netherlands Cancer Institute\/Antoni van Leeuwenhoek Hospital, and Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute\/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, the Netherlands; and Baker Norton Pharmaceuticals, Miami, FL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim W. Ten Bokkel","family":"Huinink","sequence":"additional","affiliation":[{"name":"From the Department of Medical OncologyThe Netherlands Cancer Institute\/Antoni van Leeuwenhoek Hospital, and Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute\/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, the Netherlands; and Baker Norton Pharmaceuticals, Miami, FL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Swart","sequence":"additional","affiliation":[{"name":"From the Department of Medical OncologyThe Netherlands Cancer Institute\/Antoni van Leeuwenhoek Hospital, and Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute\/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, the Netherlands; and Baker Norton Pharmaceuticals, Miami, FL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Lieverst","sequence":"additional","affiliation":[{"name":"From the Department of Medical OncologyThe Netherlands Cancer Institute\/Antoni van Leeuwenhoek Hospital, and Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute\/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, the Netherlands; and Baker Norton Pharmaceuticals, Miami, FL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan H. M.","family":"Schellens","sequence":"additional","affiliation":[{"name":"From the Department of Medical OncologyThe Netherlands Cancer Institute\/Antoni van Leeuwenhoek Hospital, and Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute\/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, the Netherlands; and Baker Norton Pharmaceuticals, Miami, FL."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"233","reference":[{"key":"R1-0321","doi-asserted-by":"publisher","DOI":"10.3109\/07357909509031919"},{"key":"R2-0321","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199504133321507"},{"key":"R3-0321","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1990.8.7.1263"},{"key":"R4-0321","doi-asserted-by":"publisher","DOI":"10.2165\/00044011-199714050-00011"},{"key":"R5-0321","doi-asserted-by":"crossref","unstructured":"Dye D, Watkins J: Suspected anaphylactic reaction to Cremophor EL. BMJ 280:1353,1980","DOI":"10.1136\/bmj.280.6228.1353"},{"key":"R6-0321","doi-asserted-by":"publisher","DOI":"10.1177\/106002809402800101"},{"key":"R7-0321","doi-asserted-by":"publisher","DOI":"10.1006\/phrs.1998.0326"},{"key":"R8-0321","doi-asserted-by":"publisher","DOI":"10.1006\/scbi.1997.0068"},{"key":"R9-0321","doi-asserted-by":"crossref","unstructured":"Fisher GA, Lum BL, Hausdorff J, et al: Pharmacological considerations in the modulation of multidrug resistance. Eur J Cancer 32A:1082,1996-1088,","DOI":"10.1016\/0959-8049(96)00111-6"},{"key":"R10-0321","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.5.2031"},{"key":"R11-0321","unstructured":"Rowinsky EK, Wright M, Monsarrat B, et al: Clinical pharmacology and metabolism of Taxol (paclitaxel): Update 1993. Ann Oncol 5:S7,1994-S16, (suppl 6)"},{"key":"R12-0321","doi-asserted-by":"crossref","unstructured":"Sonnichsen DS, Liu Q, Schuetz EG, et al: Variability in human cytochrome P450 paclitaxel metabolism. J Pharmacol Exp Ther 275:566,1995-575,","DOI":"10.1016\/S0022-3565(25)12102-2"},{"key":"R13-0321","doi-asserted-by":"crossref","unstructured":"Walle T, Walle K, Kumar GN, et al: Taxol metabolism and disposition in cancer patients. Drug Metab Dispos 23:506,1995-512,","DOI":"10.1016\/S0090-9556(25)06589-4"},{"key":"R14-0321","unstructured":"Van Asperen J, Van Tellingen O, Van der Valk MA, et al: Enhanced oral absorption and decreased elimination of paclitaxel in mice cotreated with cyclosporin A. Clin Cancer Res 4:2293,1998-2297,"},{"key":"R15-0321","doi-asserted-by":"crossref","unstructured":"Meerum Terwogt JM, Beijnen JH, ten Bokkel Huinink WW, et al: Co-administration of cyclosporin enables oral therapy with paclitaxel. Lancet 352:285,1998","DOI":"10.1016\/S0140-6736(98)24030-X"},{"key":"R16-0321","unstructured":"Meerum Terwogt JM, Malingr\u00e9 MM, Beijnen JH, et al: Co-administration of cyclosporin A enables oral therapy with paclitaxel. Clin Cancer Res 5:3379,1999-3384,"},{"key":"R19-0321","doi-asserted-by":"publisher","DOI":"10.2165\/00044011-199509060-00005"},{"key":"R20-0321","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4347(95)00308-8"},{"key":"R21-0321","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4347(94)00477-M"},{"key":"R22-0321","doi-asserted-by":"publisher","DOI":"10.1097\/00007691-199202000-00007"},{"key":"R23-0321","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4347(95)00544-7"},{"key":"R26-0321","doi-asserted-by":"crossref","unstructured":"Huizing MT, Keung AC, Rosing H, et al: Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients. J Clin Oncol 11:2117,1993-2135,","DOI":"10.1200\/JCO.1993.11.11.2127"},{"key":"R27-0321","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1997.15.1.317"},{"key":"R28-0321","doi-asserted-by":"publisher","DOI":"10.1177\/107815529800400304"},{"key":"R30-0321","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1993.11.2.374"},{"key":"R31-0321","doi-asserted-by":"publisher","DOI":"10.1007\/BF00685793"},{"key":"R32-0321","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199120060-00001"},{"key":"R33-0321","doi-asserted-by":"publisher","DOI":"10.1007\/s002800051055"},{"key":"R34-0321","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1995.13.1.180"},{"key":"R35-0321","doi-asserted-by":"publisher","DOI":"10.1097\/00001813-199601000-00009"},{"key":"R36-0321","unstructured":"Sparreboom A, Van Tellingen O, Nooijen WJ, et al: Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor EL. Cancer Res 56:2112,1996-2115,"},{"key":"R37-0321","unstructured":"Sparreboom A, Van Zuylen L, Brouwer E, et al: Cremophor EL-mediated alteration of paclitaxel distribution in human blood: Clinical pharmacokinetic implications. Cancer Res 59:1454,1999-1457,"},{"key":"R38-0321","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6690696"}],"container-title":["Journal of Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascopubs.org\/doi\/pdfdirect\/10.1200\/JCO.2000.18.12.2468","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,15]],"date-time":"2025-06-15T17:47:31Z","timestamp":1750009651000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascopubs.org\/doi\/10.1200\/JCO.2000.18.12.2468"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,6,12]]},"references-count":33,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2000,6,12]]}},"alternative-id":["10.1200\/JCO.2000.18.12.2468"],"URL":"https:\/\/doi.org\/10.1200\/jco.2000.18.12.2468","relation":{},"ISSN":["0732-183X","1527-7755"],"issn-type":[{"value":"0732-183X","type":"print"},{"value":"1527-7755","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,6,12]]}}}