title: Pharmacokinetics of cyclophosphamide and thiotepa in a conventional fractionated high-dose regimen compared with a novel simplified unfractionated regimen.
abstract: High-dose alkylating chemotherapy with cyclophosphamide (4000 or 6000 mg/m2) and thiotepa (320 or 480 mg/m2) has commonly been administered in a fractionated regimen over 4 days. A simplified unfractionated regimen would be preferable, especially because cyclophosphamide and thiotepa have been shown to influence the metabolism of each other. However, altering a dose regimen can have a profound effect on the pharmacokinetics of the compounds involved. The aim of this study was to investigate the effect of altering the fractionated administration schedule of the CTC regimen on cyclophosphamide and thiotepa pharmacokinetics. Plasma samples were collected from 124 patients who received a fractionated tiny CTC or CTC regimen of cyclophosphamide (1000 or 1500 mg m(-2) d(-1)), thiotepa (40 or 60 mg/m2 twice daily), and carboplatin (267 or 400 mg m(-2) day(-1)) for 4 days, and 16 patients who received an unfractionated mini CTC regimen of cyclophosphamide (3000 mg/m2 at day 1), carboplatin (400 mg/m2 at days 1 and 2), and thiotepa (250 mg/m2 at day 2). Plasma concentrations of cyclophosphamide and 4-hydroxycyclophosphamide were determined using high-performance liquid chromatography coupled with tandem mass spectrometric detection; plasma concentrations of thiotepa and tepa were determined using gas chromatography. Pharmacokinetics of cyclophosphamide and thiotepa were assessed using nonlinear mixed-effect modeling. The study showed that alteration of a fractionated high-dose regimen into a simplified unfractionated regimen resulted in saturation of thiotepa elimination, with a Vmax of 212 (+/-58) micromol/h and a Km of 13.7 (+/-5.9) microM. This resulted in an increased dose-corrected exposure to thiotepa (13%) and decreased dose-corrected exposure to its metabolite tepa (21%). Elimination of cyclophosphamide was not shown to be saturable. Dose-corrected exposures to cyclophosphamide and its active metabolite 4-hydroxycyclophosphamide were comparable in both regimens. Because the simplified unfractionated mini CTC regimen was more patient-friendly and because overall dose-corrected exposures to cyclophosphamide and thiotepa were not affected to a relevant extent, our data suggest that this unfractionated regimen can be used safely in future studies.
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands. corine.ekhart@slz.nl
authors.forename: Corine
authors.initials: C
authors.lastname: Ekhart
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Rodenhuis
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001711:Biotransformation; D001943:Breast Neoplasms / Q000188:drug therapy; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D003520:Cyclophosphamide / Q000008:administration & dosage; D005100:Expectorants / Q000627:therapeutic use; D005260:Female; D005544:Forecasting; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D015080:Mesna / Q000627:therapeutic use; D015233:Models, Statistical; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy; D013736:Testicular Neoplasms / Q000188:drug therapy; D013852:Thiotepa / Q000008:administration & dosage
chemical_list: D018906:Antineoplastic Agents, Alkylating; D005100:Expectorants; D003520:Cyclophosphamide; D013852:Thiotepa; D015080:Mesna