title: Population pharmacokinetics of cyclophosphamide and its metabolites 4-hydroxycyclophosphamide, 2-dechloroethylcyclophosphamide, and phosphoramide mustard in a high-dose combination with Thiotepa and Carboplatin.
abstract: The anticancer prodrug cyclophosphamide (CP) is activated by the formation of 4-hydroxycyclophosphamide (4OHCP), which decomposes into phosphoramide mustard (PM). This activation pathway is inhibited by thiotepa. CP is inactivated by formation of 2-dechloroethylcyclophosphamide (2DCECP). The aim of this study was to develop a population pharmacokinetic model describing the complex pharmacokinetics of CP, 4OHCP, 2DCECP, and PM when CP is administered in a high-dose combination with thiotepa and carboplatin. Patients received a combination of CP (1000-1500 mg/m/d), carboplatin (265-400 mg/m/d), and thiotepa (80-120 mg/m/d) administered in short infusions over 4 days. Twenty blood samples were collected per patient per course. Concentrations of CP, 4OHCP, 2DCECP, PM, thiotepa, and tepa were determined in plasma. Using NONMEM, an integrated population pharmacokinetic model was used to describe the pharmacokinetics of CP, 4OHCP, 2DCECP, and PM, including the already described processes of autoinduction of CP and the interaction with thiotepa. Data were available on 35 patients (70 courses). The pharmacokinetics of CP were described with a 2-compartment model, and those of 4OHCP, 2DCECP, and PM with 1-compartment models. Before onset of autoinduction, it was assumed that CP is eliminated through a noninducible pathway accounting for 20% of total CP clearance, whereas 2 inducible pathways resulted in formation of 4OHCP (75%) and 2DCECP (5%). It was assumed that 4OHCP was fully converted to PM. Induction of CP metabolism was mediated by 2 hypothetical amounts of enzyme whose quantities increased in time in the presence of CP (kenz=0.0223 and 0.0198 hours). Induction resulted in an increased formation of 4OHCP (approximately 50%), PM (approximately 50%), and 2DCECP (approximately 35%) during the 4-day course, and concomitant decreased exposure to CP (approximately 50%). The formation of 2DCECP was not inhibited by thiotepa. Apparent volumes of distribution of CP, PM, and 2DCECP could be estimated being 43.7, 55.5, and 18.5 L, respectively. Exposure to metabolites varied up to 9-fold. The complex population pharmacokinetics of CP, 4OHCP, 2DCECP, and PM in combination with thiotepa and carboplatin has been established and may form the basis for further treatment optimization with this combination.
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, and Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. apmil@slz.nl
authors.forename: Milly E
authors.initials: ME
authors.lastname: de Jonge
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.forename: Selma M
authors.initials: SM
authors.lastname: van Dam
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Rodenhuis
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D016190:Carboplatin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010752:Phosphoramide Mustards / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics; D013852:Thiotepa / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D013997:Time Factors; D013721:Triethylenephosphoramide / Q000097:blood
chemical_list: C440781:2-dechloroethylcyclophosphamide; D010752:Phosphoramide Mustards; D011355:Prodrugs; C030090:phosphoramide mustard; C012358:4-hydroxycyclophosphamide; D003520:Cyclophosphamide; D013852:Thiotepa; D016190:Carboplatin; D013721:Triethylenephosphoramide