title: Sparse sampling design for therapeutic drug monitoring of sequentially administered cyclophosphamide, thiotepa, and carboplatin (CTC).
abstract: The alkylating agents cyclophosphamide, thiotepa, and carboplatin (CTC) are administered simultaneously in high-dose chemotherapy regimens. This regimen is sometimes complicated by severe organ toxicities, which may be caused by interindividual variability in the pharmacokinetics of the agents. Monitoring plasma levels and adapting doses may reduce variability in exposure to the compounds and their metabolites. The aim of this study was to develop and validate a sparse sampling design for routine dose individualization of cyclophosphamide, thiotepa, and carboplatin both during and between courses in the CTC regimen. Models describing the population pharmacokinetics of the prodrug cyclophosphamide (4000 or 6000 mg/m) and its activated metabolite 4-hydroxycylophosphamide, thiotepa (320 or 480 mg/m), and its equipotent metabolite tepa, and carboplatin (1067 or 1600 mg/m) in the 4-day CTC regimen have been developed previously using the program NONMEM. Based on these models, plasma concentrations were calculated in 20 groups of 50 simulated patients in each group during multiple courses of therapy, and the exposure, expressed as area under the plasma concentration-versus-time curve (AUC), was calculated. Subsequently, individual model-predicted AUCs were calculated for all courses, based on selected simulated plasma concentrations during the first course of therapy. Strategies were compared by assessment of their predictive performance of the AUC and their applicability in clinical practice. Withdrawal of 3 samples on the first day of the course at 190, 290, and 400 minutes after start of cyclophosphamide infusion resulted in unbiased and precise first course AUC predictions of 4-hydroxycylophosphamide, thiotepa and tepa, and carboplatin (precision [root mean squared relative prediction error, %RMSE] 20%, 16%, 8.8%, respectively). Applying this same strategy at day 3 (or 4) of the course, with an additional sample at 600 minutes on both days, resulted in unbiased and precise predictions of the AUC of a following course (%RMSE 21%, 18%, 17%, respectively). Prospective validation of the strategies in 23 additional patients yielded comparable results. It can be concluded that a good and useful sparse sampling design was developed for precise and accurate estimation of the AUCs of 4-hydroxycyclophosphamide, thiotepa and tepa, and carboplatin in the CTC regimen. This method is valuable in pharmacokinetically guided dose adaptation both during and between CTC courses.
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, 1066 EC, Amsterdam, 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: Sjoerd
authors.initials: S
authors.lastname: Rodenhuis
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood*; D016190:Carboplatin / Q000097:blood*; D003520:Cyclophosphamide / Q000097:blood*; D016903:Drug Monitoring / Q000379:methods*; D006801:Humans; D013852:Thiotepa / Q000097:blood*
chemical_list: D003520:Cyclophosphamide; D013852:Thiotepa; D016190:Carboplatin