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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.

Central venous access catheters are commonly used in clinical oncology. The double lumen variant is applied in pharmacokinetic studies for simultaneous administration and blood sampling when frequent blood collections are necessary. Occlusion of one lumen, a common complication, necessitates the investigator perform blood sampling through the administration lumen after interrupting the infusion. Plasma concentrations measured in this sample can be influenced by sorption of the previously infused compound to the catheter lumen. In this study, the quality of cyclophosphamide, thiotepa, and carboplatin plasma concentrations is investigated when sampling is performed through the administration lumen.

Thiotepa is an alkylating agent widely used in high-dose chemotherapy. The pharmacokinetics of thiotepa and its main metabolite tepa show a wide interpatient variability, which may be responsible for the interpatient variability in toxicity. The aim of this study was to develop and validate a pharmacokinetically guided dosing strategy with the sum of the thiotepa and tepa area under the concentration-time curve (AUC) as the target parameter. A total of 46 patients received 77 courses of chemotherapy with thiotepa (80-120 mg/m(2) per day) divided into two daily 30-minute infusions in combination with cyclophosphamide and carboplatin. Patients received up to three courses of chemotherapy. The interpatient, course-to-course, day-to-day, and residual variability in the pharmacokinetics of thiotepa and tepa were estimated with a population analysis with the software program NONMEM. The planned strategy consisted of the collection of blood samples on day 1 and either day 3 or day 4 of each 4-day course. The thiotepa dose was planned to be adjusted on day 3 of each course and before the start of a new course on the basis of Bayesian predictions of the pharmacokinetics with data of day 1 and/or the possible previous course. The prediction procedure was validated by dividing the dataset into an index and validation set. The Bayesian predictions of the validation set were compared with true AUC values generated with individual fits of each course. The performance of the complete strategy was tested with a simulation procedure in 1,000 patients. Interpatient variability and course-to-course variability were in the same order (+/-20%); day-to-day variability was less (+/-15%). The sampling strategy resulted in predictions of the AUC without bias with acceptable precision (+/-20%). The simulation showed that variability in exposure was effectively decreased by the dosing strategy. This strategy resulted in a reduction in the variability of the exposure to thiotepa and tepa and can be implemented in a clinical study.