Llopis MC(1,3), Pérez-Ruixo JJ(1), Medina C(1), Azagra P(2), Casabó VG(2); Jiménez NV(1,3).
1Servicio de Farmacia. Hospital Universitario Dr Peset. Valencia; 2Servicio de Oncologia y Hematologia. Hospital Clinico Universitario. Valencia; 3Departamento de Farmacia y TecnologÃa Farmacéutica. Universidad de Valencia.
Background: High dose chemotherapy (HDCT) and peripheral blood stem cell transplantation (PBSCT) is a therapeutic strategy that seems improve disease free survival and overall survival in high risk breast cancer patients. Cyclophosphamide (CP) is one of the cytotoxic drugs most commonly used in HDCT prior to PBSCT. CP is an alkylating agent that requires biotransformation to produce the cytotoxic drug 4-hydroxycyclophosphamide (4OHCP).
Objective: To characterize population pharmacokinetics of high dose of CP in high risk breast cancer pacients.
Patients and Methods: 50 females with high risk breast cancer diagnosis, aged (mean± SD) 46.6± 8.6 years, weighted 70.59± 12.1 kg, and normal renal and hepatic funcion were included in the study. Patients received a STAMP-V protocol of HDCT: cyclophosphamide 6 g/m2, thiotepa 500 mg/m2 and carboplatin 800 mg/m2 administered in intravenous continuos infusion of 96 hours and PBSCT was performed three days later. Blood samples were drawn at the 6, 24, 48, 72, 96, 97 and 99 hours since begin continuos infusion, plasma was separated and stored at -20ºC until assayed for CP and 4-OHCP using a validated high performace liquid chromatography procedure. In 24 of 50 patients, CP and 4OHCP have been assayed and 26 patients remaining only CP .To characterize the pharmacokinetic behaviour of CP and 4OHCP we have used the following model:
dCCP/dt = K0-(CLCP/VCP)·CCPand CLCP = CL0+CLs·t
dC4OHCP/dt = (CLCP/V4OHCP)·CCP – (CLm/V4OHCP)·C4OHCP
in wich K0 is the rate of infusion, CLCP is the time-dependent elimination clearance of CP and the formation clearance of 4OHCP from CP, CLm is the elimination clearance of 4OHCP, VCP and V4OHCP are the apparent volumes of distribution of CP and 4OHCP respectively, and CCP and C4OHCP are plasma concentrations of CP and 4OHCP at time t. Since the bioavailability of 4OHCP was unknow, only fractional clearance rate (CLm/F) could be estimated while and equal value for VCP and V4OHCP was assumed. The interindividual and residual variabilities were modeled with and exponential error model. The estimation of population pharmacokinetic parameter was performed by NONMEM program.
Results:
Table I. Population pharmacokinetic parameters of CP and 4OHCP
| Parameter | Mean (S.E.) | Variability % (S.E.) |
| CLCP (L/h) | – | 23.5 (10.4) |
| CL0 (L/h) | 2.29 (0.13) | – |
| CLs (L/h2) | 0.0095 (0.0019) | – |
| CLm (L/h) | 174 (40.1) | 70.1 (48.4) |
| VCP (L) | 24.9 (3.1) | 67.6 (40.0) |
| Sigma CP | – | 17.4 (7.2) |
| Sigma 4OHCP | – | 52.8 (36.5) |
Conclusion: The analysis of population pharmacokinetic behaviour of CP administered in high dose can be used such a prior information in order to get an individualized dose by bayesian forecasting.
Reference: PAGE 8 (1999) Abstr 159 [www.page-meeting.org/?abstract=159]
Poster: poster