Pérez-Ruixo, JJ; Casabó, VG; Merino, M; Llopis, MC; Jiménez, NV.
Servicio de Farmacia Hospital Universitario Dr. Peset. Valencia. Departamento de Farmacia y Tecnologia Farmaceutica. Universidad de Valencia.
BACKGROUND: Time to hematologic recovery after mieloablative chemotherapy and peripheral blood stem-cell support is an important clinical outcome in breast cancer patients. In this study, a pharmacodynamic model describing the entire time course of neutropenia was developed and the influence of age, granulocyte colony-stimulating factor (G-CSF) administration and the CD34+ cell count to be reinfused was evaluated.
METHOD: 41 breast cancer patients with STAMP-V chemotherapy was included. Data on survival fraction of neutrophils was related to cyclophosphamide concentration-time profile, wich was described by one-compartment open pharmacokinetic model with time dependent systemic clearance. Pharmacodynamic mode was a indirect-response model, wich had two compartments corresponding to leukocytes in bone marrow and peripheral blood, respectively. Differentation statges of myeloid cells sensitive to cyclophosphamide were assumed, and their drug exposure during the sensitive period (SP) as a function of time and area under the curve concentration-time of cyclophosphamide was used to inhibit production rate of neutrophils in bone marrow (kin). The effect of G-CSF was modeled to stimulation of Kin and their migration rate to peripheral blood (kout). Influence os age and CD34+ cel count to be reinfused was evaluated. Fixed and random population pharmacokinetic and pharmacodynamic parameters were estimated by sequential nonlinear mixed effects model (NONMEM software). Model building was developed using the Mandema procedure (J Pharmacokinet Biopharma 1992; 20: 511-528).
RESULTS: Parameters estimated were lag time (LT) 124 hours before neutrophils count started to decline, exposure giving 50% inhibition of leukocyte production (AUCE50), 10.20 – 0.16 · Age ug·h/mL, and SP 186 hours. G-CSF increases Kin by 14.20 times and their Kout by 2.43 times. CD34+ cell count increase Kout by 10.0 times.
CONCLUSION: Our model was able to predict the time to neutrophils count recovery after mieloablatibe chemotherapy.
Reference: PAGE 9 (2000) Abstr 126 [www.page-meeting.org/?abstract=126]
Poster: poster