Semi-mechanistic PKPD model for neutropenia using K-PD model in patients receiving high dose of chemotherapy
Ramůn-Lůpez A. (1), Nalda-Molina R. (1), Valenzuela B. (1), Pťrez Ruixo J.J.(2)
(1)Pharmacy and Pharmaceutics Division, Department of Engineering, Faculty of Pharmacy, Miguel HernŠndez University, Spain.(2) Clinical Pharmacology & Experimental Medicine Division, Johnson & Johnson Pharmaceutical Research and Development. Beerse, Belgium (JJPR).
Background and Objectives: High dose chemotherapy (HDC) treatment has been used widely as adjuvant therapy in several types of cancer and is usually co-administered with autologous bone marrow transplantation or peripheral blood stem-cells transplantation (PBSCT). HDC and PBSCT are therapeutic strategies, which seems to improve disease free survival and overall survival in high risk breast cancer patients.
Neutropenia, together with thrombocytopenia and anemia are major causes of treatment-related complications following HDC and PBSCT. Because it is well known that complications are directly related to the time to reach short-term hematological recovery, several PKPD models have been used to predict the degree of haematological toxicity and time of recovery, with relative success.
The purpose of the current analysis is to model the time course of the absolute neutrophil count following administration of HDC, PBSCT and haematopoietic growth factors in breast cancer patients, using a semi-mechanistic model implemented in NONMEM.
Methods: A population pharmacokinetic and pharmacodinamic analysis was performed using data from 41 patients with primary high risk breast cancer receiving an intravenous infusion of 96 hours of cyclophosphamide, thiotepa and carboplatin. The patients also received PBSCT at day 3 after the end of the infusion, and haematopoietic growth factors at day 4 or 8 after the end of the infusion.
A six compartments semi-mechanistic model was implemented in NONMEM, including system-related parameters as mean transit time in bone marrow (MTT), absolute neutrophil count at baseline (ANC0) and a feedback parameter. Due to the absence of pharmacokinetic data, a Ďkinetics of drug action' was used in order to characterize the treatment effect.
Age, body weight and concomitant administration of growth factors were explored as potential covariates. Firstly, the covariates were added to the system-related parameters separately and finally, the covariates that improved the analysis were included all together. PBSCT was included as structural part of the model, as a compartment.
Posterior predictive check and bootstrap was used to evaluate the model.
Results: Diagnostic plots of residual and weighted residual versus predicted, observed versus predicted, observed and predicted versus time will be showed in the poster. The inclusion of the haematopoietic growth factors was found to be significant, reducing the MTT by 77%, and increasing the generation of new cells rate by 99 % as well as improving the objective function.
Conclusions: This model was able to predict the extent and time course of neutropenia following HDC, PBSCT and haematopoietic growth factors without pharmacokinetic data and therefore, the time of recover from grade 4 neutropenia can be estimated through the model.
 Armitage, J. O. Bone marrow transplantation N.Engl.J.Med., 330: 827-838, 24-3-1994
 Friberg, L. E., Henningsson, A., Maas, H., Nguyen, L., and Karlsson, M. O. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs J.Clin.Oncol., 20: 4713-4721, 15-12-2002
 Nitz, U. A., Mohrmann, S., Fischer, J., Lindemann, W., Berdel, W. E., Jackisch, C., Werner, C., Ziske, C., Kirchner, H., Metzner, B., Souchon, R., Ruffert, U., Schutt, G., Pollmanns, A., Schmoll, H. J., Middecke, C., Baltzer, J., Schrader, I., Wiebringhaus, H., Ko, Y., Rosel, S., Schwenzer, T., Wernet, P., Hinke, A., Bender, H. G., and Frick, M. Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial Lancet, 366: 1935-1944, 3-12-2005
 Pillai, G., Gieschke, R., Goggin, T., Jacqmin, P., Schimmer, R. C., and Steimer, J. L. A semimechanistic and mechanistic population PK-PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis Br.J.Clin.Pharmacol., 58: 618-631, 2004
 Sandstrom, M., Lindman, H., Nygren, P., Johansson, M., Bergh, J., and Karlsson, M. O. Population analysis of the pharmacokinetics and the haematological toxicity of the fluorouracil-epirubicin-cyclophosphamide regimen in breast cancer patients Cancer Chemother.Pharmacol., 1-14, 8-2-2006