Comparison of Inter-Occasion and Inter-Individual Variability in Chemotherapy- Induced Myelosuppression
Emma K. Hansson(1), Johan Wallin(1), Marie Sandström(1,2), Mats O. Karlsson(1), Lena E. Friberg(1)
(1)Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy, Uppsala University, Uppsala Sweden; (2)AstraZeneca R&D, Södertälje, Sweden
Objectives: A semi-physiological model of chemotherapy-induced myelosuppression has previously been developed and applied to several different anticancer drugs. Consistency in system-related parameter estimates and inter-individual variability (IIV) have been reported across drug . A requirement for the model to be a useful tool for individual dose adjustments based on neutrophil counts [2, 3] is relatively low variability between treatment courses (IOV) in relation to IIV. The aim of this study was to evaluate and compare magnitudes of IOV and IIV in myelosuppression model parameters across six different data sets.
Methods: Neutrophil counts from several treatment courses were available following therapy with paclitaxel, epirubicin + docetaxel, 5-fluorouracil + epirubicin + cyclophoshamide, topotecan, etoposide and docetaxel. One occasion was defined as one course. The PK were described using individual [4, 5, 6, 7, 8] or population  PK parameters. IOV in PK was not available. The semi-physiological myelosuppression model  was fitted to the neutrophil observations using the FOCE method in NONMEM VI. The subroutine PRIOR was used to estimate separate drug effect parameters (Slope) for the co-administered drugs. The data were Box-Cox transformed with a factor 0.2 to obtain symmetrically distributed residuals around zero and the half life of neutrophils was fixed to 7 hours. IOV in baseline neutrophil count (Base), mean transit time (MTT) and Slope were evaluated for statistical significance (P < 0.001).
Results: IOV in MTT was significant for all the investigated datasets except for topotecan and ranged from 8-16 % (CV). For etoposide and docetaxel IOV in Slope was also found significant with an estimated CV of 40 and 19 %, respectively. For topotecan IOV in Slope and Base (CV of 29 and15%, respectively) was significant. The estimated overall IOV were clearly lower than IIV in all cases. By inclusion of IOV the residual errors decreased on average by 10 %.
Conclusions: For all six investigated datasets of chemotherapy-induced myelosuppression, the overall IOV was estimated to be lower than the overall IIV. The limited IOV in relation to IIV in the myelosuppression model parameters indicate that the semi-physiological model has potential as a tool for individual dose adjustment based on neutrophil counts for which a tool is under development .
 Friberg LE., et al., J Clin Oncol; 20:4713-21, 2002.
 Wallin J., et al., PAGE 15 (2006) Abstr 966 [www.page-meeting.org/?abstract=966].
 Wallin J., et al., PAGE 15 (2007) Abstr 1169 [www.page-meeting.org/?abstract=1169].
 Henningsson A., et al., Eur J Cancer; 39:1105-1114, 2003.
 Sandström M., et al., J Clin Oncol; 23:413-21, 2005.
 Sandström M., et al., J Clin Oncol; 58:143-56, 2006.
 Toffoli G., et al., J Clin Pharmacol; 52:511-519, 2001.
 Legér F., et al., British J Cancer 90:343-347, 2004.
 Bruno R., et al., J Pharmacokinet Biopharm; 24:153-72, 1996.