Scaling the Time-Course of Myelosuppression from Rats to Patients with a Semi-Physiological Model
Lena E. Friberg* (1), Marie Sandström (1,2), Mats O. Karlsson (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
Objectives: We have earlier developed a model for chemotherapy-induced myelosuppression based on patient data that shows similar system-related parameters across drugs but the drug-related parameter estimates, related to drug potency, differed as expected [1]. The aim of the present study was to explore if drug-related parameter estimates are of comparable magnitudes in rats and patients. If similarities exist, it would be possible to early in development predict the full time-course of myelosuppression in patients based on rat PK and myelosuppression data, human PK predictions and previously determined system-related parameters in patients.
Methods: White blood cell counts (WBC) were determined in rats after administration of 5-fluoruracil (5-FU), epirubicin, cyclophosphamide (CP), docetaxel, paclitaxel or etoposide. Individual or typical population PK parameters were used to predict the drug concentration-time profile in each rat. The myelosuppression model [1] was applied to all data simultaneously, allowing only the drug-related parameter Slope to differ between drugs. Information on species differences in protein binding and in CFU-GM assay sensitivity [2] were taken from the literature. The analysis was performed using FOCE in NONMEM VI. Time-courses in patients were predicted based on patient PK models, typical system-related parameters [1] and rat Slope estimates.
Results: The myelosuppression model fit the rat data adequately although the fit improved when the drugs affected all cell types. The maturation time was approximately half of the estimate in patients while the feedback parameter was of similar magnitude. The relative difference in Slope estimates for rats and patients [1,3,4] based on total drug concentrations ranged between 28% to 7-fold for the 6 drugs. For 5-FU and CP the differences clearly reduced when correcting for species differences in IC90 ratios in the CFU-GM assay. For etoposide the 10-fold species difference in protein binding was important to consider. Following correction, the relative differences in Slope values were ≤ 50% for all drugs.
Conclusions: The estimated drug-related parameters in rats could successfully be used to predict the time-course of myelosuppression in patients. Accounting for species differences in protein binding and in vitro sensitivity improved the predictions. This scaling approach may also be promising early in development to predict combination therapies and schedule dependence of myelosuppression.
References:
[1] Friberg LE, Henningsson A, Maas H, Nguyen L and Karlsson MO (2002) Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol 20:4713-4721.
[2] Pessina A, Albella B, Bueren J, Brantom P, Casati S, Gribaldo L, Croera C, Gagliardi G, Foti P, Parchment R, Parent-Massin D, Sibiril Y and Van Den Heuvel R (2001) Prevalidation of a model for predicting acute neutropenia by colony forming unit granulocyte/macrophage (CFU-GM) assay. Toxicol In Vitro 15:729-740
[3] Sandstrom M, Lindman H, Nygren P, Johansson M, Bergh J and Karlsson MO (2006) Population analysis of the pharmacokinetics and the haematological toxicity of the fluorouracil-epirubicin-cyclophosphamide regimen in breast cancer patients. Cancer Chemother Pharmacol 58:143-156.
[4] Sandstrom M, Lindman H, Nygren P, Lidbrink E, Bergh J and Karlsson MO (2005) Model describing the relationship between pharmacokinetics and hematologic toxicity of the epirubicin-docetaxel regimen in breast cancer patients. J Clin Oncol 23:413-421
