Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model.
OBJECTIVE
To investigate the potential of a model for chemotherapy-induced myelosuppression to predict the full time-course of myelosuppression in patients based on rat data.


METHODS
White blood cell counts were determined in rats after administration of 5-fluorouracil, epirubicin, cyclophosphamide, docetaxel, paclitaxel or etoposide. Pharmacokinetic models were used to predict the concentration-time profile in each rat. A semi-physiological model of myelosuppression was applied to the rat data. The drug-related parameter Slope was allowed to differ between drugs. The analysis was performed in NONMEM VI. Time-courses of myelosuppression in patients were predicted for each drug based on patient pharmacokinetic models, typical system-related parameters previously determined in patients and the rat Slope estimates in the present study.


RESULTS
The semi-physiological model of myelosuppression fit the rat data well and the estimated maturation time in rats (53 h) was approximately half of the previous estimate in patients. The relative difference in Slope estimates for rats and patients based on total drug concentrations ranged between 28% to 8-fold for the six drugs. The differences reduced to 8-37% for all drugs when correcting the rat Slope estimates for species difference in protein binding and in CFU-GM assay sensitivity.


CONCLUSIONS
This method for interspecies scaling was successful in predicting the time-course of myelosuppression in patients based on rat data. Predictions improved when species differences in protein binding and CFU-GM assay sensitivity were accounted for. The approach appears promising for predicting myelosuppression in patients early in development.
Friberg
Lena E
LE
Department of Pharmaceutical Biosciences, Uppsala University, SE-75124, Uppsala, Sweden. lena.friberg@farmbio.uu.se
Sandström
Marie
M
Karlsson
Mats O
MO
D000818:Animals; D003198:Computer Simulation; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D022423:Myeloid Cells / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D007166:Immunosuppressive Agents