1. Background Objectives Data Simulation in human Conclusion -F14512, a polyamine-vectorized anti-cancer drug which combines an epipodophyllotoxin core targeting topoisomerase II with a spermine moiety as a tumor cell-delivery vector [1]. -Currently in clinical phase II study in combination with aracytine for patients with acute myeloid leukemia, F14512 was also investigated in ovarian cancer patients. -In parallel, F14512 is tested in pet dogs with naturally occuring lymphoma [2]. [1] Barret JM et al. Cancer Res. 2008 Dec 1;68(23):9845-53. [2] Tierny F et al. Submitted in Clinical Cancer Research- Under review. [3] Friberg LE et al. 2010 Dec;28(6):744-53.. [4] Friberg LE et al 2002 Dec 15;20(24):4713-21. References The aim of the present study was to retrospectively assess the human predictability of semi-physiological leukopenia PK/PD models built on rats, Beagle laboratory dogs and pet dogs. Model building A same semi-physiological PK/PD model of leukopenia was used to fit the data of the 3 groups of animals (rat, beagle dogs and pet dogs) separately. [3] Estimate (RSE %) RatBeagle dogPet Dogs Typical values WBC 0 (x 10 9 /L) 14.8 (2 %)7.51 (3 %)10.9 (9 %) MTT (h) 74.7 (10 %)77.1 (4 %)63.6 (6 %) γ 0.149 FIX [4] 0.2 FIX0.15 (13 %) Slope (L/mg) 5.12 (7%)59.3 (10 %)48.1 (14 %) Inter individual variabilities, CV (%) WBC 0 18.5 % (21%)15.5 % (58 %)32 % (28 %) MTT --12.4 % (57 %) Slope --52.4 % (33 %) Residual variability, CV% Prop. PD error 18.1 % (10%)25.2 % (20%)44.2 % (12 %) Models Estimated Slope from Animal (L/mg) fu human / fu animal Fu corrected predicted Slope in human (L/mg) IC90 animal /IC90 human Fu and sensivity corrected predicted Slope in human (L/mg) Rat5.120.2641.350.5940.817 Beagle dog59.30.29117.30.2324.01 Pet dog48.10.29114.00.2323.24 Human21.4- - Protein binding study in vitro stem cells study Simulation with rat slope Simulation with Beagle dog slope Simulation with Pet dog slope - Actual myelosuppression in human was considerably under-estimated by the rat model - Both Pet / Beagle dogs models with fu correction provided a good prediction of human leukopenia induced by F14512 - Considering correction for inter species differences in bone marrow sensitivity would have resulted in a large under-prediction of the human myelosuppression - PK/PD models based on larger species such as pet dogs may be a useful translational tool and its application in better predicting hematotoxicity in FIH trials can be valuable. 5 mg/m 2 /QD for 3 days 10 mg/m 2 /QD for 3 days Median of simulations Median of observations P5, P95 of simulations Observed data VPC - Rat model RatsBeagle dogsPet dogs Studies1 PK/PD3 toxicity1 clinical Schedule QD : once a day ; BID : twice daily ; SD : single dose SDQDBID SD and repeated doses (2/weeks) QD for 3 days every 2 weeks Administration routeiv bolus iv infusion (3h) Doses (mg/kg)1; 2; 30.4 ; 0.7 From 0.03 to 0.85From 0.05 to 0.085 Number of animals844623 Number of observations364189405 Ratio of unbound fraction human / animal 0.2640.291 Ratio of IC90 animal/human * 0.5940.232 Observed WBC counts in 11 patients included in a phase I ovarian cancer study where F14512 was administered as a 3h infusion once daily for 3 days System (physiological) parameters : - MTT = 4/ktr (Kprol=kcirc=ktr) - WBC 0 =baseline of WBC - γ=Feed back Drug dependant parameter : - Slope Structure of the PK-PD model describing chemotherapy induced myelosuppression Simulations were performed considering - data from the 11 patients included in the ovarian cancer study: -Individual baseline values of WBC -Individual PK parameters (EBE obtained with the post hoc options) -System related parameters of the PK/PD models previously established: -MTT=125 h (IIV,CV=26 %) and γ=0.17 [4] -Slopes estimated with PK/PD modeling in animals (IIV,CV=45%) and adjusted with the unbound fraction but without considering the inter-species in vitro sensivity results * Results of an in vitro evaluation of F14512 haematotoxicity on CFU-GM hematopoietic progenitor VPC – Beagle dog modelVPC – Pet dog model PK/PD sequential strategy :  Population PK parameters for rat and beagle dogs models  Individual PK parameters for Pet Dog model Nonmem 7.2 FOCE method Log transformed data SD Doses : 0.1 and 0.35 mg/kg 2 / week Doses : 0.03; 0.1; 0.35 Admin days : 1–5–25-29-33 Doses : 0.1-0.35-0.03-0.6-0.85 mg/kg Admin days : 1–5–15 Dose 0.5 mg/kg Prediction interval of simulations in black Observed values in blue Inter-species comparison of semi-physiological pre-clinical PK/PD models to better predict the time course of myelosuppression in human: application to a novel vectorized epipodophyllotoxin (F14512) A. Petain (1), B. Gomes (1), D. Tierny (2), A. Bidaut (1), P. Ferre (1) and L. Nguyen (1) (1) Institut de Recherche Pierre Fabre, Research & Development center, Toulouse, France (2) Oncovet Clinical research, Villeneuve d’Ascq, France