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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 Background Simulation in human Objectives 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. Data Studies Rats Beagle dogs Pet dogs 1 PK/PD 3 toxicity 1 clinical SD and repeated doses (2/weeks) QD for 3 days every 2 weeks iv bolus iv infusion (3h) From 0.03 to 0.85 From 0.05 to 0.085 Schedule QD : once a day ; BID : twice daily ; SD : single dose SD QD Administration route BID iv bolus Doses (mg/kg) 1; 2; 3 0.4 ; 0.7 0.4 ; 0.7 Number of animals 84 46 23 Number of observations 364 189 405 Ratio of unbound fraction human / animal 0.264 0.291 0.291 Ratio of IC90 animal/human * 0.594 0.232 0.232 * Results of an in vitro evaluation of F14512 haematotoxicity on CFU-GM hematopoietic progenitor • 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 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 fuhuman / fu animal Fu corrected predicted Slope in human (L/mg) IC90animal /IC90human Fu and sensivity corrected predicted Slope in human (L/mg) 5.12 0.264 1.35 0.594 0.817 Beagle dog 59.3 0.291 17.3 0.232 4.01 Pet dog 48.1 0.291 14.0 0.232 3.24 Human 21.4 - 21.4 - 21.4 Models Estimated Slope from Animal (L/mg) Rat Protein binding study 5 mg/m2/QD for 3 days in vitro stem cells study 10 mg/m2/QD for 3 days Simulation with rat slope -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]. 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] Structure of the PK-PD model describing chemotherapy induced myelosuppression WBC0 WBC Circulating Kprol Proliferating Progenitors cells ktr ktr Transit Transit ktr Transit ktr Circulating WBC Effect = Slope x Conc Kcirc System (physiological) parameters : - MTT = 4/ktr (Kprol=kcirc=ktr) - WBC0=baseline of WBC - γ=Feed back Drug dependant parameter : - Slope F14512 PK model Estimate (RSE %) Rat 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 Observations 100 150 200 0 100 Time 200 300 10.9 (9 %) MTT (h) γ Slope (L/mg) 74.7 (10 %) 77.1 (4 %) 63.6 (6 %) 0.149 FIX [4] 0.2 FIX 0.15 (13 %) 5.12 (7%) 59.3 (10 %) 48.1 (14 %) Inter individual variabilities , CV (%) WBC0 MTT Slope 18.5 % (21%) 15.5 % (58 %) 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 SD Doses : 0.1 and 0.35 mg/kg 2 / week Doses : 0.03; 0.1; 0.35 400 BID (0.4 & 0.7 mg/kg) Observations Observations 10 200 7.51 (3 %) Time Once daily (0.4 & 0.7 mg/kg) 100 14.8 (2 %) 10 Time 0 WBC0 (x 109/L) 300 400 32 % (28 %) - - 12.4 % (57 %) - - 52.4 % (33 %) VPC – Beagle dog model SDDU (1,2&3 mg/kg) Observations 50 Typical values Prop. PD error 18.1 % (10%) 25.2 % (20%) 44.2 % (12 %) VPCRUN-214Rat model 0 Pet Dogs Residual variability, CV% Log transformed data Control Beagle dog Simulation with Pet dog slope Feedback loop = Simulation with Beagle dog slope Model building VPC – Pet dog model Median of simulations P5, P95 of simulations 0 100 200 300 400 Time Prediction interval of simulations in black Observed values in blue Median of observations Conclusion - 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. References [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. 10 Observed data