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
Objectives: A chemotherapy-induced myelosuppression model based on rat data was proposed to predict the time-course of myelosuppression in cancer patients [1]. The aim of the present study was to retrospectively assess the human predictability of semi-physiological PK/PD models built on rats, Beagle laboratory dogs and pet dogs. This comparative analysis was performed on 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 [2].
Methods: In a first and prospective approach, the myelosuppression model was applied to rat data in order to predict hematotoxicity in a FIH trial including patients with solid tumors. A specific PK/PD study in Sprague Dawley rats using a wide dose range and various dosing schedules was performed to develop the model. Rat PK and white blood cells (WBC) counts were fitted by NONMEM VI. The time-course of WBC in patients was predicted both on typical system related PD parameters (i.e.: MTT, Baseline and γ) previously defined in cancer patients [3] and the rat slope estimate (drug-related parameter) corrected for species differences in plasma protein binding and bone marrow sensitivity (in vitro CFU-GM assay).
In a second and retrospective step, PK/PD models were developed on Beagle dogs and pet dogs (patient dogs presenting spontaneous lymphoma tumors) data separately. For Beagle dog, data from toxicological studies were analysed. For the pet dogs, a specific PK/PD study was conducted by mimicking the dosing schedule used in human [4]. Leukopenia in human was predicted using drug-related PK parameters obtained in Beagle and pet dog models, respectively.
Results: The time-course of WBC in each species was adequately described by the PK/PD models. The estimated system parameters from the rat model were similar to those previously published. The PK/PD models in dogs predicted a more potent hematotoxicity in human compared to the predictions provided by the rat model. The preliminary clinical data showed that:
(1) actual myelosuppression in human was under-estimated by the rat model
(2) Myelosuppression from the dogs model was close to that observed in human
Updated results in pets will be presented.
Conclusions: 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] Friberg LE, Sandström M, Karlsson MO. Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model. Invest New Drugs. 2010 Dec;28(6):744-53
[2] Barret JM, Kruczynski A, Vispé S, Annereau JP, Brel V, Guminski Y, Delcros JG, Lansiaux A, Guilbaud N, Imbert T, Bailly C. F14512, a potent antitumor agent targeting topoisomerase II vectored into cancer cells via the polyamine transport system. Cancer Res. 2008 Dec 1;68(23):9845-53
[3] Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. JClin Oncol. 2002 Dec 15;20(24):4713-21.
[4] Tierny F. Serres, Z. Segaoula et al. Phase 1 clinical pharmacology study of F14512, a new polyamine-vectorized anti-cancer drug, in naturally occurring canine lymphoma. Submitted in Clinical Cancer Research- Under review.
Reference: PAGE 24 () Abstr 3575 [www.page-meeting.org/?abstract=3575]
Poster: Drug/Disease modeling - Oncology