The purpose of this study was to evaluate the serum concentration of ASKP1240 (pharmacokinetics [PK]) and the CD40 occupancy of ASKP1240 (pharmacodynamics [PD]) in normal and renal transplanted Cynomolgus monkeys to clarify the PK/PD relationship.
In a 70-day study, two ASKP1240 doses (2 and 5 mg/kg) were evaluated in normal and transplanted monkeys. Full doses were administered during the induction phase, and half doses were administered during the maintenance phase. The PK and PD were assessed using ELISA and FACS assays.
The serum concentration and receptor occupancy of ASKP1240 reached their maximum levels rapidly after the first dose and remained at an almost saturated rate during the induction phase. They then decreased gradually during the maintenance phase in all of the groups. The serum concentration and duration of full receptor occupancy were dose dependent in the normal and transplanted monkeys. On day 70 after therapy with 5 mg/kg ASKP1240, the transplanted monkeys presented a significantly lower occupancy of the CD40 receptors compared with the normal animals (5.5%±14.1% vs. 72.8%±3.4%). The serum concentration of ASKP1240 was also strongly correlated with the occupancy of the ASKP1240 receptors.
This study showed strong positive PK/PD relationships in renal transplanted and normal monkeys. The results may thus serve as a guide for optimal dosage and timing of ASKP1240 therapy in clinical trials and will propel the translation of ASKP1240 therapeutics from the bench to preclinical and clinical trials.
1 Department of Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Canada.
2 Laboratory Animals Center, the Academy of Military Medical Sciences, Beijing, China.
3 Translational & Development Pharmacology–US, Astellas Research Institute of America LLC, Northbrook, IL.
4 Drug Metabolism Research Labs, Astellas Pharma Inc., Osaka, Japan.
5 Drug Safety Research Labs, Astellas Pharma Inc., Osaka, Japan.
6 Pharmacological Research Labs, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan.
7 Pharmacokinetic Research Labs, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan.
8 Address correspondence to: Huifang Chen, M.D., Ph.D., Laboratory of Experimental Surgery, Research Center, CHUM, Room Y1611, Notre-Dame Hospital, Department of Surgery, University of Montréal, 2099 Alexandre de Sève, Montréal, Québec, Canada H2L 2W5.
This work was supported by Astellas Pharma Inc., Japan, and Kyowa Hakko Kirin Co., Ltd., Japan.
The authors declare no conflicts of interest.
F.K., Y.M., K.O., and N.K. participated in the study design. A.M. drafted the article. A.M., Y.M., L.S., Y.H., and H.D. contributed to the data analysis. A.M. provided statistical expertise. G.Z., L.Z., and J.B. helped with data collection. H.C., F.K., and P.D. provided critical revision of the article for important intellectual content. H.C. and F.K. provided the final approval for the article.
Received 3 September 2013. Revision requested 6 September 2013.
Accepted 6 November 2013.
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Accepted January 3, 2014