Projection of exposure and efficacious dose prior to first-in-human studies: How successful have we been?

被引:18
作者
Huang, Christine [1 ]
Zheng, Ming [2 ]
Yang, Zheng [1 ]
Rodrigues, A. David [1 ]
Marathe, Punit [1 ]
机构
[1] Bristol Myers Squibb Co, Pharmaceut Candidate Optimizat, Metab & Pharmacokinet, Princeton, NJ 08543 USA
[2] Pharmaceut Candidate Optimizat, Metab & Pharmacokinet, Wallingford, CT 06492 USA
关键词
allometric scaling; efficacy; exposure; pharmacokinetics; projection;
D O I
10.1007/s11095-007-9411-4
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Purpose. Preclinical and clinical data for 35 proprietary Bristol-Myers Squibb discovery compounds (years 1997 to 2005) were collected and analyzed. In each case, exposure and efficacy in human subjects were projected at the time of nomination (for development) prior to first-in-human dosing. Materials and Methods. Projections of area under the plasma concentration-time curve (AUC) in humans involved the use of one or more methods: (1) allometric scaling of animal pharmacokinetic data; (2) clearance projection employing in vitro data (liver microsomes and hepatocytes); (3) chimpanzee as an animal model; (4) the species-invariant time method; and (5) the Css-mean residence time or "Css-MRT" method. Whenever possible, prior clinical experience with lead compounds enabled the selection of the most appropriate method(s). Multiple approaches were also available at the time of the human efficacious dose projections: (1) efficacious exposure from animal efficacy models; (2) in vitro potency; and (3) prior experience with clinical leads. Results. Over the 8 year period described, AUC in humans was projected within 2-fold (20 out of 35 compounds; 57%), greater than 2-fold to 4-fold (11 out of 35 compounds; 32%), and greater than 4-fold (4 out of 35 compounds; 11%) of the observed value. At the time of writing, clinical efficacy data were available for 10 compounds only. In this instance, the efficacious doses were also projected within 2-fold (7 out of 10 compounds; 70%), greater than 2-fold to 4-fold (2 out of 10 compounds; 20%), and greater than 4-fold (1 out of 10 compounds; 10%) of the actual clinical dose. Conclusion. Overall, it was possible to project human exposure and efficacious dose within 4-fold of observed clinical values for about 90% of the compounds.
引用
收藏
页码:713 / 726
页数:14
相关论文
共 67 条
[1]   Prediction of in vivo hepatic clearance from in vitro data using cryopreserved human hepatocytes [J].
Bachmann, K ;
Byers, J ;
Ghosh, R .
XENOBIOTICA, 2003, 33 (05) :475-483
[3]   Prediction of the disposition of midazolam in surgical patients by a physiologically based pharmacokinetic model [J].
Björkman, S ;
Wada, DR ;
Berling, BM ;
Benoni, G .
JOURNAL OF PHARMACEUTICAL SCIENCES, 2001, 90 (09) :1226-1241
[4]   Expression profiles of 50 xenobiotic transporter genes in humans and pre-clinical species: A resource for investigations into drug disposition [J].
Bleasby, K. ;
Castle, J. C. ;
Roberts, C. J. ;
Cheng, C. ;
Bailey, W. J. ;
Sina, J. F. ;
Kulkarni, A. V. ;
Hafey, M. J. ;
Evers, R. ;
Johnson, J. M. ;
Ulrich, R. G. ;
Slatter, J. G. .
XENOBIOTICA, 2006, 36 (10-11) :963-988
[5]   INTERSPECIES PHARMACOKINETIC SCALING AND THE DEDRICK PLOTS [J].
BOXENBAUM, H ;
RONFELD, R .
AMERICAN JOURNAL OF PHYSIOLOGY, 1983, 245 (06) :R768-R775
[6]   Allometric scaling of pharmacokinetic parameters in drug discovery:: Can human CL, VSS and t1/2 be predicted from in-vivo rat data? [J].
Caldwell, GW ;
Masucci, JA ;
Yan, ZY ;
Hageman, W .
EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 2004, 29 (02) :133-143
[7]  
*CDER, 2005, GUID IND EST MAX SAF
[8]   PHYSIOLOGICAL-PARAMETERS IN LABORATORY-ANIMALS AND HUMANS [J].
DAVIES, B ;
MORRIS, T .
PHARMACEUTICAL RESEARCH, 1993, 10 (07) :1093-1095
[9]   ANIMAL SCALE-UP [J].
DEDRICK, RL .
JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS, 1973, 1 (05) :435-460
[10]   In vitro-in vivo correlations for lipophilic, poorly water-soluble drugs [J].
Dressman, JB ;
Reppas, C .
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 2000, 11 :S73-S80