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Projection of Exposure and Efficacious Dose Prior to First-in-Human Studies: How Successful Have We Been?

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Abstract

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.

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Abbreviations

ADME:

absorption, distribution, metabolism, and excretion

AUC:

area under the concentration versus time curve

AUCIPT :

area under the concentration versus time curve after intraportal administration

AUCIV :

area under the concentration versus time curve after intravenous administration

BMS:

Bristol-Myers Squibb Co.

CL:

clearance

CLhb:

hepatic blood clearance

CLh,int:

hepatic intrinsic clearance

C max :

maximum concentration

C min :

trough concentration

Css:

dose divided by steady-state volume of distribution

E.R.:

hepatic extraction ratio

f a :

fraction of the dose absorbed

f g :

fraction of the dose escaping first-pass metabolism by the gastrointestinal mucosa

FPO :

oral bioavailability

f u :

fraction unbound

HH:

human hepatocytes

HLM:

human liver microsomes

IC50 :

concentration required for 50% inhibition

IC90 :

concentration required for 90% inhibition

IPT:

intraportal

IV:

intravenous

LC-MS/MS:

liquid chromatography-tandem mass spectrometry

MRT:

mean residence time

NOAEL:

no observable adverse effect level

PB/PK:

physiologically based pharmacokinetic model

PD:

pharmacodynamics

PK:

pharmacokinetics

Qhb:

hepatic blood flow

Vss:

steady-state volume of distribution

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Acknowledgments

The authors would like to thank all of the BMS colleagues who made the various data available for collation. Their help is greatly appreciated.

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Authors and Affiliations

  1. Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., P.O. Box 5400, Princeton, New Jersey, 08543-5400, USA

    Christine Huang, Zheng Yang, A. David Rodrigues & Punit Marathe

  2. Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization, Wallingford, Connecticut, 06492-7660, USA

    Ming Zheng

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  1. Christine Huang
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Correspondence to Christine Huang.

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Huang, C., Zheng, M., Yang, Z. et al. Projection of Exposure and Efficacious Dose Prior to First-in-Human Studies: How Successful Have We Been?. Pharm Res 25, 713–726 (2008). https://doi.org/10.1007/s11095-007-9411-4

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