Single-species Allometric Scaling: A Strategic Approach to Support Drug Discovery
Dipal Patel *
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pennington, NJ 08534, USA.
Elizabeth Dierks
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pennington, NJ 08534, USA.
*Author to whom correspondence should be addressed.
Abstract
Aims: Multi-species Allometric Scaling (MSS) from at least three species have been used traditionally to predict human CL and Vss. Single-species Scaling (SSS) can be applied to predict these parameters from a single species using a fixed body weight exponent. SSS is less time- and resource-intense compared to MSS and thus appears to be a very promising method to implement in a screening strategy during the drug discovery phase.
Study Design: To evaluate SSS predictivity compared to MSS, six discovery compounds were evaluated in pharmacokinetic studies with the intravenous administration to rat, rabbit, dog, and/or cynomolgus monkey. Human CL and Vss were predicted by MSS and SSS, applying protein binding correction. Relative fold difference between these two methods was calculated to define success rate as a percent of the predictions of SSS within two- to four-fold of MSS predictions.
Results: SSS showed a high success rate for human CL prediction with 67% within 2-fold and 94% within 4-fold of MSS. The success rate of human Vss prediction by SSS was also good with 61% within 2-fold and 89% within 4-fold of MSS.
Conclusion: These data demonstrate the potential application of SSS to streamline the screening strategy of drug discovery programs.
Keywords: Single-species scaling, allometric scaling, drug discovery strategy, clearance, volume of distribution.