Use of “N-in-one” Dosing to Create an in Vivo Pharmacokinetics Database for use in Developing Structure—Pharmacokinetic Relationships

Abstract

The purpose of this work was (1) to determine if useful in vivo pharmacokinetic data could be obtained after simultaneous administration of 5-22 compounds of a chemically congeneric series to dogs and (2) to determine if structure-pharmacokinetic relationships could be derived from such studies. Mixtures of structurally related alpha-1 antagonist compounds (5-22) were administered intravenously to conscious dogs. Blood samples were taken over the next 24 h and analyzed by LC/MS to determine plasma levels and pharmacokinetics of each compound. The pharmacokinetics of 17 of these compounds were also determined after individual administration. Results obtained in the N-in-One format for 17 compounds correlated well with results obtained when these same compounds were administered individually. The N-in-One method is a useful method for obtaining pharmacokinetic data on 5-20 molecules in a single animal at one time. The increased throughput in obtaining important pharmacokinetic information should enhance the drug discovery process. In addition, it was possible to determine the extent to which various chemical substitutions did or did not affect pharmacokinetic parameters.

Cassette Dosing for Pharmacokinetic Screening in Drug Discovery: Comparison of Clearance, Volume of Distribution, Half-Life, Mean Residence Time, and Oral Bioavailability Obtained by Cassette and Discrete Dosing in Rats

“…The merit of cassette dosing has long been debated in the literature, with researchers reaching contradicting conclusions. 6,13,16,24,25 A summary of the published cassette studies has been recently compiled by Smith et al, 2 which implies that cassette dosing has been used successfully to test wide range of chemical structures in multiple species including rats, dogs, and mice. The current report is derived from a retrospective analysis of cassette-and discrete-dosingderived PK data generated over a period of about 10 years for 12 drug discovery programs.…”

“…5 Therefore, the ability to rapidly generate the PK properties for a large number of compounds has become very important during lead optimization. Several approaches such as pooling of plasma samples, [6][7][8] truncating PK sample period collection, 9 cassette-accelerated rapid rat screen, 10 snapshot PK, 11 automation of extraction processes, and column switching [12][13][14] have been suggested to increase throughput.…”

“…Cassette dosing, also known as N-in-1 dosing, 13 represents an attractive way to rapidly screen relatively large sets of compounds for their PK properties while minimizing the number of animals otherwise needed, using a traditional discrete dosing paradigm. Cassette dosing was proposed in the late 1990s when Berman et al 6 evaluated the correlation between cassette and discrete dosing in dogs for five compounds and demonstrated that comparable PK parameters are obtained with the two study designs.…”

“…Nonetheless, the reliability and merits of cassette dosing have been debated in the scientific community. 13,[16][17][18] Potential drawbacks of the cassette-dosing paradigm include increased time and difficulties sometimes encountered during analytical method development and dose formulation, 17 and the potential for drug-drug interactions upon coadministration of multiple compounds. 6,15,19 On the basis of a recent publication that surveyed the use of cassette dosing in the pharmaceutical industry, it has been suggested that about 50% of pharmaceutical companies have tried and abandoned the use of some form of a cassette-dosing regimen.…”

Application of parallel liquid chromatography/mass spectrometry for high throughput microsomal stability screening of compound libraries

“…Another approach is to dose multiple compounds together, known as cassette dosing. Berman and coworkers described how cassette dosing is applied to rapid pharmacokinetic screening [13]. Pooling strategies and cassette dosing are compromised principally by sensitivity and solubility issues (the larger the number of compounds pooled, the lower the concentration of each individual component possible) and the greater the potential for synergistic and/or antagonistic effects.…”