Elsevier

Drug Discovery Today

Volume 9, Issue 15, August 2004, Pages 652-658
Drug Discovery Today

Review
Whatever happened to cassette-dosing pharmacokinetics?

https://doi.org/10.1016/S1359-6446(04)03137-XGet rights and content

Abstract

Cassette dosing is a procedure that is used for rapidly assessing the pharmacokinetics of a series of discovery drug candidates by dosing a mixture of compounds rather than a single compound. Cassette dosing has advantages and disadvantages associated with its use, which leads to controversy about how and if it should be used. To assess the current practices of the pharmaceutical industry regarding cassette dosing, a survey of several pharmaceutical companies was conducted. Analysis of the survey revealed that opinion on this subject is divided within the pharmaceutical industry. In addition, it was determined that approximately only a half of those companies that perform in vivo pharmacokinetic screening use cassette dosing for this purpose.

Section snippets

Current cassette dosing industrial practices

To address the current status of the cassette-dosing pharmacokinetic technique, we decided to poll industry-based colleagues directly. Thirty-one international pharmaceutical companies (ranging from small to large companies) were queried about their past experience of and present use of CD. Twenty-five completed and returned the questionnaire, giving an overall response rate of 81%. Therefore, the data should present an accurate representation of the pharmaceutical industry. Twenty-two (88%) of

What is the problem with using cassette dosing?

The diversity in opinion on the use of CD can be understood by examining the advantages and disadvantages of this technique. Features that make the CD approach attractive to a drug discovery team include:

  • Rapid analysis time resulting from a reduced analytical sample load. Several respondents reported impressive numbers of candidates being screened each week.

  • Reduction in interanimal variability in comparisons of compounds. The testing of several compounds simultaneously in a single animal

What is the solution?

It must be remembered that CD was invented to provide rapid in vivo PK data to keep up with the fast pace of candidate production and evaluation in drug discovery [9]. That need has not changed. Therefore, there is a continued active publication of CD-based screening programs, but now investigators are more aware of the dangers and design their studies more carefully to incorporate the precautions outlined [8]. For example, Hasegawa et al. [10] reported good results in evaluating the PK of

‘Right box’ analysis

The term ‘right box’ analysis was introduced in 2001 to denote the placement of a drug candidate into the correct broad category (i.e. the right box) [8]. The suitability of a drug candidate can be assessed in terms of PK parameters, such as clearance, half-life and oral bioavailability, which have clearly defined ranges of acceptable values. For instance, oral bioavailability could be divided into four categories - poor (0-10%), moderate (10-50%), good (50-80%) and excellent (80-100%). If the

Alternatives to cassette dosing

The 50% of scientists that choose not to use CD have had to explore other options for the acquisition of rapid, in vivo PK information, and several innovations have been reported. The two general approaches described are: (i) assay enhancement, or the use of various technological tricks such as rapid sample preparation and parallel HPLC, to accelerate the analytical step; and (ii) sample reduction, or minimizing the number of samples that must be assayed by such means as pooling plasma samples

Conclusion

Based on a survey of the pharmaceutical industry, we identified a decline in the frequency of use of CD in drug discovery, a finding that is supported by the recent literature. Only a half of the companies surveyed are still actively and extensively using CD. More importantly, following the publication of our analysis of PK theory and consequent recommendations [8], the application of CD has been modified. Specifically, we discovered that the majority of CD users now limit cassettes to five or

References (29)

  • J. Berman

    Simultaneous pharmacokinetic screening of a mixture of compounds in the dog using API LC/MS/MS analysis for increased throughput

    J. Med. Chem.

    (1997)
  • B.L. Ackermann

    Recent advances in use of LC/MS/MS for quantitative high-throughput bioanalytical support of drug discovery

    Curr. Top. Med. Chem.

    (2002)
  • M.K. Bayliss et al.

    High-throughput pharmacokinetics: cassette dosing

    Curr. Opin. Drug Disc. Dev.

    (1999)
  • R.E. White et al.

    Pharmacokinetic theory of cassette dosing in drug discovery screening

    Drug Metab. Dispos.

    (2001)
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