ReviewWhatever happened to cassette-dosing pharmacokinetics?
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:
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Rapid analysis time resulting from a reduced analytical sample load. Several respondents reported impressive numbers of candidates being screened each week.
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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)
- et al.
Pharmaceutical profiling in drug discovery
Drug Discov. Today
(2003) - et al.
Profiling drug-like properties in discovery research
Curr. Opin. Chem. Biol.
(2003) Determination of rat oral bioavailability of soy-derived phytoestrogens using an automated on-column extraction procedure and electrospray tandem mass spectrometry
J. Chromatog. B. Analyt. Technol. Biomed. Life Sci.
(2003)Brain and plasma exposure profiling in early drug discovery using cassette administration and fast liquid chromatography-tandem mass spectrometry
J. Pharm. Biomed. Anal.
(2004)- et al.
LC fluorescence method for multiple synthetic compounds to rapidly create in vivo pharmacokinetic database utilizing ‘N-in-one’ dosing
J. Pharm. Biomed. Anal.
(2001) A new generic column switching system for quantitation in cassette dosing using LC/MS/MS
J. Pharm. Biomed. Anal.
(2003)Sample pooling to enhance throughput of brain penetration study
J. Pharm. Biomed. Anal.
(1999)Direct cocktail analysis of drug discovery compounds in pooled plasma samples using liquid chromatography-tandem mass spectrometry
J. Chromatog. B. Analyt. Technol. Biomed. Life Sci.
(2002)A comprehensive strategy for ADME screening in drug discovery
High-throughput screening approaches for investigating drug metabolism and pharmacokinetics
Xenobiotica
(2001)
Simultaneous pharmacokinetic screening of a mixture of compounds in the dog using API LC/MS/MS analysis for increased throughput
J. Med. Chem.
Recent advances in use of LC/MS/MS for quantitative high-throughput bioanalytical support of drug discovery
Curr. Top. Med. Chem.
High-throughput pharmacokinetics: cassette dosing
Curr. Opin. Drug Disc. Dev.
Pharmacokinetic theory of cassette dosing in drug discovery screening
Drug Metab. Dispos.
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