Dosing cassette

Cassette dosing or N into 1 dosing was one of the first techniques used to enhance the throughput of ADME/PK studies. It has the advantage of reducing the number of animals used, and increasing the number of compounds that can be 

The potential for the metabolites that are formed to have the same masses as other parent compounds is another factor that limits the number of compounds that may be included in the cassette, as does the potential for drug-drug interactions [35]. Other limitations are the total dose that can be administered without saturating important pathways of metabolism or distribution, and the solubility of the compounds in the dosing formulation. However, there is a balance to be achieved as, if the dose of each component given is very low, it is likely that the analytical method will not have sufficient sensitivity to provide an accurate assessment of the pharmacokinetics. 

Nonetheless the approach can provide - both routinely and rapidly - large amounts of pharmacokinetic or other distribution information on several compounds without significantly increasing the burden on the animals, whilst also minimizing the number of animals used. It is common to include a compound of known pharmacokinetics that acts as a control in each of these studies. This can help in identifying when the co-administered compounds have changed the kinetics. However, such marker compounds will not necessarily highlight problems with compounds that are subject to different clearance mechanisms [35], 

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There are a number of solutions that have been proposed to address the limitations on throughput in PK assays, including cassette dosing [37], where typically five compounds are dosed in a mixture, pooling of plasma samples from multiple animals receiving a specific dose, or the cassette-accelerated rapid rat screen where the processing of samples is streamlined [38]. 

White, R. E., Manitpisitkul, P., Pharmacokinetic theory of cassette dosing in drug discovery screening, Drug Metab. Dispos. 2001, 29, 957-966. 

There are a number of issues with using cassette dosing, not only in terms of... 

Bayliss, M. K., Frick, L. W., High-throughput pharmacokinetics cassette dosing, Curr. Opin. Drug Disc. Dev. 1999, 2, 20-25. 

MUX, cassette dosing, and sample pooling (parallel chromatography) approaches time-share MS by reducing dwell windows or reducing the number of data points across a chromatographic peak. These approaches in which the data parcels in milliseconds can monitor multiple channels rapidly... 

FIGURE 7.3 Conventional dosing versus cassette dosing. With conventional dosing, only one compound is dosed into each rat. Cassette dosing involves multiple compounds dosed in each rat. (Source Adapted from Manitpisitkul, P. and White, R.E., Drug Dis. Today, 2004, 9, 652. With permission of Elsevier.)... 

Beaudry F. et al., 1998. In vivo pharmacokinetic screening in cassette dosing experiments Use of online Pros-pekt liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry technology in drug discovery. Rapid Commun Mass Spectrom 12 1216. 

Frick, L.W., Adkison, K.L., Wells-Knecht, K.J., Woolard, R, and Higton, D.M., Cassette dosing rapid in vivo assessment of pharmacokinetics, Pharmaceut. Sci. Technol. Today, 1, 12, 1998. 

In order to expand the throughput for PK screening, cassette-dosing or N-in-1 was also employed. This cassette dosing method can provide plasma samples containing a mixure of multiple compounds. 

Typically, fewer than five compounds are cassette-dosed to animals with one of the compounds as the benchmark. The advantage of cassette-dosing is quite obvious it can process more compounds at a time and reduce the number of animals needed for an assay. However, the PK exposure of testing compounds may be compromised due to the potential of systemic drug-drug interactions. ... 

Hasegawa, K., Shindoh, H., Shiratori, Y., Ohtsuka, T., Aoki, Y., Ichihara, S., Horii, L, and Shimma, N. Cassette dosing approach and quantitative structure-pharmacokinetic relationship study of antifungal N-myristoyl-transferaseinhibitors./. Chem. Inf. Comput. Sci. 2002, 42, 968—975. 

Fig. 13.4 Conventional dosing vs cassette dosing. In conventional dosing, only one compound is dosed in each rat in cassette dosing, multiple compounds are dosed in each rat. Adapted from [78], with permission from Elsevier.

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