Results from a bench marking survey on cassette dosing practices in the pharmaceutical industry

Ackermann, Bradley L.

doi:10.1016/j.jasms.2004.06.001

Cited by 12 publications

(6 citation statements)

References 5 publications

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“…Whereas cassette dosing reduces the number of animals used, in addition to increasing throughput, there are disadvantages of this approach, including the potential for drug-drug interactions (26,27). The results of two recent surveys of the pharmaceutical industry suggest that cassette dosing is still widely used despite controversy surrounding this technique (28,29). In our experience, we have found the suitability of cassette dosing to evaluate the pharmacokinetics of novel anticancer agents to be entirely dependent on the compound series under investigation.…”

Section: Introductionmentioning

confidence: 94%

Preclinical pharmacokinetics and metabolism of a novel diaryl pyrazole resorcinol series of heat shock protein 90 inhibitors

Smith

Hayes²,

James³

et al. 2006

Molecular Cancer Therapeutics

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CCT018159 was recently identified as a novel inhibitor of heat shock protein (Hsp) 90, a promising target for cancer therapy. Pharmacokinetic and metabolic properties are likely to be important for efficacy and need to be optimized during drug development. Here, we define the preclinical metabolism and pharmacokinetics of CCT018159 and some early derivatives. In addition, we assess in vitro metabolic stability screening and in vivo cassette dosing (simultaneous administration of several compounds to a single animal) as approaches to investigate these compounds. The plasma clearance following individual i.v. administration to mice was rapid (0.128 -0.816 L/h), exceeding hepatic blood flow. For CCT066950 and CCT066952, this could be attributed in part to extensive (>80%) blood cell binding. Oral bioavailability ranged from 1.8% to 29.6%. Tissue distribution of CCT066952 was rapid and moderate, and renal excretion of the compounds was minimal (<1% of dose excreted). Compounds underwent rapid glucuronidation both in vivo and following incubation with mouse liver microsomes. However, whereas CCT066965 was metabolized to the greatest extent in vitro, this compound displayed the slowest plasma clearance. The rank order of the compounds from the highest to lowest area under the curve was the same following discrete and cassette dosing. Furthermore, pharmacokinetic variables were similar whether the compounds were dosed alone or in combination. We conclude that the pharmacokinetics of CCT018159 are complex. Cassette dosing is currently the best option available to assess the pharmacokinetics of this promising series of compounds in relatively high throughput and is now being applied to identify compounds with optimal pharmacokinetic properties during structural analogue synthesis.

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Section: Introductionmentioning

confidence: 94%

Preclinical pharmacokinetics and metabolism of a novel diaryl pyrazole resorcinol series of heat shock protein 90 inhibitors

Smith

Hayes²,

James³

et al. 2006

Molecular Cancer Therapeutics

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“…20 About 80% of those who discontinued the use of cassette dosing listed unreliability as a primary reason; the complexity associated with the development of the liquid chromatographytandem mass spectrometry (LC-MS/MS) analytical methods was a common secondary reason. Another survey reported by Ackermann 21 indicated that 25% of the pharmaceutical companies never employed cassette dosing, 8% employed the dosing paradigm as the default for exposure screening, and the remaining 67% used cassette dosing depending on project requirements.…”

Section: Introductionmentioning

confidence: 99%

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

Nagilla

Nord

McAtee

et al. 2011

Journal of Pharmaceutical Sciences

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“…Cassette dosing is widely used as a drug discovery tool (43,44). However, the published literature is limited due the predominant use of the technique in corporate programs.…”

Section: Discussionmentioning

confidence: 99%

Section: Dmpk In Drug Discoverymentioning

confidence: 99%

“…The results of two surveys that were conducted to assess the popularity of cassette dosing were published several years later in 2004 (43,44). The first survey, carried out by Ackerman (43), revealed that 75% of respondents (including representatives from small and large pharmaceutical companies, biotechnology companies, and contract research organizations) used cassette dosing, ranging from 'upon request' to their 'default method' for pharmaceutical screening. The second survey conducted by Manitpisitkul and White (44) showed that of the several participating pharmaceutical companies, 88% had used cassette dosing at some point and 44% of these continued to do so, with the frequency ranging from rarely to six times weekly.…”

Section: Dmpk In Drug Discoverymentioning

confidence: 99%

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The application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery

Smith

Raynaud

Workman

2007

Molecular Cancer Therapeutics

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Pharmacokinetic evaluation is an essential component of drug discovery and should be conducted early in the process so that those compounds with the best chance of success are prioritized and progressed. However, pharmacokinetic analysis has become a serious bottleneck during the 'hit-to-lead' and lead optimization phases due to the availability of new targets and the large numbers of compounds resulting from advances in synthesis and screening technologies. Cassette dosing, which involves the simultaneous administration of several compounds to a single animal followed by rapid sample analysis by liquid chromatography/tandem mass spectrometry, was developed to increase the throughput of in vivo pharmacokinetic screening. Although cassette dosing is advantageous in terms of resources and throughput, there are possible complications associated with this approach, such as the potential for compound interactions. Following an overview of the cassette dosing literature, this article focuses on the application of the technique in anticancer drug discovery. Specific examples are discussed, including the evaluation of cassette dosing to assess pharmacokinetic properties in the development of cyclin-dependent kinase and heat shock protein 90 inhibitors. Subject to critical analysis and validation in each case, the use of cassette dosing is recommended in appropriate chemical series to enhance the efficiency of drug discovery and reduce animal usage. [Mol Cancer Ther 2007;6(2):428 -40]

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Results from a bench marking survey on cassette dosing practices in the pharmaceutical industry

Cited by 12 publications

References 5 publications

Preclinical pharmacokinetics and metabolism of a novel diaryl pyrazole resorcinol series of heat shock protein 90 inhibitors

Preclinical pharmacokinetics and metabolism of a novel diaryl pyrazole resorcinol series of heat shock protein 90 inhibitors

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 application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery

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