Cassette dosing is a technique primarily used in drug discovery efforts in non-clinical studies to collect pharmacokinetic data from multiple drug candidates in a single experiment. A typical cassette dosing pharmacokinetic study involves simultaneous administration of 5-10 compounds to a set of animals. Serial blood samples are obtained and LC/MS/MS techniques are used to measure the concentration of each analyte in each sample. Therefore, instead of running 5-10 separate PK studies, a similar amount of information can be obtained from a single study. This methodology can facilitate rapid evaluation of many compounds with fewer animals.
This sounds great … but there are some drawbacks. First, generally the 5-10 drug candidates are of similar chemical structure. Because of the structural similarities, metabolic drug interactions are more likely. The common structures likely use similar metabolic pathways which can lead to saturation of metabolic pathways resulting in low clearance values. This may suggest that drugs have longer residence times than would be expected when dosed alone.
Second, oral dosing presents the additional problem of interactions related to absorption and first pass metabolism. It is preferable to use intravenous (IV) dosing; however, in many cases compound solubility prevents preparation of an acceptable IV formulation. In addition, oral dosing requires larger amounts of compound which may be difficult to obtain during early discovery stages.
Third, analytical challenges are magnified with cassette dosing. The advances in mass spectrometry over the past 15 years has reduced the need for chromatographic separation on a column. However, with structurally similar compounds that differ by small molecular weight differences, there can be issues with collision-cell cross talk, in-source fragmentation from metabolites, and ion-suppression issues. These analytical issues can be solved, but usually require extra analytical work to ensure that some temporal separation of analytes occurs on the column.
In spite of these challenges, cassette dosing remains a useful technique for assessing the comparative pharmacokinetics of a series of compounds during early discovery efforts. If you choose to use this technique, be aware of the challenges and proactively address them.
Precision dosing—the right dose, for the right patient, at the right time—is crucial to providing patients with the most efficacious medications with minimal probability of adverse events. One key step towards achieving the delivery of individualized dosing is testing potential dosing regimens in a patient’s ‘virtual twin.’The other key step is to have as much drug information as possible. Achieving these key steps requires generating a large amount of data. A computer modeling and simulation platform is needed to assimilate these data together to study their interactions. Watch this webinar to learn more!
