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| Phase 1 Clinical Studies |
Information-Rich Phase I Trials Conventional Phase I trials provide researchers with the ability to test experimental drugs to evaluate the drug’s safety, determine its safe dosage range, and identify side effects. Accium BioSciences is proud to offer bioanalytical services that can make these Phase I trials significantly more information rich. Accium BioSciences provides bioanalytical services based on Accelerator Mass Spectrometry (AMS), an extremely sensitive instrument that detects 14C-labeled drugs and metabolites in biological samples with attomole (10-18 M) sensitivity. AMS delivers 103-fold improvement in sensitivity compared to most LC/MS/MS methods while reducing radiation exposure to study subjects by 106-fold. Researchers can now gain valuable information about drug metabolism and mass balance in these information-rich Phase I clinical trials. Traditionally, absolute bioavailability of a drug candidate is determined in a two part cross over study designed clinical trial. In a randomized fashion, study subjects are administered either a pharmacological oral or IV dose of a compound followed by a washout period before administration of the second IV or oral dose. Absolute bioavailability is determined by subtracting the area under the plasma concentration-time curve (AUC) of the oral dose from the AUC of the IV dose. By using AMS analytical techniques the clinician can perform human absolute bioavailability studies in a single clinical stay with the administration of a lightly labeled 14C IV microdose simultaneously with a conventional pharmacological oral dose of the same drug. The plasma PK of the IV "hot" dose (14C lightly labeled) is traced using accelerator mass spectrometer analysis and the "cold" oral dose is traced using conventional LC or LC/MS methods. The results yield important information about the gastrointestinal versus first-pass metabolism turn over as well determining the absolute bioavailability of the compound. In addition to gaining valuable pharmacokinetic information, using an IV "microdose" of the test compound overcomes the need for formulating high IV doses of insoluble drugs for absolute bioavailability studies.
AMS-based protocols permit the most sensitive clinical characterization of drug metabolism and provide critical data about a drug’s metabolic and biotransformation properties. AMS is used to:
Extremely sensitive metabolic profiling can be conducted in dedicated clinical studies or obtained in parallel with conventional Phase I studies through administration of a lightly-labeled 14C-compound. Metabolites in plasma, urine or other samples of interest are first fractionated by an appropriate HPLC protocol. Fractions can be collected in 10 second intervals (high-resolution) through to 5 minute (low-resolution) intervals. Each fraction is prepared separately and the total amount of 14C present in each fraction is determined by AMS. A highly sensitive radiochromatogram is then created representing the metabolic profile of the sample.
An example of an HPLC-AMS Metabolite Profiling application is shown to the right. Non-labeled reference standards for the known parent compound and metabolite were mixed with the sample prior to HPLC separation to serve as co-eluting reference marks.
AMS is an ideal platform for conducting mass balance studies in healthy human subjects. The general protocol involves administration of a lightly-labeled 14C-compound followed by urine and feces collection. Samples are processed by Accium BioSciences and the amount of 14C present in each collection is determined by AMS. The route of elimination and the degree of loss through each route is easily quantified by AMS.
An example of a mass balance study conducted with a single dose administration of a lightly-labeled 14C-compound in a healthy adult volunteer. All urine and feces samples were collected over a 42-day period and measured by AMS. The chart shows cumulative losses in urine and feces, demonstrating 90% bioavailability of the dose.
Long-Term Pharmacokinetics (PK) AMS-based protocols are also helpful in Phase 1 trials where the long-term pharmacokinetic (PK) properties of a drug can be determined well past the detection limits of other analytical methods. This eliminates the need to make forward trend estimations, resulting in more reliable determinations of elimination half-life, especially in drugs with complex elimination mechanisms. Most AMS-based clinical studies are conducted using 100 nanoCuries or less of 14C tracer. This ~106-fold reduction in radiation exposure compared to conventional studies significantly reduces the amount of 14C-compound required for these studies, reduces waste-handling costs and is a more ethical approach for conducting radiotracer studies in healthy human subjects.
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Please call +1 (206) 281-3915 to learn more information about our AMS bioanalytical services. |
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