AMS traces very low chemical doses (micrograms) and radiative doses (100 nCi or less) of 14C labeled compound in humans with high precision. As a consequence of this sensitivity, subtherapeutic doses can be studied in healthy volunteers. This application of AMS has been dubbed microdosing. However, but the real power of the method for clinical pharmacology is the hidden human information it unmasks through making accessible measurements that were previously unobtainable. In this poster we show the microdose pharmacokinetics of the antiviral alpha-Hydroxyglycinamide (Tripep). AlphaHGA's anti-HIV mechanism is completely novel relative to know HIV drugs, as it inhibits the spread of the virus from the infected cell Experiment: A 100 nCi microdose was administered to eight subjects who were enrolled into a single dose cross-over study that was randomized for route of administration). Plasma, lymphocytes isolated from whole blood, and urine were quantified for 14C using accelerator mass spectrometry. Measurements were performed on a 1 MV compact bio-AMS instrument at LLNL. Pharmacokinetic parameters for the drug were estimated by noncompartmental analysis. Plasma PK parameters included exposure (AUC), Cmax, Tmax, clearance and terminal elimination rate constant and half-life. Urine PK parameters included exposure, Dmax and fraction of the drug excreted in urine. Results: The drug appeared to be completely (100%) orally bioavailable and bioavailability was relatively consistent across all subjects. Terminal elimination half-life in the plasma was approximately 10 hours following both routes of administration. Interestingly, the drug was rapidly taken up by lymphocytes; lymphocyte concentrations were sustained throughout the observation period for the lymphocytes (2 hr postdose). The pattern differs from the plasma concentration time course, suggesting differences in cellular and plasma kinetics. Elimination behavior of the drug from the cells cannot be determined from 2 hr sample set, but the data suggests that multicomponent elimination at a slower rate of clearance than plasma. This should be viewed as positive if the cells are the pharmacodynamic sites for the drug. Conclusion; The ability to quantify drug concentrations at target tissue sites (in this case lymphocytes) opens up the possibility for personalizing drug treatment regimens based upon the individual metabolic response. Thus, microdosing may be a useful tool for clinical pharmacology if it can link the patient with the best drug treatment option based their personal response to a drug.
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See more of AMS in Low Dose Bioscience Workshop
See more of The 10th International Conference on Accelerator Mass Spectrometry (September 5-10, 2005)