Combining AMS and PET microdosing allows long-term pharmacokinetic data along with information on drug tissue distribution to be acquired in the same subjects thus making it a promising approach to maximize data output from a single clinical study.

PF-184298 ((S)-2,3-dichloro-N-isobutyl-N-pyrrolidin-3-ylbenzamide) and PF-4776548 ((3-(4-fluoro-2-methoxy-benzyl)-7-hydroxy-8,9-dihydro-3H,7H-pyrrolo[2,3-c][1,7]naphthyridin-6-one)) are novel compounds which were selected to progress to human studies. Discordant human pharmacokinetic predictions arose from pre-clinical in vivo studies in rat and dog, and from human in vitro studies, resulting in a clearance prediction range of 3 to >20 mL min⁻¹ kg⁻¹ for PF-184298, and 5 to >20 mL min⁻¹ kg⁻¹ for PF-4776548. A package of work to investigate the discordance for PF-184298 is described. Although ultimately complementary to the human pharmacokinetic data in characterising the disposition of PF-184298 in humans, these data did not provide any further confidence in pharmacokinetic prediction. A fit for purpose human pharmacokinetic study was conducted for each compound, with an oral pharmacologically active dose for PF-184298, and an intravenous and oral microdose for PF-4776548. This provided a relatively low cost, clear decision making approach, resulting in the termination of PF-4776548 and further progression of PF-184298. A retrospective analysis of the data showed that, if the tools had been available at the time, the pharmacokinetics of PF-184298 in human could have been predicted from a population based simulation tool in combination with physicochemical properties and in vitro human intrinsic clearance.

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The plasma concentrations of alphaxalone were measured with a gas chromatographic technique in six patients following a single i.v. injection of Althesin, and in five volunteers following oral administration. A two-compartment open model was used in the pharmacokinetic analysis of the data, and the plasma clearance of alphaxalone was similar to the blood flow through the liver. A comparison with the pharmacokinetics of lignocaine was made.

Background: A microdose study was performed where 50 μg R/S- 14C-verapamil was dosed intravenously to human volunteers. In order to quantify the individual R- and S-enantiomers in human plasma a 2D chiral HPLC method with subsequent analysis by accelerator mass spectrometry was verified. Results: R/S-verapamil was separated on a C18 column and the isolated fraction was applied to a chiral column where the verapamil enantiomers were separated. Experimental recovery (�73 coefficient of variation {CV} = 16% and 66% CV = 21% for R- and S-verapamil, respectively) was accounted for by the use of internal standardization from the fluorescence response of nonlabeled R- and S-verapamil. The precision of the assay ranged from 4.1 to 15.9% CV and the limit of quantitation was 1.95-4.81 pg/ml for R-verapamil and 1.76-3.34 pg/ml for S-verapamil. Conclusion: This method was successfully applied to the analysis of R- and S-verapamil in human plasma. © 2010 Future Science Ltd

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The National Aging and Vision Network established the National Agenda on Vision and Aging in 1998 and identified employment opportunities for older individuals with visual impairments (those who are blind or have low vision) as a major goal. A work group was formed to address this goal. One of its first tasks was to identify examples of strategies to increase the employment of older persons with visual impairments. Project VIEW was selected to epitomize a model program for the employment of older workers.