A Combined Accelerator Mass Spectrometry-Positron Emission Tomography Human Microdose Study with ¹⁴C- and ¹¹C-Labelled Verapamil

In microdose studies, the pharmacokinetic profile of a drug in blood after administration of a dose up to 100μg is measured with sensitive analytical techniques, such as accelerator mass spectrometry (AMS). As most drugs exert their effect in tissue rather than blood, methodology is needed for extending pharmacokinetic analysis to different tissue compartments. In the present study, we combined, for the first time, AMS analysis with positron emission tomography (PET) in order to determine the pharmacokinetic profile of the model drug verapamil in plasma and brain of humans. In order to assess pharmacokinetic dose linearity of verapamil, data were acquired and compared after administration of an intravenous microdose and after an intravenous microdose administered concomitantly with an oral therapeutic dose.

Six healthy male subjects received an intravenous microdose [0.05 mg] (period 1) and an intravenous microdose administered concomitantly with an oral therapeutic dose [80 mg] of verapamil (period 2) in a randomized, crossover, two-period study design. The intravenous dose was a mixture of (R/S)-[¹⁴C] verapamil and (R)-[¹¹C]verapamil and the oral dose was unlabelled racaemic verapamil. Brain distribution of radioactivity was measured with PET whereas plasma pharmacokinetics of (_R)- and (_S)-verapamil were determined with AMS. PET data were analysed by pharmacokinetic modelling to estimate the rate constants for transfer (k) of radioactivity across the blood-brain barrier.

Most pharmacokinetic parameters of (R)- and (S)-verapamil as well as parameters describing exchange of radioactivity between plasma and brain (influx rate constant [K₁] =0.030 ±0.003 and 0.031±0.005 mL/ mL/min and efflux rate constant [k₂] = 0.099 ± 0.006 and 0.095 ± 0.008 min−1 for period 1 and 2, respectively) were not statistically different between the two periods although there was a trend for nonlinear pharmacokinetics for the (R)-enantiomer. On the other hand, all pharmacokinetic parameters (except for the terminal elimination half-life [t_1/2]) differed significantly between the (R)- and (S)-enantiomers for both periods. The maximum plasma concentration (C_max), area under the plasma concentration-time curve (AUC) from 0 to 24 hours (AUC₂₄) and AUC from time zero to infinity (AUC_∞) were higher and the total clearance (CL), volume of distribution (V_d) and volume of distribution at steady state (V_ss) were lower for the (R)- than for the (S)-enantiomer.

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.