Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs

Objectives. A volunteer trial was performed to compare the pharmacokinetics of 5 drugs-warfarin, ZK253 (Schering), diazepam, midazolam, and erythromycin-when administered at a microdose or pharmacologic dose. Each compound was chosen to represent a situation in which prediction of pharmacokinetics from either animal or in vitro studies (or both) was or is likely to be problematic. Methods: In a crossover design volunteers received (1) 1 of the 5 compounds as a microdose labeled with radioactive carbon (carbon 14) (100 mu g), (2) the corresponding C-14-labeled therapeutic dose on a separate occasion, and (3) simultaneous administration of an intravenous C-14-labeled microdose and an oral therapeutic dose for ZK253, midazolam, and erythromycin. Analysis of C-14-labeled drugs in plasma was done by use of HPLC followed by accelerator mass spectrometry. Liquid chromatography tandem mass spectrometry was used to measure plasma concentrations of ZK253, midazolam, and erythromycin at therapeutic concentrations, whereas HPLC-accelerator mass spectrometry was used to measure warfarin and diazepam concentrations. Results: Good concordance between microdose and therapeutic dose pharmacokinetics was observed for diazepam (half-life [t(1/2)] of 45.1 hours, clearance [CL] of 1.38 L/h, and volume of distribution [V] of 90.1 L for 100 mu g and t(1/2) of 35.7 hours, CL of 1.3 L/h, and V of 123 L for 10 mg), midazolam (t(1/2) of 4.87 hours, CL of 21.2 L/h, V of 145 L, and oral bioavailability [F] of 0.23 for 100 mu g and t(1/2) of 3.31 hours, CL of 20.4 L/h, V of 75 L, and F of 0.22 for 7.5 mg), and development compound ZK253 (F = < 1% for both 100 mu g and 50 mg). For warfarin, clearance was reasonably well predicted (0.17 L/h for 100 mu g and 0.26 L/h for 5 mg), but the discrepancy observed in distribution (67 L for 100 mu g and 17.9 L for 5 mg) was probably a result of high-affinity, low-capacity tissue binding. The oral microdose of erythromycin failed to provide detectable plasma levels as a result of possible acid lability in the stomach. Absolute bioavailability for the 3 compounds examined yielded excellent concordance with data from the literature or data generated in house. Conclusion: Overall, when used appropriately, microdosing offers the potential to aid in early drug candidate selection.