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Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs
Author(s) -
Lappin Graham,
Kuhnz Wilhelm,
Jochemsen Roeline,
Kneer Johannes,
Chaudhary Ajai,
Oosterhuis Berend,
Drijfhout Willem Jan,
Rowland Malcolm,
Garner R. Colin
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2006.05.008
Subject(s) - microdose , pharmacokinetics , pharmacology , therapeutic index , volume of distribution , bioavailability , chemistry , crossover study , midazolam , medicine , drug , placebo , alternative medicine , pathology , sedation
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 μg), (2) the corresponding 14 C‐labeled therapeutic dose on a separate occasion, and (3) simultaneous administration of an intravenous 14 C‐labeled microdose and an oral therapeutic dose for ZK253, midazolam, and erythromycin. Analysis of 14 C‐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 ½ ] of 45.1 hours, clearance [CL] of 1.38 L/h, and volume of distribution [V] of 90.1 L for 100 μg and t ½ of 35.7 hours, CL of 1.3 L/h, and V of 123 L for 10 mg), midazolam (t ½ of 4.87 hours, CL of 21.2 L/h, V of 145 L, and oral bioavailability [F] of 0.23 for 100 μg and t ½ 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 μg and 50 mg). For warfarin, clearance was reasonably well predicted (0.17 L/h for 100 μg and 0.26 L/h for 5 mg), but the discrepancy observed in distribution (67 L for 100 μg 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. Clinical Pharmacology & Therapeutics (2006) 80 , 203–215; doi: 10.1016/j.clpt.2006.05.008