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

Lappin, Graham, Kuhnz, Wilhelm, Jochemsen, Roeline , Kneer, Johannes, Chaudhary, Ajai, Oosterhuis, Berend, Drijfhout, Willem Jan, Rowland, Malcolm and Garner, R. Colin (2006) Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs. Clinical Pharmacology and Therapeutics, 80 (3). pp. 203-215. ISSN 0009-9236

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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 14C-labeled therapeutic dose on a separate occasion, and (3) simultaneous administration of an intravenous 14C-labeled microdose and an oral therapeutic dose for ZK253, midazolam, and erythromycin. Analysis of 14C-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 t1/2 of 45.1 hours, clearance CL of 1.38 L/h, and volume of distribution V of 90.1 L for 100 μg and t1/2 of 35.7 hours, CL of 1.3 L/h, and V of 123 L for 10 mg), midazolam (t1/2 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 t1/2 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 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. © 2006 American Society for Clinical Pharmacology and Therapeutics.

Additional Information:cited By (since 1996) 103
Keywords:antiestrogen, carbon 14, diazepam, erythromycin, midazolam, unclassified drug, warfarin, zk 253, adult, area under the curve, article, clinical trial, controlled clinical trial, controlled study, data analysis, drug bioavailability, drug blood level, drug clearance, female, half life time, high performance liquid chromatography, human, liquid chromatography, male, mass spectrometry, medical literature, normal human, priority journal, Administration, Oral, Adolescent, Adult, Aged, Aged, 80 and over, Anticoagulants, Area Under Curve, Carbon Radioisotopes, Chromatography, Liquid, Cross-Over Studies, Dose-Response Relationship, Drug, Drug Monitoring, Estradiol, GABA Modulators, Humans, Injections, Intravenous, Middle Aged
Subjects:B Subjects allied to Medicine > B210 Pharmacology
B Subjects allied to Medicine > B230 Pharmacy
B Subjects allied to Medicine > B200 Pharmacology, Toxicology and Pharmacy
Divisions:College of Science > School of Pharmacy
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ID Code:8229
Deposited On:27 Mar 2013 16:42

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