Use of microdosing to predict pharmacokinetics at the therapeutic dose: experience with 5 drugs. Export

@article{citeulike:3378460, abstract = {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 microg), (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((1/2))] of 45.1 hours, clearance [CL] of 1.38 L/h, and volume of distribution [V] of 90.1 L for 100 microg 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 microg 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 microg and 50 mg). For warfarin, clearance was reasonably well predicted (0.17 L/h for 100 microg and 0.26 L/h for 5 mg), but the discrepancy observed in distribution (67 L for 100 microg 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.}, author = {Lappin, G. and Kuhnz, W. and Jochemsen, R. and Kneer, J. and Chaudhary, A. and Oosterhuis, B. and Drijfhout, W. J. and Rowland, M. and Garner, R. C.}, citeulike-article-id = {3378460}, citeulike-linkout-0 = {http://dx.doi.org/10.1016/j.clpt.2006.05.008}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/16952487}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=16952487}, doi = {10.1016/j.clpt.2006.05.008}, issn = {0009-9236}, journal = {Clinical pharmacology and therapeutics}, keywords = {microdosing, nce, pharmacokinetics}, month = {September}, number = {3}, pages = {203--215}, posted-at = {2008-10-06 05:29:34}, priority = {2}, title = {Use of microdosing to predict pharmacokinetics at the therapeutic dose: experience with 5 drugs.}, url = {http://dx.doi.org/10.1016/j.clpt.2006.05.008}, volume = {80}, year = {2006} }

TY - JOUR ID - citeulike:3378460 L3 - citeulike-article-id:3378460 N2 - 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 microg), (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((1/2))] of 45.1 hours, clearance [CL] of 1.38 L/h, and volume of distribution [V] of 90.1 L for 100 microg 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 microg 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 microg and 50 mg). For warfarin, clearance was reasonably well predicted (0.17 L/h for 100 microg and 0.26 L/h for 5 mg), but the discrepancy observed in distribution (67 L for 100 microg 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. IS - 3 JF - Clinical pharmacology and therapeutics SN - 0009-9236 EP - 215 TI - Use of microdosing to predict pharmacokinetics at the therapeutic dose: experience with 5 drugs. VL - 80 SP - 203 KW - microdosing KW - nce KW - pharmacokinetics AU - Lappin, G AU - Kuhnz, W AU - Jochemsen, R AU - Kneer, J AU - Chaudhary, A AU - Oosterhuis, B AU - Drijfhout, WJ AU - Rowland, M AU - Garner, RC PY - 2006/09// UR - http://dx.doi.org/10.1016/j.clpt.2006.05.008 ER -