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 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.

Ursodeoxycholic acid does not affect ethinylestradiol bioavailability in women taking oral contraceptives.

OBJECTIVE: Contraception is recommended for female patients during ursodeoxycholic acid (UDCA) treatment for the potential teratogenic effect of this bile acid, and the aim of our study was to determine whether this treatment affects the bioavailability of ethinylestradiol (EE2). METHODS: In this double-blind, randomised study, we measured EE2 pharmacokinetics in eight healthy volunteers randomly allocated to receive oral contraceptive (30 microg EE2 and 75 microg gestodene) plus either UDCA (8-10 mg/kg per day) or placebo for 21 days during the first of three consecutive menstrual cycles. After a washout period during the second cycle, the subjects received the alternative treatment during the third menstrual cycle. Serum EE2 and UDCA were measured using radioimmunoassay and gas chromatography-mass spectrometry, respectively. RESULTS: The profile for serum EE2 concentration was similar during UDCA (mean maximum serum concentration 177 pg/ml, SEM 59) and during placebo treatment (153 pg/ml, SEM 62), and mean area under the curve (AUC) was 1374 pg/h per ml (SEM 580) and 1320 pg/h per ml (SEM 551) during the two regimens, respectively. The point estimates and 90% confidence intervals of UDCA/placebo ratios for EE2 AUC and for maximum serum concentration were 1.1 (0.8-1.5) and 1.2 (1.0-1.4), respectively. Mean serum triglycerides concentration increased from 58.3 mg/dl (SEM 6.8) at enrolment to 91.4 mg/dl (SEM 10.7) during placebo (P < 0.01) and to 88.6 mg/dl (SEM 13.7) during UDCA treatment (P < 0.05). During UDCA treatment, serum enrichment with this bile acid and with the metabolite iso-UDCA was 29% (16%) and 3% (2%), respectively. CONCLUSION: Co-administration with UDCA does not affect the bioavailability of EE2 in healthy volunteers, indicating that contraceptive efficacy is not affected.