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Two studies characterized single- and multiple-dose pharmacokinetics of licarbazepine immediate-release tablets and food effects on single-dose pharmacokinetics. In 1 study, 12 volunteers received 500 mg licarbazepine on day 1, 500 mg bid on days 3 to 6, and 500 mg on day 7. In the second study, 12 subjects received one 500-mg licarbazepine dose under fasted and fed conditions. After multiple dosing, geometric mean (%CV) Cmax ss, Cmin ss, and AUCtau were 77.6 micromol/L (18), 45.3 micromol/L (25), and 747 h.mol/L (19), respectively, with a tmax of 2 hours. Mean half-lives were 9.3 and 11.3 hours for single and multiple dosing, respectively. Food had no clinically significant effect on single-dose pharmacokinetics. Half-life ( approximately 10 hours) and low intersubject variability in main pharmacokinetic parameters were similar under fasted and fed conditions. Median tmax increased from 1.5 to 2.5 hours with food. Licarbazepine is well tolerated and has predictable pharmacokinetics.

Vatalanib (PTK787/ZK-222584) is a new oral antiangiogenic molecule that inhibits all known vascular endothelial growth factor receptors. Vatalanib is under investigation for the treatment of solid tumors. Disposition and biotransformation of vatalanib were studied in an open-label, single-center study in patients with advanced cancer. Seven patients were given a single oral (14)C-radiolabeled dose of 1,000 mg of vatalanib administered at steady state, obtained after 14 consecutive daily oral doses of 1,000 mg of nonradiolabeled vatalanib. Plasma, urine, and feces were analyzed for radioactivity, vatalanib, and its metabolites. Metabolite patterns were determined by high-performance liquid chromatography coupled to radioactivity detection with off-line microplate solid scintillation counting and characterized by LC-MS. Vatalanib was well tolerated. The majority of adverse effects corresponded to common toxicity criteria grade 1 or 2. Two patients had stable disease for at least 7 months. Plasma C(max) values of (14)C radioactivity (38.3 +/- 26.0 microM; mean +/- S.D., n = 7) and vatalanib (15.8 +/- 9.5 microM) were reached after 2 and 1.5 h (median), respectively, indicating rapid onset of absorption. Terminal elimination half-lives in plasma were 23.4 +/- 5.5 h for (14)C radioactivity and 4.6 +/- 1.1 h for vatalanib. Vatalanib cleared mainly through oxidative metabolism. Two pharmacologically inactive metabolites, CGP-84368/ZK-260120 [(4-chlorophenyl)-[4-(1-oxy-pyridin-4-yl-methyl)-phthalazin-1-yl]-amine] and NVP-AAW378/ZK-261557 [rac-4-[(4-chloro-phenyl)amino]-alpha-(1-oxido-4-pyridyl)phthalazine-1-methanol], having systemic exposure comparable to that of vatalanib, contributed mainly to the total systemic exposure. Vatalanib and its metabolites were excreted rapidly and mainly via the biliary-fecal route. Excretion of radioactivity was largely complete, with a radiocarbon recovery between 67% and 96% of dose within 7 days (42-74% in feces, 13-29% in urine).

In this open-label study, the safety, tolerability, and pharmacokinetics of oxcarbazepine as monotherapy or adjunctive therapy were studied in infants and young children with partial seizures. In a 30-day treatment phase, oxcarbazepine was titrated from 10 mg/kg/day to 60 mg/kg/day. Blood samples for analysis of the oxcarbazepine metabolite, the 10-monohydroxy derivative (MHD), were obtained at regular intervals. Patients completing the treatment phase entered a 6-month extension phase. Safety and tolerability were assessed throughout the study. Twenty-four patients (mean [range] age, 20.4 [2-45] months) were enrolled. Nineteen (79%) patients completed the treatment phase and, together with one patient who discontinued prematurely during the treatment phase, entered the extension phase. Thirteen of 20 (65%) patients completed the extension phase. The most common adverse events were pyrexia, ear infection, and irritability. Whether patients (n = 23) received enzyme-inducing antiepileptic drugs or not, MHD concentrations were consistent with those predicted from a linear, one-compartment, population-pharmacokinetic model based on a model previously fitted for 3- to 17-year-old children. Oxcarbazepine was safe and well tolerated in infants and young children. The pharmacokinetic profile of MHD was predicted by extension of a model based on older children.

Aims: To evaluate whether the potent CYP3A4 inhibitor ketoconazole has any influence on the pharmacokinetic and electrocardiographic parameters of the antimalarial co-artemether (artemether-lumefantrine) in healthy subjects., Methods: Sixteen subjects were randomized in an open-label, two period crossover design study. Subjects received a single dose of co-artemether (day 1) either alone or in combination with multiple oral doses of ketoconazole (400 mg on day 1 followed by 200 mg o.d. for 4 additional days). Serial blood samples were taken and assayed for artemether and its main active metabolite dihydroartemisinin (DHA), and lumefantrine., Results: The pharmacokinetics of artemether, its metabolite DHA, and lumefantrine were influenced by the presence of ketoconazole. AUC(0, infinity ) was increased from 320 to 740 ng ml-1 h (ratio 2.4, 90% CI 2.00, 2.86) for artemether, from 331 to 501 ng ml-1 h (ratio 1.7, 90% CI 1.40, 1.98) for DHA, and from 207 to 333 micro g ml-1 h (ratio 1.7, 90% CI 1.23, 2.21) for lumefantrine in the presence of ketoconazole. Cmax also increased in similar proportions for the three compounds (ratio 2.2 (90% CI 1.78, 2.83), 1.4 (90% CI 1.12, 1.74), and 1.3 (90% CI 0.96, 1.64), respectively). The terminal elimination half-life was increased for artemether (2.5 vs 1.9 h, 90% CI 1.12, 1.72) and DHA (3.1 vs 2.1 h, 90% CI 0.02, 3.36), but remained unchanged for lumefantrine (88 vs 95 h, 90% CI 0.81, 1.04). These increases in exposure to the antimalarial combination were much smaller than observed with food intake (up to 16 fold), and were not associated with increased side-effects or changes in electrocardiographic parameters. The study medications were well tolerated., Conclusions: The concurrent administration of ketoconazole with co-artemether led to modest increases in artemether, DHA, and lumefantrine exposure in healthy subjects. Dose adjustment of co-artemether is probably unnecessary in falciparum malaria patients when administered in association with ketoconazole or other potent CYP3A4 inhibitors.

Letrozole (trademark Femara) is a new orally active, potent and selective aromatase inhibitor for the hormonal treatment of advanced breast cancer in postmenopausal women. The pharmacokinetics of letrozole and the suppression of peripheral estrogens were studied in 28 breast cancer patients after a single dose and at steady state. The pharmacokinetics of two distinct age groups (> or =50, < or =65, N=15 and > or =70 years old, N=9) were compared. There were no significant differences in area under the curve (AUC) or terminal half-life between the two age groups neither after a single dose nor at steady state. However, when comparing steady state to single dose kinetics, half-life and AUC increased significantly by 42% (90% CI: 1.13, 1.78) and 28% (90% CI: 1.12, 1.47), respectively. This deviation from linearity was probably due to a partial saturation or auto-inhibition of the dominant metabolic clearance mechanism of letrozole. At steady state, approximately 70% of the administered dose was excreted in urine as unchanged letrozole (6.0+/-3.8%) or as the glucuronide of the major, pharmacologically inactive metabolite CGP44645 (64.2+/-22.7%). A single dose of letrozole caused suppression of serum estrogen levels close to the quantification limit of the assay. No difference between single dose suppression and suppression at steady state could be detected., (Copyright 2001 John Wiley & Sons, Ltd.)

Automated procedures for the determination of CGP 33,101 in plasma and the simultaneous determination of CGP 33,101 and its carboxylic acid metabolite, CGP 47,292, in urine are described. Plasma was diluted with water and urine with a pH 2 buffer prior to extraction. The compounds were automatically extracted on reversed-phase extraction columns and injected onto an HPLC system by the automatic sample preparation with extraction columns (ASPEC) automate. A Superlosil LC-18 (5 microns) column was used for chromatography. The mobile phase was a mixture of an aqueous solution of potassium dihydrogen phosphate, acetonitrile and methanol for the assay in plasma, and of an aqueous solution of tetrabutylammonium hydrogen sulfate, tripotassium phosphate and phosphoric acid and of acetonitrile for the assay in urine. The compounds were detected at 230 nm. The limit of quantitation was 0.11 mumol/l (25 ng/ml) for the assay of CGP 33,101 in plasma, 11 mumol/l (2.5 micrograms/ml) for its assay in urine and 21 mumol/l (5 micrograms/ml) for the assay of CGP 47,292 in urine.

Sulfinpyrazone kinetics has been investigated after intravenous and oral doses. They may be described by a 3-compartment open model. In the body about half the drug is in the plasma or in interstitial fluids, which equilibrated with plasma. Most of the rest is in an extravascular compartment, from which it easily diffuses back to the plasma. About 3% of the dose is still in the body after 24 hr and is located mainly in a deep compartment. After oral administration, sulfinpyrazone is quickly absorbed, largely from the stomach.

A method for the quantitative determination of sulphinpyrazone in plasma and urine is described. The drug is extracted from the acidified aqueous phase with 1-chlorobutane-ethylene dichloride (4:1) and separated from its metabolites by high-performance liquid chromatography on 5-mum LiChrosorb using dichloromethane-ethanol-water-acetic acid (79.1:19:1.9:0.002) as the mobile phase. The sensitivity limit is 0,2mug/ml using a 1-ml sample. Examples of applications are given.

The polarity of a drug is one of the most important parameters for the elaboration of switching systems. If the polarity of the drug is low or medium, "reversed-phase" chromatography is well adapted. The plasma or urine sample is diluted with water, centrifuged and injected first into a column of medium polarity (C2, CN or diol bonded phases). The compounds of interest are stopped on the top of the column and rinsed with water, then eluted and chromatographed on a C8 or C18 analytical column. A third column of still lower polarity can be added to improve the specificity of the system. In each successive step, the polarities of the mobile phases and columns should be decreased to reconcentrate the sample and reduce the band broadening that occurred in the previous step. Compounds of high polarity show almost no retention on reversed-phase columns, and normal-phase chromatography should be used. Aqueous solutions cannot be injected into polar bonded-phase columns as they lead to excessive band broadening. This problem can be solved by diluting plasma or urine with a large volume of a water-miscible organic solvent and injecting the clear supernatant. The compounds to be assayed are first reconcentrated on a polar column (NH2 or N(CH3)2 bonded phase) and then eluted. The selected "heart cut" of the eluate is chromatographed on another, more polar column. The influence of the polarity of drugs on the choice of switching systems is exemplified by assay methods for drugs of low, medium and high polarity.