Relative bioavailability of deferasirox tablets administered without dispersion and dispersed in various drinks.

UNLABELLED: Deferasirox (ExjadeA, ICL670) is a new, once-daily oral iron chelator, recently approved as first-line therapy in the treatment of iron overload resulting from blood transfusions. In registration studies, deferasirox tablets were dispersed in non-carbonated water prior to administration. In routine clinical practice, however, patients may prefer to take the tablet dispersed in a flavored drink rather than with water. OBJECTIVE: Stability and compatibility tests were performed to identify beverages suitable for the dispersion of tablets for further testing in man. This was followed by a pharmacokinetic study to assess the relative bioavailability of deferasirox tablets dispersed in two types of soft drinks, dispersed in water, and without dispersion. METHODS: An open-label, randomized, 4-period, crossover study was carried out with 28 healthy volunteers who received single 20 mg/kg oral doses of deferasirox without dispersion, dispersed in orange juice, dispersed in apple juice and dispersed in non-carbonated water (reference). Deferasirox and Fe-[deferasirox]2 were measured in plasma using liquid chromatography-mass spectrometry. Pharmacokinetic parameters were compared using standard bioequivalence tests. RESULTS: Mean deferasirox AUC0-t were 1,040 A+/- 530, 1,010 A+/- 278, 882 A+/- 252 and 996 A+/- 352 h x micromol/l when deferasirox tablets were administered without dispersion, dispersed in orange juice, dispersed in apple juice and dispersed in water, respectively, indicating that these forms of deferasirox administrations met bioequivalence criteria. Therefore, the oral bioavailability of deferasirox tablets was not affected neither by the degree of dispersion nor by the type of drink (orange or apple juice versus water) used for dispersion. CONCLUSIONS: This study shows that deferasirox bioavailability is unaltered when dispersed with orange or apple juice compared with dispersion in water. Thus, in addition to water, patients have the option of taking deferasirox tablets in orange or apple juice. The degree of dispersion did not affect deferasirox bioavailability. Therefore, deferasirox therapy will not be compromised if dispersion of the tablet is not fully complete; although the latter should be avoided.

Pharmacokinetics and pharmacodynamics of the novel daily rivastigmine transdermal patch compared with twice-daily capsules in Alzheimer's disease patients.

A transdermal patch has been developed for the cholinesterase inhibitor rivastigmine. This study investigated the pharmacokinetics and pharmacodynamics of rivastigmine and NAP226-90, and compared drug exposure between patch and capsule administrations. This was an open-label, parallel-group study in Alzheimer's disease patients randomized to receive either capsule (1.5-6 mg Q12H, i.e., 3-12 mg/day) or patch (5-20 cm2) in ascending doses through four 14-day periods. The patch showed lower Cmax (ca. 30% lower at 20 cm2, 19.5 versus 29.3 ng/ml), longer tmax (8.0 versus 1.0 h), and greater AUC (ca. 1.8-fold at 20 cm2, 345 versus 191 ng x h/ml) compared with the 6 mg Q12H capsule dose, with markedly less fluctuation between peak and trough plasma levels (80% at 20 cm2 versus 620% at 1.5 mg Q12H). Plasma butyrylcholinesterase inhibition rose slowly after patch administration, whereas two distinct peaks were seen after capsule administration. Average exposure with the 10 cm2 patch was comparable to the highest capsule dose (6 mg Q12H, i.e., 12 mg/day).

Similar bioavailability of dexmethylphenidate extended (bimodal) release, dexmethyl-phenidate immediate release and racemic methylphenidate extended (bimodal) release formulations in man.

OBJECTIVE: The d-isomer of methylphenidate (d-MPH) is the pharmacologically active part of the racemic mixture of methylphenidate (d,l-MPH), which has been used for decades in the treatment of attention-deficit/hyperactivity disorder (ADHD). A modified release formulation with bimodal release for the pure d-enantiomer (Focalin XR) has been developed to enable a fast onset of action and a sustained activity for once-daily administration. It was intended to achieve a bimodal concentration-time profile as observed after administration of two immediate release Focalin tablets. The pharmacokinetics of this d-MPH bimodal release formulation were compared with a d-MPH immediate release formulation and a similar bimodal release formulation of d,l-MPH in healthy adult volunteers. MATERIALS AND METHODS: 25 volunteers received a single 20 mg dose of d-MPH bimodal release formulation, two 10 mg doses of a d-MPH immediate release formulation given 4 h apart and a single 40 mg dose of d,l-MPH bimodal release formulation (1 : 1 ratio for d : l enantiomers). The washout between treatments in this 3-way crossover study was 7 days. RESULTS: All three formulations were well-tolerated at the doses tested. The d-MPH bimodal release formulation generated two distinct d-MPH plasma concentration peaks and both peak concentrations and the time to peak were similar to those of the d-MPH immediate release formulation given 4 h apart and the d,l-MPH bimodal release formulation. The three formulations had Cmax and AUC0-infinity values of 15.5 +/- 4.3 ng/ml and 119 +/- 41 ng x h/ml for bimodal release d-MPH, 17.9 +/- 5.3 ng/ml and 115 +/- 40 ng A h/ml for immediate release d-MPH, and 16.4 +/- 4.4 ng/ml and 122 +/- 36 ng x h/ml for d,l-MPH bimodal release, respectively. CONCLUSIONS: In summary, the 20 mg extended (bimodal) release formulation of d-MPH (Focalin XR) demonstrated a bimodal concentration-time profile and was bioequivalent to two 10 mg doses of immediate release d-MPH (Focalin) and was bioequivalent to 40 mg extended (bimodal) release d,l-MPH (Ritalin LA).

Quantitative determination of rivastigmine and its major metabolite in human plasma by liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry.

A sensitive, specific, accurate and reproducible LC-MS-MS method was developed and validated for the simultaneous determination of rivastigmine and its major metabolite NAP 226-90 in human plasma according to International Regulatory Requirements. After addition of their respective labelled internal standards, the compounds were extracted from plasma using methyl-tert.-butyl ether at basic pH with a simultaneous derivatization of NAP 226-90 with propionic anhydride, and backextracted into an acidic solution. After re-extraction the compounds were analyzed on a 3-micrometer Purospher Star RP-18 column interfaced with a MDS Sciex API 3000 triple quadrupole mass spectrometer. Positive atmospheric chemical ionization was employed as the ionization source. The analytes and their internal standards were detected by use of multiple reaction monitoring mode. Intra- and inter-day accuracy and precision were found suitable over the range of concentrations between 0.200 and 30.0 ng/ml. The LC-MS-MS method was crossvalidated with a previously developed in-house GC-MS method by the analysis of plasma samples obtained from patients after administration of Exelon((R)) capsules and showed excellent correlation between the methods.

Quantitative determination of benazepril and benazeprilat in human plasma by gas chromatography-mass spectrometry using automated 96-well disk plate solid-phase extraction for sample preparation.

An analytical method for the determination of benazepril and its active metabolite, benazeprilat, in human plasma by capillary gas chromatography-mass-selective detection, with their respective labelled internal standard, was developed and validated according to international regulatory requirements. After addition of the internal standards, the compounds were extracted from plasma by solid-phase extraction using automated 96-well plate technology. After elution, the compounds were converted into their methyl ester derivatives by means of a safe and stable diazomethane derivative. The methyl ester derivatives were determined by gas chromatography using a mass-selective detector at m/z 365 for benazepril and benazeprilat and m/z 370 for the internal standards. Intra- and inter-day accuracy and precision were found to be suitable over the range of concentrations between 2.50 and 1000 ng/mL.

Tegaserod coadministration does not alter the pharmacokinetics of theophylline in healthy subjects.

Tegaserod (HTF 919), a selective 5-HT4 receptor partial agonist, is in development for the treatment of functional gastrointestinal motility disorders. Tegaserod has been found to inhibit cytochrome P-450 (CYP) 1A2, for which theophylline is a prototype substrate. This study was designed to assess the effect of tegaserod on the single-dose pharmacokinetic and safety profile of theophylline. Eighteen subjects were enrolled in a randomized, open-label, two-period crossover study. After an overnight fast, subjects were randomized to receive one of two treatments: (1) a single dose of controlled-release formulation of theophylline (Theo-Dur, 600 mg) on day 1 or (2) a single dose of tegaserod (6 mg) on day 1, concomitant administration of tegaserod (6 mg) and theophylline (600 mg) on the morning of day 2, followed by an additional dose of tegaserod (6 mg) 12 hours later. Four to 10 days later, the subjects received the alternative treatment regimen. The pharmacokinetic parameters of theophylline, including AUC, Cmax, and t(1/2lambda z), were similar for both treatment regimens, although the tmax of theophylline was statistically different between the treatments. Except for a decrease in partial metabolic formation clearance from theophylline to 1-methyluric acid, which is unlikely to be clinically relevant, there were no statistically significant differences in renal clearance of theophylline and partial metabolic formation clearances following the combined treatment compared with theophylline alone. The results of the current study indicate that no dose adjustment is required when drugs metabolized via CYP1A2 are coadministered with tegaserod.

Multiple-dose pharmacokinetics confirm no accumulation and dose proportionality of the novel promotile drug tegaserod (HTF 919).

OBJECTIVE: To evaluate the steady-state pharmacokinetics (PK) and dose proportionality of the selective 5-HT4 receptor partial agonist tegaserod (HTF 919) in healthy subjects. METHODS: Eighteen subjects were given 2, 6, or 12-mg doses of tegaserod twice daily (b.i.d.) for 5 days, with PK and safety assessments made during the 12 h or 24 h following first administration, and 12 h after the final dose. RESULTS: Tegaserod was rapidly absorbed [time to reach measured maximum plasma concentration after multiple administrations (tmax,ss) 1 h]. Steady-state PK were consistent with single-dose PK characteristics supporting that there was no accumulation of tegaserod in plasma based on systemic exposure. Mean measured maximum plasma concentration after multiple administrations (Cmax,ss) and area under the plasma concentration-time curve over one dosing interval (tau, 0-12 h after drug administration, AUC tau) were between 0.7 +/- 0.3 ng/ml and 5.6 +/- 2.9 ng/ml and 2.4 +/- 1.3 h.ng/ml and 20.4 +/- 14.0 h.ng/ml, respectively, indicating dose-proportional PK of tegaserod in the range 2-12 mg b.i.d. Tegaserod was safe and well tolerated. No serious adverse events were reported. CONCLUSION: Tegaserod exhibits no accumulation and dose-proportional PK after multiple doses.

Simultaneous determination of imipramine and its metabolite desipramine in human plasma by capillary gas chromatography with mass-selective detection.

An analytical method for the simultaneous determination of imipramine (IMI) and its N-desmethyl metabolite, desipramine (DIMI) in human plasma by capillary gas chromatography-mass selective detection (GC-MS), with D4-imipramine (D4-IMI) and D4-desipramine (D4-DIMI) as internal standards, was developed and validated. After addition of the internal standards, the compounds were extracted from plasma at basic pH into n-heptane-isoamyl alcohol (99:1, v/v), back-extracted into acidic aqueous solution and re-extracted at basic pH into toluene. Desipramine and D4-desipramine were converted into their pentafluoropropionyl derivatives. The compounds were determined by gas chromatography using a mass selective detector at m/z 234 for IMI, m/z 238 for D4-IMI, m/z 412 for DIMI and m/z 416 for D4-DIMI. The method was applied to clinical samples.

Quantitative determination of norethisterone acetate in human plasma by capillary gas chromatography with mass-selective detection.

An analytical method for the determination of norethisterone acetate (NETA) in human plasma by capillary gas chromatography-mass-selective detection (GC-MS), with testosterone acetate as internal standard, was developed and validated. After addition of the internal standard, the compounds were extracted from plasma at basic pH into diethyl ether-dichloromethane (3:2, v/v), which was then evaporated to dryness. The compounds were converted into their pentafluoropropionyl derivatives which were determined by gas chromatography using a mass selective detector at m/z 486 for NETA and m/z 476 for the internal standard. Intra-day and inter-day accuracy and precision were found suitable over the range of concentrations between 0.10 to 10 ng/ml. The method was applied to clinical samples.

Simultaneous determination of isosorbide dinitrate and its mononitrate metabolites in human plasma by capillary gas chromatography with electron-capture detection.

A method for the simultaneous determination of isosorbide dinitrate (ISDN) and its mononitrate metabolites (2- and 5-ISMN) in human plasma by capillary gas chromatography with electron-capture detection was developed. Two internal standards were used: isomannide dinitrate (IMDN) for the determination of ISDN and isomannide mononitrate (IMMN) for the determinations of 2- and 5-ISMN. After addition of the internal standards, the compounds were isolated from plasma by solid-liquid extraction. They were determined by gas chromatography using an electron-capture detector. The reproducibility and accuracy of the method were found suitable in the range of concentrations 2.5-83 ng/ml for ISDN, 2.6-208 ng/ml for 2-ISMN and 2.3-1010 ng/ml for 5-ISMN. The limit of quantitation (LOQ) was about 2.5 ng/ml for each compound. The method was applied to clinical samples.

Simultaneous determination of norethisterone and six metabolites in human plasma by capillary gas chromatography with mass-selective detection.

A method for the simultaneous determination of norethisterone (NET) and six metabolites in human plasma by capillary gas chromatography-mass-selective detection (GC-MS) is described. The compounds are determined in plasma after enzymatic hydrolysis. After addition of norgestrel as the internal standard, the compounds are extracted from plasma at pH 5 using an Extrelut column and elution with dichloromethane. After evaporation, the compounds are converted into bistrimethylsilyl derivatives which are determined by gas chromatography using a mass-selective detector at m/z 429 for the two dihydro-NET (5 beta-NET and 5 alpha-NET), m/z 431 for the four tetrahydro-NET (3 alpha,5 alpha-NET, 3 beta,5 beta-NET and 3 beta,5 alpha-NET), m/z 442 for NET and m/z 456 for the internal standard. The reproducibility and accuracy of the method were found suitable over the range of concentrations between 0.50 and 8 ng/ml for NET, and metabolites except for 5 alpha-dihydro-NET (between 1 and 8 ng/ml). The method was applied to clinical samples.

Percutaneous absorption of diclofenac in healthy volunteers after single and repeated topical application of diclofenac Emulgel.

The percutaneous absorption of diclofenac was studied in ten healthy volunteers treated with Emulgel containing 1.16% diclofenac diethylammonium for 8 d as follows: a single application of 5 g Emulgel on days 1 and 8, and two applications d-1 on days 2-7. Plasma concentration profiles of unchanged diclofenac and urinary concentrations of total diclofenac and metabolites (sum of free and conjugated) were determined. High inter-individual variations in plasma and urine data were recorded, due probably to the permeability and the hydration of the skin. Steady state was reached after 2 d of twice-daily administration. Plasma concentrations were low but remained in the range 10-50 nmol L-1 over the full day for most of the subjects, indicating prolonged absorption from the application site.

The absence of a pharmacokinetic interaction between aspirin and the angiotensin-converting enzyme inhibitor benazepril in healthy volunteers.

Potential effects of the coadministration of single doses of aspirin (325 mg) and of benazepril hydrochloride (20 mg) on the pharmacokinetics and the metabolism of these two drugs were evaluated in 12 healthy subjects. Plasma concentration profiles of benazepril, its active metabolite benazeprilat, and total salicylic acid were determined together with urinary excretion of benazeprilat, salicylic acid, salicyluric acid, and salicylate glucuronides. Almost superimposable plasma profiles of benazepril, benazeprilat, and total salicylic acid were achieved with the drugs given alone and concomitantly. The coadministration of benazepril hydrochloride and aspirin did not modify the pharmacokinetics or the metabolism of the two drugs.

Determination of acenocoumarol in human plasma by capillary gas chromatography with mass-selective detection.

A method for the determination of acenocoumarol in human plasma by capillary gas chromatography-mass-selective detection is described. After addition of a structurally related analogue as the internal standard, the compounds are extracted from plasma at acidic pH into toluene, back-extracted with a basic solution and re-extracted from hydrochloric acid solution with toluene, which is then evaporated to dryness. The compounds are converted into their methyl derivatives, which are determined by gas chromatography using a mass-selective detector at m/z 324 for acenocoumarol and m/z 338 for the internal standard. The reproducibility and accuracy of the method were found to be suitable over the acenocoumarol concentrations range 2.2-74 nmol/l. The method could be considered as selective for acenocoumarol in the presence of its major metabolites in plasma.

Determination of diclofenac in plasma and urine by capillary gas chromatography-mass spectrometry with possible simultaneous determination of deuterium-labelled diclofenac.

A specific and sensitive method for the determination of diclofenac at concentrations down to ca. 1 ng/ml, the limit of detection being 100 pg/ml, in human plasma and urine by gas chromatography-mass spectrometry with 2H4-labelled diclofenac as internal standard is described. The method is also suitable for the simultaneous assay of these two compounds when both are present in samples of human plasma or urine. In this case, 5-chlorodiclofenac is used as internal standard. After toluene extraction from plasma or without extraction for urine, the method involves the formation of a dimethylindolinone derivative by extractive alkylation. The technique was applied to determine low plasma concentrations and urinary excretion of labelled and unlabelled diclofenac after percutaneous applications of Voltaren Emulgel to humans applied simultaneously under occlusive dressing as deuterated diclofenac sodium, and without occlusive dressing as unlabelled diclofenac sodium.

Simultaneous determination of clomipramine and its N-desmethyl metabolite in human whole blood by capillary gas chromatography with mass-selective detection.

A method for the simultaneous determination of clomipramine and its N-desmethyl metabolite at concentrations down to ca. 2 nmol/l in human whole blood is described. After addition of a known amount of deuterium-labelled internal standards, compounds are extracted into n-heptane-isoamyl alcohol (99:1, v/v) at basic pH, back-extracted into an acidic aqueous solution and re-extracted at basic pH into n-heptane. N-Desmethylclomipramine and the internal standard are derivatized with pentafluoropropionic anhydride. The compounds are determined by capillary gas chromatography with mass-selective detection. The technique was applied to determine the human blood concentrations of clomipramine and its N-desmethyl metabolite after oral administration of Anafranil; mean blood concentrations are reported.

Determination of the two dinitrate metabolites of nitroglycerin in human plasma by capillary gas chromatography with electron-capture detection.

This paper describes a sensitive method for the specific determination of 1,2-glyceryl dinitrate and 1,3-glyceryl dinitrate as metabolites of nitroglycerin at concentrations down to 250 pg/ml plasma. After addition of a known amount of 2-isosorbide mononitrate as internal standard, plasma is introduced onto an Extrelut cartridge and the compounds of interest are eluted with dichloromethane. The glyceryl dinitrates are then quantitated by capillary gas chromatography with electron-capture detection.

Quantitative determination of nitroglycerin in human plasma by capillary gas chromatography with electron-capture detection.

A sensitive method for the selective determination of nitroglycerin at concentrations down to 50 pg/ml in human plasma is described. After the addition to plasma of a known amount of butane-1,2,4-triol trinitrate as internal standard, both compounds are extracted into hexane. Nitroglycerin is then quantitated by capillary gas chromatography with electron-capture detection.