Effect of food on the bioavailability of triclabendazole in patients with fascioliasis.

AIMS: Preliminary results indicate higher absorption of triclabendazole (TCBZ) administered postprandially. Therefore, the influence of food on the pharmacokinetics of TCBZ and its active sulphoxide (TCBZ-SO) and sulphone (TCBZ-SO2) metabolites was investigated. METHODS: Two single doses (10 mg kg(-1)) of TCBZ were administered to 20 patients with fascioliasis. Ten patients were first given the drug after a high energy breakfast and then, 48 h later, after an overnight fast. The other 10 patients first received the drug in fasting state and then, 48 h later, after breakfast. A low energy breakfast was served 2 h after drug administration for fasting state. RESULTS: Compared with the fasting state, an increased AUC and Cmax after food intake (significant, P < 0.0001) was shown from the values of TCBZ, TCBZ-SO and TCBZ-SO2. The mean AUC for TCBZ (fasting: 1.55, fed: 5.72 micromol l(-1) h), TCBZ-SO (fasting: 177, fed: 386 micromol l(-1) h) and TCBZ-SO2 (fasting: 13.9, fed: 30.5 micromol l(-1) h) indicated a large availability increase with food and the strong systemic predominance of the active sulphoxide metabolite over the unchanged drug. (All patients were cured at the end of the trial except one who required a second course of two postprandial doses of triclabendazole (10 mg kg(-1) each). Tolerability to the treatment among the patients was good. CONCLUSIONS: The administration of triclabendazole with food is recommended for improved systemic availability in patients with fascioliasis or paragonimiasis.

The effect of age on the pharmacokinetics of valsartan.

Twelve young (mean age 23 years, range 18-28) and 12 elderly (mean age 76 years, range 65-89) volunteers were given a single oral dose of 80 mg valsartan after an overnight fast. Each group consisted of six male and six female subjects. Mean systemic exposure to valsartan was higher in the elderly when compared with the young (AUC(0-24 h), 52% increase and AUC(0-infinity), 70% increase). Variability, as shown by the coefficient of variation (CV), was larger for the elderly subjects and ANOVA of the log transformed AUC showed a significant difference between the two groups. This difference was largely brought about by five elderly subjects (one male, four females), whose AUC was about 2-fold higher than the rest of the group. For the remaining elderly subjects, plasma valsartan AUC was similar to that observed for the young volunteers. This higher systemic exposure in five of the elderly subjects is not thought to be of clinical relevance when data from the patient population are considered. Other covariates--such as body weight, comedication, creatinine clearance, valsartan kinetics (absorption rate, distribution, and elimination)--did not explain the higher AUC in this subset of the elderly group. Data from the present study were compared with population kinetic data obtained from larger clinical trials including hypertensive patients in all age groups. Using this population approach, there was no difference in the pharmacokinetics of valsartan between male and female patients. Also, a relationship between plasma clearance of valsartan and age was established. The median age of patients in the hypertensive pool was 55 years. For an average 70-year-old patient, plasma clearance of valsartan is predicted to fall by 22% compared with an average 55-year-old. For the population this difference is not sufficient to warrant initial dose adjustment based on age per se. The covariate age, does not completely explain the variability in the pharmacokinetics of valsartan within the general population. The treatment was well tolerated.

The influence of food on the disposition of the antiepileptic rufinamide in healthy volunteers.

The effect of food on the pharmacokinetics of the antiepileptic rufinamide was investigated in healthy volunteers. Twelve subjects were treated with single pre-oral doses of 600 mg of rufinamide after overnight fasting or a fat and protein rich breakfast. Mean (+/- S.D.) areas under the plasma concentration-time curves (AUCs) of the unchanged compound were 57.2 (16) micrograms mL-1 h when given to the fasted volunteers and 81.7 (22.2) micrograms mL-1 h (p = 0.0001) when given after the breakfast. The average AUC was increased by 44% when rufinamide was given with food and the maximum concentration (Cmax) by about 100%. The time at which Cmax was reached (tmax) was shorter (8 h in fasted conditions and 6 h in fed after breakfast); the terminal half-life was not influenced by concomitant intake of food.

Comparative bioavailability of letrozole under fed and fasting conditions in 12 healthy subjects after a 2.5 mg single oral administration.

Letrozole is a new non-steroidal inhibitor of the aromatase enzyme system. It is currently under development for the treatment of postmenopausal women with advanced breast cancer. To investigate the influence of food on the bioavailability of letrozole, 12 healthy male volunteers were treated under fed and fasted conditions with single oral doses of 2.5 mg letrozole in film-coated tablets. Plasma concentration profiles were determined. No significant difference in the extent of absorption (AUC or AUC0-8 h) was observed between the two treatments but the rate of letrozole absorption decreased slightly under fed conditions. However, in view of the half-life of about 2 d this small change in the absorption rate is not considered to be of clinical relevance for treatment with repeated administrations.

Determination of artemether and its metabolite, dihydroartemisinin, in plasma by high-performance liquid chromatography and electrochemical detection in the reductive mode.

An analytical method for the determination of artemether (A) and its metabolite dihydroartemisinin (DHA) in human plasma has been developed and validated. The method is based on high-performance liquid chromatography (HPLC) and electrochemical detection in the reductive mode. A, DHA and artemisinin, the internal standard (I.S.), were extracted from plasma (1 ml) with 1-chlorobutane-isooctane (55:45, v/v). The solvent was transferred, evaporated to dryness under nitrogen and the residue dissolved in 600 microliters of water-ethyl alcohol (50:50, v/v). Chromatography was performed on a Nova-Pak CN, 4 microns analytical column (150 mm x 3.9 mm I.D.) at 35 degrees C. The mobile phase consisted of pH 5 acetate-acetonitrile (85:15, v/v) at a flow-rate of 1 ml/min. The analytes were detected by electrochemical detection in the reductive mode at a potential of -1.0 V. Intra-day accuracy and precision were assessed from the relative recoveries (found concentration in % of the nominal value) of spiked samples analysed on the same day (concentration range 10.9 to 202 ng/ml of A and 11.2 to 206 ng/ml of DHA in plasma). The mean recoveries over the entire concentration range were from 96 to 100% for A with C.V. from 6 to 13%, from 92% to 100% for DHA (alpha-tautomer) with C.V. from 4 to 16%. For A, the mean recovery was 96% at the limit of quantitation (LOQ) of 10.9 ng/ml with a C.V. of 13%. For DHA, the mean recovery was 100% at the LOQ of 11.2 ng/ml with a C.V. of 16%.

Absolute bioavailability of letrozole in healthy postmenopausal women.

Letrozole is a new non-steroidal inhibitor of the aromatase enzyme system. It is currently under development for the treatment of postmenopausal women with advanced breast cancer. Absolute bioavailability of letrozole when given orally as one 2.5 mg film-coated tablet in comparison to the same dose given intravenously as a bolus injection was studied in 12 healthy postmenopausal women. Letrozole absolute systemic bioavailability after p.o. administration was 99.9 +/- 16.3%. Elimination of letrozole was slow. Total-body clearance of letrozole from plasma after i.v. administration was low (2.21 L h-1). The calculated distribution volume at steady state (1.87 L kg-1) suggests a rather high tissue distribution. Biotransformation of letrozole is the main elimination mechanism with the glucuronide conjugate of the secondary alcohol metabolite being the predominant species found in urine. The two study treatments were tolerated equally well.

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.

Automated and sensitive method for the determination of formoterol in human plasma by high-performance liquid chromatography and electrochemical detection.

An automated high-performance liquid chromatography (HPLC) method for the determination of formoterol in human plasma with improved sensitivity has been developed and validated. Formoterol and CGP 47086, the internal standard, were extracted from plasma (1 ml) using a cation-exchange solid-phase extraction (SPE) cartridge. The compounds were eluted with pH 6 buffer solution-methanol (70:30, v/v) and the eluate was further diluted with water. An aliquot of the extract solution was injected and analyzed by HPLC. The extraction, dilution, injection and chromatographic analysis were combined and automated using the automate (ASPEC) system. The chromatographic separations were achieved on a 5 microm, Hypersil ODS analytical column (200 mm x 3 mm I.D.), using (pH 6 phosphate buffer, 0.035 M + 20 mg/l EDTA)-MeOH-CH3CN (70:25:5, v/v/v) as the mobile phase at a flow-rate of 0.4 ml/min. The analytes were detected with electrochemical detection at an operating potential of +0.63 V. Intra-day accuracy and precision were assessed from the relative recoveries of calibration/quality control plasma samples in the concentration range of 7.14 to 238 pmol/l of formoterol base. The accuracy over the entire concentration range varied from 81 to 105%, and the precision (C.V.) ranged from 3 to 14%. Inter-day accuracy and precision were assessed in the concentration range of 11.9 to 238 pmol/l of formoterol base in plasma. The accuracy over the entire concentration range varied from 98 to 109%, and precision ranged from 8 to 19%. At the limit of quantitation (LOQ) of 11.9 pmol/l for inter-day measurements, the recovery value was 109% and C.V. was 19%. As shown from intra-day accuracy and precision results, favorable conditions (a newly used column, a newly washed detector cell and moderate residual cell current level) allowed us to reach a LOQ of 7.14 pmol/l of formoterol base (3 pg/ml of formoterol fumarate dihydrate). Improvement of the limit of detection by a factor of about 10 was reached as compared to the previously described methods. The method has been applied for quantifying formoterol in plasma after 120 microg drug inhalation to volunteers. Formoterol was still measurable at 24 h post-dosing in most subjects and a slow elimination of formoterol from plasma beyond 6-8 h after inhalation was demonstrated for the first time thanks to the sensitivity of the method.

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.

Bioequivalence assessment: a pharmaceutical industry perspective.

Various aspects of bioequivalence are investigated in this paper. Some aspects dealing with bioequivalence studies conducted either during the development of the drug or after its marketing will be presented and discussed: Bioequivalence of highly variable drugs with the associated problem of widening the acceptance range or alternative solutions. Bioequivalence for the final market image. Bioequivalence for investigating the food effect. Bioequivalence in special population such as children, non Caucasian population. Bioequivalence based on in vitro data or literature. New approaches in bioequivalence interpretation. Bioequivalence and analytical methods which are not sensitive or specific enough.

Direct microtitre plate radioimmunoassay of savoxepine in unextracted plasma.

An original solid phase method for direct radioimmunoassay of the antipsychotic savoxepine (CGP 19,486 A) in plasma has been developed which does not require the extraction of the parent drug with organic solvents. The assay showed good reproducibility over the working concentration range 1.9-30.6 nmol/l with intra- and inter-assay coefficients of variation < or = 16%. The procedure, which requires only small volumes of plasma (10 microliters), is simple to handle and well suited for routine analysis. The method allowed to investigate the pharmacokinetics of savoxepine in schizophrenic patients given low oral doses of the drug.

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.

Automated analysis of a novel anti-epileptic compound, CGP 33,101, and its metabolite, CGP 47,292, in body fluids by high-performance liquid chromatography and liquid-solid extraction.

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.

Stereospecific high-performance liquid chromatographic determination of an S(-)-benzopyran methyl ester derivative (CGP 50 068), its (-)-carboxylic acid metabolite (CGP 55 461) and the related (+)-enantiomer (CGP 54 228) in human and dog plasma.

The simultaneous determination of CGP 50 068, S(-)-enantiomer (I), its (-)-carboxylic acid metabolite CGP 55 461 (II) and the related (+)-enantiomer CGP 54 228 (III) by stereospecific high-performance liquid chromatography, in human plasma, is described. The three compounds and racemic acebutolol, used as internal standard, were isolated from plasma by liquid-solid extraction on disposable C18 columns. The resolution and determination of I and the two carboxylic acid enantiomers were achieved by direct chromatography using a Chiral-AGP column refrigerated at 5 degrees C. The mobile phase was tetrabutylammonium iodide in a pH 7 phosphate buffer solution used at a constant flow-rate of 0.5 ml/min. The UV detection wavelength was set at 270 nm. The reproducibility and accuracy of the method were found to be suitable over the concentration range 0.56-28.0 mumol/l for II and III and 2.0-26.7 mumol/l for I.

Stable isotope methodology for studying the performance of metoprolol Oros tablets in comparison to conventional and slow release formulations.

Metoprolol Oros tablets were designed to deliver their drug content as a constant rate over a period of time longer than that currently recorded with slow-release dosage forms. The bioavailability of 7/95, 14/190 and 21/285 Oros tablets was compared to that of either 100 mg conventional or 200 mg slow-release Lopresor tablets in 3 two-period change over experiments. In each experiment, 6 healthy volunteers received intravenous deuterated metoprolol concomitantly with one of the Oros systems or with one of the other two formulations. The Oros tablets gave rise to lower and steady plasma levels of metoprolol over 24 h than the other formulations. Their mean absorption time was around 3 times longer than that of the slow-release tablets. The amount of the drug absorbed unchanged was linearly related to the dose. The influence of the gastrointestinal transit time on the performance of Oros tablet was limited. These studies demonstrated the value of the stable isotope methodology in bioavailability assessment for drugs presenting a high inter-subject variability in their plasma clearance such as metoprolol.

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.

Automated microanalysis of oxcarbazepine and its monohydroxy and transdiol metabolites in plasma by liquid chromatography.

An automated high-performance liquid chromatographic method for the simultaneous determination of oxcarbazepine and its monohydroxy and transdiol metabolites in plasma is described. 5,6-Dihydro-11-oxo-11H-dibenz[b,e]azepine-5-carboxamide was used as internal standard. Liquid-solid extraction from plasma (100 microliters) on 50 mg Bond-Elut C18 cartridges was automatically performed by the Automatic Sample Preparation with Extraction Columns (ASPEC) system. A reversed-phase column (ODS Hypersil, 3 microns particle size, 4 cm x 4.6 mm I.D.) was used with acetonitrile-methanol-0.01 M potassium dihydrogenphosphate as mobile phase. The eluted compounds were detected at 210 nm. The limit of quantitation was 0.2 mumol/l for oxcarbazepine and 0.1 mumol/l for its metabolites. No interference with concomitantly administered anti-epileptic drugs such as phenobarbital, phenytoin, valproic acid or carbamazepine, was found.

Inter- and intra-subject variability of metoprolol kinetics after intravenous administration.

The pharmacokinetics of metoprolol were assessed from the data of 3 experiments in which intravenous deuterated metoprolol was given concomitantly with various oral metoprolol formulations to healthy volunteers. The plasma levels after intravenous administration were well described by a biexponential equation. However, a deviation from a pure biphasic decline was observed over a short period of time, immediately after the rapid elimination phase. The inter- and intra-subject variability of the parameters describing the two-compartment model was large. The intra-subject variability of the terminal half-life and the plasma clearance was lower than their inter-subject variability. The plasma clearance was linearly related to 1/t1/2. Contrarily to the other parameters of the model, t1/2 appeared to be a characteristic of the subject.