Pharmacokinetics and tolerability of formoterol in healthy volunteers after a single high dose of Foradil dry powder inhalation via Aerolizer.

OBJECTIVE: The pharmacokinetics of the long-acting beta2-agonist formoterol fumarate, which is a racemate of the (S,S)- and (R,R)-enantiomers were evaluated in 12 healthy (eight male, four female) volunteers after a single inhaled high dose of 120 microg of formoterol fumarate. The tolerability and safety were also assessed. METHODS: Each volunteer inhaled the single 120-microg dose through the Aerolizer device within 2-5 min, using ten 12-microg dry powder capsules for inhalation. Formoterol, i.e., the sum of both enantiomers, was determined in plasma over 24 h, whereas the separate enantiomers were determined in urine over 48 h. Incidence, seriousness and severity of adverse experiences, electrocardiogram (ECG), including the corrected QT interval (QTc) calculation, systolic blood pressure, heart rate, and plasma potassium levels were recorded. RESULTS: In nine of the 12 volunteers, the peak plasma concentration of formoterol was observed already at 5 min after inhalation. The absorption kinetics were complex, as depicted by multiple peaks or shoulders within 0.5-6 h after inhalation. Mean with (SD; n = 12) of maximum concentration (Cmax) and area under the curve (AUC) of formoterol in plasma were 266 (108) pmol x l(-1) and 1330 (398) pmol x l(-1), respectively. The moderate inter-individual variability in systemic exposure of formoterol reflects the homogeneous pharmacokinetics of the drug. A predominant slow elimination of formoterol from plasma with a mean half-life (t1/2) of 10 h was demonstrated. Assuming linear kinetics in plasma suggested by urinary data, the steady-state trough plasma levels of formoterol for a b.i.d. dosing regimen are predicted to amount to 20% of Cmax. In urine, mean with (SD; n = 10) of the amount excreted over 48 h was 3.61 (0.89)% of dose for the pharmacologically active (R,R)-enantiomer and 4.80 (1.33)% of dose for the (S,S)-enantiomer. The terminal half-lives calculated from the excretion rate-time curves, i.e., 13.9 h and 12.3 h for the (R,R)- and (S,S)-enantiomer, respectively, confirm the slow elimination of formoterol from plasma. The dose inhaled was 10 times the most frequently recommended dose (12 microg) and 5 times the highest recommended dose (24 microg). Ten of 12 subjects experienced mild and transient nervousness. Pulse readings demonstrated the maximum mean increase of 25.8 beats x min(-1) at 6 h. The mean maximum QTc increase was 25 msec at 6 h. Pulse and QTc values returned to baseline or close to baseline values at 24 h or before. Potassium levels in plasma decreased in eight out of 12 subjects; the lowest mean value was 3.53 mmol x l(-1) at 2 h post-dose. The lowest individual potassium measurement was 2.95 mmol x l(-1) between 15 min and 6 h. By 8 h post-dose all values had returned to within the normal ranges. CONCLUSIONS: The extremely fast appearance of formoterol in plasma shows the predominance of airways absorption shortly after inhalation. Due to a terminal elimination half-life of about 10 h, sustained systemic concentrations of formoterol are predicted for a twice daily treatment regimen without noteworthy accumulation. The excreted amounts in percent of dose of the enantiomers in urine and the enantiomer ratio are similar to data reported previously after lower doses and suggest linear kinetics for doses between 12 microg and 120 microg of formoterol fumarate. The expected side effects on heart rate, QTc interval, and plasma potassium were small and had no clinical consequences in spite of the very high dose of 120 microg (5 to 10 times the recommended therapeutic dose of Foradil). It should be noted that the impact of high doses may be greater in patients. Nevertheless these findings provide reassurance on the safety margin of formoterol after accidental and intentional overdosing.

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 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.

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.

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.

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.

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.

The effect of renal impairment on the pharmacokinetics of oxcarbazepine and its metabolites.

We have studied the effect of renal impairment on the pharmacokinetics of oxcarbazepine, its active monohydroxy-metabolite (which predominates in plasma), their glucuronides, and the inactive dihydroxy-metabolite after a single oral dose of oxcarbazepine (300 mg). Six subjects with normal renal function and 20 patients with various degrees of renal impairment participated. The mean areas under the plasma concentration-time curves of oxcarbazepine and its monohydroxy-metabolite were 2-2.5-times higher in patients with severe renal impairment (CLCR < 10 ml.min-1) than in healthy subjects. The apparent elimination half-life of the monohydroxy-metabolite [19 (SD 3) h] in these patients was about twice that in healthy subjects. The effect of renal impairment on the plasma concentrations of glucuronides was more marked. The renal clearances of the unconjugated monohydroxy-metabolite and its glucuronides (the main compounds recovered in urine) correlated well with creatinine clearance. The maximum target dose in patients with slight renal impairment (CLCR > 30 ml.min-1) should not be changed. In patients with moderate renal impairment (CLCR 10-30 ml.min-1) it should be reduced by 50%. In patients with severe renal impairment (CLCR < 10 ml.min-1), the glucuronides of oxcarbazepine and its monohydroxy-metabolite are likely to accumulate during repeated administration, and dosage adjustment of oxcarbazepine in these patients could not be proposed from this single administration study.

Pharmacokinetics of cadralazine and its hydrazino-metabolite in patients with renal impairment after repeated administration of 5 mg once daily.

Since the hydrazino-pyridazine metabolite of cadralazine, CGP 22 639 is believed to contribute to the activity of the drug, its pharmacokinetics and that of cadralazine were investigated in 8 hypertensive patients with renal impairment. The creatinine clearance (CLcr) of patients ranged from 10 to 60 ml/min. The concentrations of cadralazine in plasma and urine, and of CGP 22 639 (plus its possible hydrazones) in plasma were measured after single and repeated administration of 5 mg of cadralazine once daily. A hypotension possibly linked to cadralazine treatment was recorded on day 3 for the patient with CLcr = 10 ml/min. Metabolite concentrations were found to be at least twice as high as in other patients indicating that in this patient, the daily dose of 5 mg was probably too high. The pharmacokinetics of cadralazine were not modified by repeated administration. The drug and its metabolite were eliminated more slowly in patients with low creatinine clearance. The t1/2 of CGP 22 639 was about twice the t1/2 of the unchanged drug. In patients whose CLcr ranged from 19-37 ml/min the mean accumulation factor of apparent CGP 22 639 was 1.7 times that of the unchanged drug. It shows that the apparent CGP 22 639 accumulated more than the unchanged drug. A starting daily dose of 2.5 mg of cadralazine in patients with CLcr < 40 ml/min appears to be suited to take into account the pharmacokinetics of CGP 22 639. This dose can be increased by 2.5 mg steps if the antihypertensive effect is not sufficient (maximum dose with CLcr < 40 ml/min: 10 mg).(ABSTRACT TRUNCATED AT 250 WORDS)

Rapid determination of propyphenazone in plasma by high-performance liquid chromatography.

A rapid and simple high-performance liquid chromatographic assay for the determination of propyphenazone in plasma is described. Phenylbutazone was used as the internal standard. Plasma proteins were precipitated with acetonitrile before injection onto a 3-microns Supelcosil LC-18 column. The mobile phase, ethanol containing 0.2% (v/v) heptylamine-0.005 M potassium dihydrogenphosphate (30:70, v/v), was used at a flow-rate of 1.3 ml/min. The quantitation was performed by ultraviolet detection at a wavelength of 270 nm. The chromatographic time was 7 min. The within- and between-day coefficients of variation were less than 6% and the recoveries close to 100% for concentrations between 0.4 and 22 mumol/l. The limit of quantitation was 0.4 mumol/l (ca. 100 ng/ml).

[Distomatosis of the bile ducts. Value of retrograde cholangiography. Efficacy of triclabendazole]. / Distomatose des voies biliaires. Intérêt de la cholangiographie rétrograde. Efficacité du triclabendazole.

A case of chronic biliary fascioliasis is reported, which was confirmed by endoscopic retrograde cholangiography. After unsuccessful attempts of treatment with classic antiparasitic drugs, cure was obtained with triclabendazole the absorption of which was studied.

Fast liquid chromatography for the determination of drugs in plasma and combination with liquid-solid extraction in a fully automated system.

Fast liquid chromatography was applied to the assay of several drugs in plasma. Short columns, 3.3-4 cm long, packed with C18 material, 3 microns particle size, were used. The peaks were little subject to extra-column band-broadening because the investigated drugs were eluted with high capacity factors in order to obtain an adequate separation from plasma components. The main influences on efficiency were the response time of the detector and the solvent composition of the injected sample. Conventional apparatus was used. A fully automated analytical system combining liquid-solid extraction via disposable extraction columns and fast liquid chromatography on a small-dimensioned 3 microns particle size column is described for the assay of drugs in plasma. Automation was accomplished by using the Automatic Sample Preparation with Extraction Columns system.

Automated microanalysis of carbamazepine and its epoxide and trans-diol metabolites in plasma by column liquid chromatography.

A fully automated high-performance liquid chromatographic procedure for the simultaneous determination of carbamazepine and its main metabolites, epoxycarbamazepine and dihydroxycarbamazepine, in plasma is described. Liquid-solid extraction on disposable C18 columns and reversed-phase chromatography on a 3 microns particle size C18 column were combined and automated by using the Automatic Sample Preparation with Extraction Columns system. Ultraviolet detection was performed at 210 nm. 5,6-Dihydro-11-oxo-11H-dibenz[b,e]azepine-5-carboxamide was used as internal standard. A small plasma volume (100 microliters) was required. The total run time for the assay of one sample was about 10 min. The assay demonstrated good reproducibility. The limit of quantitation was 0.1 mumol/l (about 25 ng/ml).

Amocarzine investigated as oral onchocercacidal drug in 272 adult male patients from Guatemala. Results from three dose regimens spread over three days.

The clinical investigations with three types of a three days regimen of amocarzine permitted to adjust the fixed dosing to the body weight related dosing and subsequently the administration of amocarzine from fasting state to drug intake after food. The main objective to reach a dose with predictable and sustained absorption was achieved, and this in turn proved to be onchocercacidal and safe. A combined clinicopharmacokinetic study showed enhancement and consistency of amocarzine absorption after food. Quantitative assessment of the urinary excretion confirmed the presence of the N-oxide metabolite, which qualitatively was visible by a urine colorimetry. This assay proved useful for drug monitoring. Ultrasonography of onchocercal skin nodules detected changes within the nodules following amocarzine therapy. Histology after nodul-ectomy at four months post-therapy showed that 57% of the female worms were dead, 24% necrobiotic, and 19% alive; male worms were more necrobiotic. Skin microfilariae were reduced within one week to about 10% of the initial level and after one year they remained at about 20%. Skin punch biopsies on day 5 showed that most microfilariae were dead or moribund. Ocular reduction of microfilariae was also observed, although it was slower than in the skin. The visual acuity improved within the one year's observation time. Ocular and clinical tolerability was good, with one exception of neurological disturbance, which was fully reversible. Sequential testing of the liver function showed average values within the normal range. In conclusion, a repeat low dose regimen of amocarzine (3 mg/kg twice daily post-prandially for three consecutive days) was well absorbed with predictable plasma levels, macro- and microfilaricidal with good local and systemic tolerability in patients with moderate to heavy onchocerciasis. Amorcarzine is recommended for further clinical investigations, particularly in females and juveniles. Urine colorimetry and nodular ultrasonography are recommended for optional monitoring of amocarzine.

Onchocercacidal effect of three drug regimens of amocarzine in 148 patients of two races and both sexes from Esmeraldas, Ecuador.

The objective of this multidisciplinary clinical investigation was to test whether amocarzine was absorbed effectively and safely in patients of two races and either sex infected with Onchocerca volvulus while living in the holoendemic area of Esmeraldas Province, Ecuador. The prerequisite for a systemic onchocercacidal effect is the regular absorption of orally administered amocarzine. Single dosing after overnight fasting proved to produce irregular absorption of amocarzine, although some microfilaricidal effect was achieved. A pilot study with repeated low dose and postprandial administration of amocarzine showed a regular and predictable absorption with acceptable tolerability and a microfilaricidal effect lasting up to one year post-therapy. Since amocarzine and its major N-oxide metabolite are coloured agents, urine colorimetry was used to assess the urinary excretion of the N-oxide qualitatively. For the postprandial drug regimens plasma concentrations of amocarzine and its metabolite were determined at two selected time points in patients of two races and either sex; the results showed no major differences. Excision of onchocercal nodules was performed four months post-therapy. The pooled results of the histologic analysis of 100 patients with the same drug regimen read under blinded condition showed that 65% of the adult female worms were dead, 20% necrobiotic and 15% alive. The male worms were fewer and mainly necrobiotic. Control worm populations in Esmeraldas without chemotherapy showed that on the average 81.5% were alive and 18.5% dead. Amocarzine was also microfilaricidal producing a reduction of skin dwelling microfilariae to about 10% of the initial value within the first week after start of therapy and lasting for half a year at a 20% level. The reduction of ocular microfilarial was slower and reached 35-40% after one year. The general tolerability was acceptable to good. Reversible dermal reactions were usually mild and peaked as a rash in 57% of the patients on day 6. No prohibitive ocular intolerance was observed. Mild and reversible dizziness peaked on day 4 in 74% of patients. A positive reversible Romberg sign was found in 12 patients on day 4. Amocarzine, the first oral micro- and macrofilaricidal agent administered as a low dose repeat regimen (3 mg/kg twice daily and postprandial for three consecutive days) can be recommended for oral onchocercacidal therapy in adult patients. Clinical trials in juveniles should be encouraged.

Influence of food related to dose on the pharmacokinetics of amocarzine and of its N-oxide metabolite, CGP 13 231, after oral administration to 20 onchocerciasis male patients from Guatemala.

Twenty male patients from Guatemala infected with Onchocerca volvulus received a 3 mg/kg oral dose of amocarzine twice daily for three days. The patients were randomly assigned to the sequence fasting/non-fasting and non-fasting/fasting for the morning administration on days 1 and 3. All other doses were given after food intake. Blood samples on days 1 and 3 and urine fractions from days 3 to 5 were collected for the determination of the unchanged drug and of its N-oxide metabolite, CGP 13 231. The absorption of amocarzine and CGP 13 231 was slower and sustained for longer time in fed patients than in fasting ones. The mean AUC of amocarzine was significantly higher (about 20%) in fed patients. No significant difference was found for CGP 13 231. The relative improvement of bioavailability of amocarzine due to food was less prominent than previously obtained after a high dose of 1200 mg which demonstrated a bioavailability improvement of a factor of three. Therefore, saturable dose dependent absorption processes are likely to be involved for the administration in fasting conditions. Conversely, the concentrations of amocarzine in fed patients after 150 and 1200 mg were dose proportional, thus indicating linear kinetics. The cumulative urinary excretions of CGP 6140 ranged from 0.1 to 3.8% of the daily dose. Those of CGP 13 231 ranged from 31 to 64%. This total excretion was larger than that previously recorded in fasting patients after a single oral dose. The present results confirm the improvement of the bioavailability of the drug administered after food intake.

Concentrations of amocarzine in plasma of 71 Ecuadorian patients of two different races receiving 3 mg/kg b.i.d. and 5 mg/kg o.d. oral postprandial doses for 3 days.

The possible influence of sex, race and of postprandial administration conditions (either immediately after the end of meal or one hour later) on the plasma concentrations of amocarzine and its N-oxide metabolite, CGP 13 231, was investigated. 71 Ecuadorian patients (48 males and 23 females) of two different races (Indio and Negro) infected with Onchocerca volvulus participated in the study. The concentrations were measured on day 3 at times 3 and 6 h after postprandial administration in the morning of a treatment with either a dose of 5 mg/kg of amocarzine once daily (12 patients) or 3 mg/kg twice daily (59 patients) for 3 days. The concentrations of unchanged drug and of CGP 13 231 measured after the 5 mg/kg treatment were in the low range of those expected from dose proportionality by the comparison with the 3 mg/kg. After the 3 mg/kg dose, no significant difference in concentration of both compounds were detected between the male and female patients between Indio and Negro patients, between the administration immediately after food intake and one hour later. The only detected difference (P = 0.05) was that between Indio and Negro patients for the concentrations of CGP 13 231 at time 3 h. This difference was not confirmed at time 6 h. Therefore, the administration of amocarzine either immediately or one hour after food intake appeared to produce reproducible absorption conditions which were not influenced by sex and race.

Pharmacokinetics of cadralazine in a large group of hypertensive patients chronically treated with cadralazine: advantage over a conventional study in a small group of patients.

The concentrations of cadralazine in plasma were studied in 101 hypertensive patients treated with oral doses of 10, 15, or 20 mg of cadralazine once daily. Most of the patients received additionally a beta-blocking drug (n = 87) and a diuretic (n = 52). Few blood samples were collected in each patient on several occasions during the treatment, which usually lasted for more than 6 months. No accumulation of cadralazine in plasma occurred in any of the patients and the maximum concentrations were similar to those recorded in a small sample of healthy volunteers. The terminal half-life of elimination (3.6 h) was longer than that observed in healthy subjects (approximately 2.5 h). Conversely, the total clearance (197 ml/min) was lower (285 ml/min in healthy). The half-life and the total clearance in plasma were not dose dependent. In the patients treated for more than 6 months, no change in the pharmacokinetics of cadralazine was detected. The description of the distribution of concentrations showed that one-half of the patients behaved similarly to healthy subjects concerning half-life and total clearance. The other half presented a slower elimination of the drug (t 1/2 = 4.4 h and ClT = 130 ml/min) and these patients were significantly older (p = 0.01) than the former. This suggests that special attention should be paid to old hypertensive patients when a dose higher than 15 mg once daily is prescribed. Though concentrations were proportional to the dose, the body weight was not found to be a determining factor for dose adjustment.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of CGP 6140 (amocarzine) after oral administration of single 100-1600 mg doses to patients with onchocerciasis.

The concentrations of CGP 6140 [4-nitro-4'-(N-methyl-piperazinylthiocarbonylamido)-diphenylamine] and of its N-oxide metabolite, CGP 13,231, were measured in plasma and urine after single oral dose of 100-1600 mg of CGP 6140 to 41 fasted Ghanaian patients with Onchocerca volvulus infections. The absorption of CGP 6140 was rapid and its terminal elimination half-life was about 3 h. The plasma concentrations of CGP 6140 were essentially proportional to the dose. A greater variability in plasma concentrations was apparent after the 800 and 1600 mg doses indicating a poor bioavailability of the drug administered in fasting conditions to several patients. In plasma, the concentrations of CGP 13,231 were similar to those of CGP 6140. The amount of CGP 13,231 excreted in urine was 25-40% of the dose of CGP 6140 whereas only 1.5% was excreted as unchanged drug. If a single dose of drug is used for the treatment, the plasma concentration would be maintained for 3-4 h at a high level. At 8 h, the concentration falls to about 10% of the Cmax. If sustained plasma concentrations of the drug are needed for efficacy, twice daily administration would maintain the minimum concentration at about 10% of the Cmax.

The influence of food on the pharmacokinetics of CGP 6140 (amocarzine) after oral administration of a 1200 mg single dose to patients with onchocerciasis.

Eleven male patients from Mali with Onchocerca volvulus infections received in random order a 1200 mg single oral dose of CGP 6140 after an overnight fast and after food intake. The concentrations of CGP 6140 and of its N-oxide metabolite, CGP 13231, were measured in plasma and urine. Mean (+/- s.d.) AUC CGP 6140 values were 67.0 +/- 10.8 mumol l-1 h in fed and 22.0 +/- 17.2 mumol l-1 h in fasting patients. The mean maximum concentrations (Cmax) in plasma +/- s.d. were 12.7 +/- 2.8 mumol l-1 in fed and 4.7 +/- 4.1 mumol l-1 in fasting patients. The median time to Cmax was 3 h in fed and 2 h in fasting patients. Mean (+/- s.d.) AUC of the N-oxide metabolite was 59.9 +/- 10.7 mumol l-1 h in fed and 23.4 +/- 16.2 mumol l-1 h in fasting patients. The urinary recovery was less than 0.5% of dose for CGP 6140 in both fed and fasting conditions. It was 30.1 +/- 11.5 and 11.4 +/- 8.0% of the dose for the N-oxide metabolite in fed and fasting conditions, respectively. Variability in plasma concentrations and urinary recovery of CGP 6140 and of the N-oxide metabolite was greater in fasted patients. The low solubility of CGP 6140 in aqueous solutions at neutral pH and its higher solubility at acidic pH might explain the increase in bioavailability after food intake. The administration of CGP 6140 after food intake is therefore recommended for an optimal systemic effect.