Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer.

PURPOSE: To determine the maximum-tolerated dose, toxicities, and pharmacokinetic profile of the farnesyl protein transferase inhibitor R115777 when administered orally bid for 5 days every 2 weeks. PATIENTS AND METHODS: Twenty-seven patients with a median age of 58 years received 85 cycles of R115777 using an intrapatient and interpatient dose escalation schema. Drug was administered orally at escalating doses as a solution (25 to 850 mg bid) or as pellet capsules (500 to 1300 mg bid). Pharmacokinetics were assessed after the first dose and the last dose administered during cycle 1. RESULTS: Dose-limiting toxicity of grade 3 neuropathy was observed in one patient and grade 2 fatigue (decrease in two performance status levels) was seen in four of six patients treated with 1,300 mg bid. The most frequent clinical grade 2 or 3 adverse events in any cycle included nausea, vomiting, headache, fatigue, anemia, and hypotension. Myelosuppression was mild and infrequent. Peak plasma concentrations of R115777 were achieved within 0.5 to 4 hours after oral drug administration. The elimination of R115777 from plasma was biphasic, with sequential half-lives of about 5 hours and 16 hours. There was little drug accumulation after bid dosing, and steady-state concentrations were achieved within 2 to 3 days. The pharmacokinetics were dose proportional in the 25 to 325 mg/dose range for the oral solution. Urinary excretion of unchanged R115777 was less than 0.1% of the oral dose. One patient with metastatic colon cancer treated at the 500-mg bid dose had a 46% decrease in carcinoembryonic antigen levels, improvement in cough, and radiographically stable disease for 5 months. CONCLUSION: R115777 is bioavailable after oral administration and has an acceptable toxicity profile. Based upon pharmacokinetic data, the recommended dose for phase II trials is 500 mg orally bid (total daily dose, 1, 000 mg) for 5 consecutive days followed by 9 days of rest. Studies of continuous dosing and studies of R115777 in combination with chemotherapy are ongoing.

The orally administered P-glycoprotein inhibitor R101933 does not alter the plasma pharmacokinetics of docetaxel.

This Phase I study was performed to assess the feasibility of combining docetaxel with the new P-glycoprotein inhibitor R101933 and to determine the dose limiting toxicity of this combination. Fifteen patients received oral R101933 alone at a dose escalated from 200 to 300 mg twice daily (b.i.d.; cycle 0), an escalating i.v. dose of docetaxel (60, 75, and 100 mg/m2) as a 1-h infusion (cycle 1), and the combination (cycle 2 and further). Dose limiting toxicity consisting of mucositis and neutropenic fever was reached at the combination of docetaxel, 100 mg/m2, and R101933, 300 mg b.i.d., and the maximum tolerated dose was established at docetaxel, 100 mg/m2, and R101933, 200 mg b.i.d. Plasma concentrations of R101933 achieved in patients were in the same range as required in preclinical rodent models to overcome paclitaxel resistance. The plasma pharmacokinetics of docetaxel were not influenced by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 26.5 +/- 7.78 liters/h/m2 and 23.4 +/- 4.52 liters/h/m2 (P = 0.15) in cycles 1 and 2, respectively. These findings indicate that the contribution of a P-glycoprotein inhibitor to the activity of anticancer chemotherapy can now be assessed in patients for the first time independent of its effect on drug pharmacokinetics.

Alfentanil kinetics in the elderly.

Alfentanil disposition after an intravenous bolus of 50 micrograms/kg was followed in 15 elderly surgical patients and was compared to that in nine young adults. A two-compartment open model described alfentanil disappearance from plasma. Apparent volumes of distribution of the central compartment (201 and 211 ml/kg; means), at steady state (460 and 543 ml/kg), and of the AUC (746 and 722 ml/kg) in young adults and in elderly subjects did not differ. Plasma clearance was lower in elderly subjects (4.4 ml/min/kg) than in young adults (6.5 ml/min/kg), whereas terminal plasma t1/2 was longer in the elderly patients (137 and 83 min). Alfentanil dosage should therefore be reduced in elderly patients when large single doses, multiple doses, or long-term infusions are required.

Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects.

The pharmacokinetics of a novel antipsychotic agent, risperidone, and the prolactin response were studied in 12 dextromethorphan-phenotyped healthy men after administration of 1 mg risperidone intravenously, intramuscularly, and orally. The formation of the equipotent major metabolite, 9-hydroxyrisperidone, exhibited CYP2D6-related polymorphism. The plasma area under the concentration-time curve from time zero to infinity ratio of 9-hydroxyrisperidone to risperidone averaged 3 (intravenous and intramuscular) and 6 (oral administration) in the extensive metabolizers and 0.2 in the poor metabolizers. Risperidone half-life was about 3 hours in extensive metabolizers and 22 hours in poor metabolizers. Risperidone absolute oral bioavailability was 66%. The pharmacokinetics of the active moiety (risperidone plus 9-hydroxyrisperidone) varied little among subjects (mean terminal half-life, 20 +/- 2 1/2 hours; absolute oral and intramuscular bioavailability, 100%). The prolactin response correlated best with the plasma active moiety, which showed little hysteresis. It is concluded that risperidone metabolic polymorphism on increased plasma prolactin is minimal and that the active moiety is clinically relevant.

The pharmacokinetic properties of topical levocabastine. A review.

The linear and predictable pharmacokinetic properties of the histamine H1-receptor antagonist levocabastine make it particularly suitable for intranasal or ocular treatment of allergic rhinoconjunctivitis. Peak plasma concentrations (Cmax) occur within 1 to 2 hours of administration of single doses of levocabastine nasal spray and eye drops (0.2mg and 0.04mg, respectively). Drug absorption is incomplete after intranasal and ocular administration, with systemic availability ranging from 60 to 80% for levocabastine nasal spray and from 30 to 60% for the eye drops. However, as the amount of levocabastine applied intranasally and ocularly is small, the levocabastine plasma concentrations achieved are extremely low, with Cmax values in the ranges 1.4 to 2.2 micrograms/L and 0.26 to 0.29 micrograms/L for intranasal and ocular administration, respectively. Pharmacokinetic-pharmacodynamic modelling has indicated that the clinical benefits of levocabastine are predominantly mediated through local antihistaminic effects, although some systemic activity may contribute to the therapeutic efficacy of levocabastine nasal spray during long term use. Levocabastine undergoes minimal hepatic metabolism, i.e. ester glucuronidation, and is predominantly cleared by the kidneys. Approximately 70% of parent drug is recovered unchanged in the urine. Plasma protein binding is approximately 55% and the potential for drug interactions involving binding site displacement is negligible. Furthermore, the pharmacokinetics of this agent do not appear to be influenced by either age or gender. Levocabastine nasal spray and eye drops may thus be considered suitable for the treatment of allergic rhinoconjunctivitis in a wide patient population.

The pharmacokinetics of risperidone in humans: a summary.

Risperidone is rapidly and completely absorbed after oral administration; less than 1% is excreted unchanged in the feces. The principal metabolite was found to be 9-hydroxyrisperidone. Hydroxylation of risperidone is subject to the same genetic polymorphism as debrisoquine and dextromethorphan. In poor metabolizers the half-life of risperidone was about 19 hours compared with about 3 hours in extensive metabolizers. However, becuase the pharmacology of 9-hydroxyrisperidone is very similar to that of risperidone, the half-life for the "active fraction" (risperidone +9-hydroxyrisperidone) was found to be approximately 20 hours in extensive and poor metabolizers. We found that risperidone exhibited linear elimination kinetics and that steady state was reached within 1 day for risperidone and within 5 days for the active fraction.

Down regulation of serotonin-S2 receptor sites in rat brain by chronic treatment with the serotonin-S2 antagonists: ritanserin and setoperone.

Ritanserin is a potent and selective serotonin-S2 antagonist which slowly dissociates from the receptor sites, while setoperone has potent serotonin and moderate dopamine antagonistic properties and dissociates rapidly from the receptor sites. Acute administration of ritanserin (1-10 mg/kg) produced a non-competitive inhibition of 3H-ketanserin binding, measured ex vivo in washed frontal cortex membranes, which lasted for 12 h. This is in accordance with the slow dissociation of the drug from the receptor sites. Setoperone (1-10 mg/kg orally) also produced a partially non-competitive inhibition of 3H-ketanserin binding in washed membranes, which is unlike its rapid dissociation. In contrast, there was no inhibition of dopamine receptor binding in washed striatal membranes. Chronic oral administration of 10 mg/kg X day of the drugs significantly reduced the Bmax values of 3H-ketanserin, without changing the KD value when drug-free periods were longer than 1 day. The maximum reduction following 25 days' treatment with 14 mg/kg ritanserin was 50% at 1 day drug-free; the Bmax values gradually returned to the control value in about 12 days. The receptor half-life was calculated to be 3.5 days and the receptor synthesis rate 4 fmoles/mg tissue X day. Ritanserin treatment did not alter radioligand binding to serotonin-S1, alpha 1-, alpha 2- and beta-adrenergic, dopamine-D2, benzodiazepine and substance P sites. Chronic treatment with setoperone at 10 mg/kg X day, orally, significantly reduced the Bmax value of 3H-ketanserin binding in frontal cortex but treatment with 1 mg/kg X day did not. In contrast, a dose-dependent increase in the number of striatal dopamine-D2 sites was observed, in accordance with the moderate dopamine-antagonistic properties of setoperone. Dopamine-D2 receptor up regulation up to 150% of control values, was maintained at the same level for 9 days, it started to decline 12 days after stopping drug treatment. Following chronic treatment and drug withdrawal for more than 1 day, ritanserin and setoperone levels in whole brain homogenates were below detection level (less than 1 ng/g). The similar reduction in the Bmax values of 3H-ketanserin binding following chronic treatment with the rapidly dissociating setoperone and the slowly dissociating ritanserin, the absence of effect on the KD value, the slow reappearance of the receptor sites and the opposite effect on serotonin-S2 and dopamine-D2 receptors with setoperone suggest that real serotonin-S2 receptor down regulation occurs following antagonist treatment. The findings illustrate the difference in receptor regulation between the serotonergic and the dopaminergic system.(ABSTRACT TRUNCATED AT 400 WORDS)

Influence of age, renal and liver impairment on the pharmacokinetics of risperidone in man.

The pharmacokinetics of the antipsychotic agent risperidone were investigated in healthy young and elderly subjects, cirrhotic patients and patients with moderate and severe renal insufficiency. In a comparative trial, a single oral 1-mg dose was administered to fasting subjects. Plasma and urine concentrations of the parent compound risperidone and the active moiety (i.e. risperidone plus 9-hydroxy-risperidone) were measured by radioimmunoassays. No or only small changes in plasma protein binding were observed in hepatic and renal disease, whereas the protein binding was not influenced by aging. The inter-individual variability in plasma concentrations of the active moiety was much less than the variability in plasma concentrations of risperidone. Three out of six subjects, behaving like poor metabolizers, were on medication (thiethylperazine, amitriptyline, metoprolol) that may inhibit risperidone metabolism by CYP2D6 (debrisoquine 4-hydroxylase). The pharmacokinetics of risperidone in elderly and cirrhotic patients were comparable to those in young subjects, whereas total oral clearance was reduced in renal disease patients. The elimination rate and clearance of 9-hydroxy-risperidone was reduced in elderly and renal disease patients because of a diminished creatinine clearance. The CL(oral) of the active moiety, which is primarily 9-hydroxy-risperidone, was reduced by about 30% in the elderly and by about 50% in renal disease patients. In addition, the t1/2 of the active moiety was prolonged (19 h in young subjects versus about 25 h in elderly and renal disease patients). Based upon the pharmacokinetics of the active moiety, a dose reduction and a cautious dose titration is advised in the elderly and in patients with renal disease. In cirrhotic patients, the single-dose pharmacokinetics were comparable to those in healthy young subjects.

Pharmacokinetics and dose proportionality of domperidone in healthy volunteers.

Domperidone is a potent gastrokinetic agent and antinauseant currently undergoing clinical trials in the United States. The bioequivalence of 20 mg of domperidone given as free-base tablets and maleate salt tablets, and the bioavailability of base and maleate tablets relative to a solution, were studied in 21 fasting men using a crossover design. Plasma samples collected for up to 48 hours were analyzed for domperidone levels, using a sensitive and specific radioimmunoassay (RIA). The absorption of domperidone was very rapid, with mean peak plasma concentration (Cmax) values of 18.8, 15.0, and 20.7 ng/mL attained at 0.9, 1.2, and 0.6 hours after the administration of base tablet, maleate tablet, and solution, respectively. The mean elimination half-life (t1/2) ranged from 12.6 to 16.0 hours. The mean oral clearance (CL/F) after the solution dose was 4,735 +/- 2,017 mL/min and the mean apparent volume of distribution (Vd/F) was 6,272 +/- 5,100 L, indicating an extensive distribution of domperidone in the body. The area under the plasma concentration-time curve (AUC) data demonstrated bioequivalence of base and maleate tablets. The relative bioavailability for base tablet and maleate tablet was 107 +/- 50% and 116 +/- 47%, respectively, of that of the solution. Dose proportionality of domperidone was also studied in 12 subjects at solution doses of 10, 20, and 40 mg. Linear correlations between the dose and Cmax and AUC values were observed. Mean CL/F remained relatively constant after doses of 10, 20, and 40 mg (5,255 +/- 3,159, 4,842 +/- 1,774, and 4,380 +/- 1,289 mL/min, respectively), indicating linear pharmacokinetics of domperidone over the dose range studied.

Pharmacokinetics of orally administered levocabastine in patients with renal insufficiency.

The effects of renal insufficiency and hemodialysis on the pharmacokinetics of orally administered levocabastine were studied in six nondialysis patients and in six patients undergoing regular hemodialysis. Levocabastine .5 mg, supplied as a solution, was administered orally to each patient 1 hour after breakfast. Compared with data in healthy volunteers, the oral absorption and disposition of levocabastine were impaired in patients with renal insufficiency. The time to reach peak plasma concentration was increased and the peak plasma concentration was decreased in the patients with renal insufficiency compared with healthy volunteers. Urinary excretion of the unchanged drug, which is the major elimination pathway of levocabastine, was reduced in the patients with renal insufficiency. The decreased urinary excretion most likely contributed to the prolonged half-life (from 36 hours to 95 hours) and increased area under the plasma concentration-time curve (+56%) in the patients with renal insufficiency as compared with the healthy volunteers. Although the 6-hour hemodialysis procedure starting 4 hours after dosing eliminated 10% of the oral dose, the terminal half-life and the total area under the plasma concentration-time curve did not differ significantly between the hemodialysis and the nonhemodialysis patients. In conclusion, the current study showed that the initial oral absorption of levocabastine is reduced and that levocabastine elimination is prolonged in patients with renal insufficiency.

A pharmacokinetic study of intravenous itraconazole followed by oral administration of itraconazole capsules in patients with advanced human immunodeficiency virus infection.

A randomized, open-label, comparative study was conducted in 30 male patients with moderately advanced human immunodeficiency virus (HIV) infection to examine the pharmacokinetics of an investigational intravenous preparation of itraconazole compared with pharmacokinetics after administration of itraconazole capsules. The study also assessed whether adequate plasma concentrations of itraconazole could be rapidly achieved with the intravenous formulation and then maintained after cessation of intravenous therapy with itraconazole capsules. All patients received 200 mg intravenous itraconazole as a 1-hour infusion in 40% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) vehicle twice daily for 2 days, and then 200 mg intravenously once daily for 5 days. Patients then received itraconazole capsules, either 200 mg twice daily or 200 mg once daily for 28 days. Steady-state plasma concentrations of itraconazole were reached by day 3 with intravenous infusion, a much shorter time than observed with administration of itraconazole capsules. Steady-state concentrations of itraconazole and hydroxyitraconazole were effectively maintained during the rest of the intravenous infusions of itraconazole. Oral follow-up with administration of 200-mg capsules once daily could not maintain the plasma concentrations of itraconazole and hydroxyitraconazole obtained at the end of the intravenous treatment, whereas twice-daily oral administration maintained or increased these concentrations. Mean plasma concentrations of itraconazole and hydroxyitraconazole on day 7 were similar to those on day 36 in the twice-daily group. Mean renal clearance was comparable to mean total body clearance, and approximately 93% to 101% of the HP-beta-CD was excreted unchanged in urine within 12 hours of administration. The HP-beta-CD was essentially eliminated through the kidney, and little accumulation in the body was observed in this patient population. Adverse events during the intravenous phase were most commonly associated with intravenous administration. Intravenous infusion of itraconazole for 7 days followed by administration of itraconazole capsules twice daily for 28 days is an effective dose regimen in patients with advanced HIV infection.

Determination of the dose proportionality of single intravenous doses (5, 10, and 15 mg) of lubeluzole in healthy volunteers.

The dose proportionality of lubeluzole, a drug in clinical development for the treatment of acute ischemic stroke, was evaluated in a Phase I, single-center, open-label, randomized-dosing-sequence, three-way crossover clinical trial in 12 healthy adults. An equal number of male and female volunteers were enrolled in the trial, with a mean weight (+/- SD) of 73.2 +/- 11.9 kg, mean height (+/- SD) of 66.8 +/- 4.6 inches, and a mean age of 36.1 +/- 5.2 years. Subjects received intravenous infusions of 5 (A), 10 (B), and 15 mg (C) of lubeluzole over 1 hour on three separate occasions, with a minimum washout period of 2 weeks. The treatment sequences were A-B-C; A-C-B; B-A-C; B-C-A; C-A-B; and C-B-A. One male and one female were assigned to each sequence. After the 5-, 10-, and 15-mg doses, maximum concentration (Cmax) was 58.1, 113, and 138 microg/L, respectively, and the area under the curve from 0 to (AUC(0-infinity)) was 771, 1384, and 2025 microg x h/L. There were no statistically significant differences among the groups in mean terminal half-life, steady-state volume of distribution, total plasma clearance, or dose-normalized AUC(0-infinity). Dose-normalized values of Cmax differed significantly between the groups. No serious adverse events were reported, and no changes were observed in cardiac function, as judged by the QT(c) interval. The pharmacokinetics of lubeluzole appear to be linear at intravenous infusion doses of 5, 10, and 15 mg, and these doses are well tolerated by healthy adults.

Safety and pharmacokinetics of the neuroprotective drug lubeluzole in patients with ischemic stroke.

A total of 22 patients with acute ischemic stroke participated in two randomized, single-masked, placebo-controlled studies that evaluated the safety and pharmacokinetics of single escalating intravenous doses of lubeluzole. The first dose of study medication in all patients was given within 6 hours of the first sign of stroke onset. In the first study, 6 patients received a single 1-hour intravenous infusion of 5 mg of lubeluzole; 4 of these patients received an additional 10-mg dose 3 to 4 days later. Two additional patients received placebo. In the second study, 4 patients received a single 1-hour infusion of 10 mg of lubeluzole, and 2 patients received placebo. After a safety evaluation of the second study, 6 additional patients received 15 mg of lubeluzole, and 2 other patients received placebo. Lubeluzole had no clinically relevant effects on any cardiovascular variable compared with placebo. The majority of adverse experiences were mild to moderate and resolved during treatment. No unexpected electroencephalogram abnormalities were observed, and no evidence of epileptiform discharges was found in any of the patients. At the end of the infusion, plasma lubeluzole concentrations decayed biphasically, with mean distribution half-lives of 46.3 to 101.0 minutes and mean terminal half-lives of 20.8 to 27.7 hours. Comparisons of the dose-normalized value of the individual plasma concentrations at the end of the infusion and the total area under the curve from time 0 to infinity suggested that lubeluzole exhibited linear kinetics over the dose range evaluated in patients with ischemic stroke. In the small number of patients studied, lubeluzole's favorable safety profile was demonstrated by the lack of clinically relevant effects on cardiovascular variables and by neurologic examination and clinical laboratory findings.

Antifungal pulse therapy for onychomycosis. A pharmacokinetic and pharmacodynamic investigation of monthly cycles of 1-week pulse therapy with itraconazole.

BACKGROUND AND DESIGN: In the treatment of onychomycosis, oral therapies have generally been given as a continuous-dosing regimen. For example, the suggested dose of itraconazole for the treatment of onychomycosis has thus far been 200 mg/d for 3 months. Based on the advances in our understanding of the pharmacokinetics of itraconazole, we investigated the efficacy and nail kinetics of intermittent pulse-dosing therapy with oral itraconazole in patients who were suffering from onychomycosis. Fifty patients with confirmed onychomycosis of the toenails, predominantly Trichophyton rubrum, were recruited and randomly assigned to three (n = 25) or four (n = 25) pulses of 1-week itraconazole therapy (200 mg twice daily for each month). Clinical and mycological evaluation of the infected toenails, and determination of the drug levels in the distal nail ends of the fingernails and toenails, were performed at the end of each month up to month 6 and then every 2 months up to 1 year. RESULTS: In the three-pulse treatment group, the mean concentration of itraconazole in the distal ends of the toenails ranged from 67 (month 1) to 471 (month 6) ng/g, and in the distal ends of the fingernails, it ranged from 103 (month 1) to 424 (month 6) ng/g. At month 11, the drug was still present in the distal ends of the toenails at an average concentration of 186 ng/g. The highest individual concentrations of 1064 and 1166 ng/g were reached at month 6 for toenails and fingernails, respectively. At end-point follow-up, toenails in 84% of the patients were clinically cured with a negative potassium hydroxide preparation and culture in 72% and 80% of the patients, respectively. In the four-pulse treatment group, the mean concentration of itraconazole in the distal ends of the toenails ranged from 32 (month 1) to 623 (month 8) ng/g, and in the distal ends of the fingernails, it ranged from 42 (month 1) to 380 (month 6) ng/g. The highest individual concentrations of 1549 and 946 ng/g were reached at month 7 for toenails and at month 9 for fingernails, respectively. At month 12, the drug was still present in the distal ends of the toenails at an average concentration of 196 ng/g. At end-point follow-up, toenails in 76% of the patients were clinically cured with a negative potassium hydroxide preparation and culture in 72% and 80% of the patients, respectively. There were no significant intergroup differences between the three- and four-pulse treatment groups for the primary efficacy parameters. The drug was well tolerated with no significant side effects in either patient group. CONCLUSIONS: Following pulse therapy with itraconazole (400 mg/d given for 1 week each month for 3 to 4 months), the drug has been detected in the distal ends of nails after the first pulse, and it has reached therapeutic concentrations with further therapy. After stopping the last pulse, the drug remains in the nail plate at levels above 300 ng/g for several months. Clinical cure rates between 76% and 84% and negative mycological examination findings between 72% and 80%, respectively, were observed in toenail onychomycosis. The data suggest that pulse therapy with itraconazole is an effective and safe treatment option for onychomycosis.

Risperidone: effects of formulations on oral bioavailability.

The bioavailability of risperidone was evaluated in an open-label, randomized, two-way, crossover study comparing a 1-mg tablet with a 1-mg/ml oral solution. Both formulations were administered as a single 1-mg dose with a 10-day washout period between treatments. Of 26 healthy men who entered the study, 23 completed both treatment periods. Plasma concentrations of risperidone and the active moiety (risperidone plus its active metabolite, 9-hydroxyrisperidone) were determined by radioimmunoassays. For key pharmacokinetic values (Cmax, AUC), the 90% CIs on the relative bioequivalence of risperidone, 9-hydroxyrisperidone, and the active moiety were contained within the equivalence range of 80-120% (80-125% for log-transformed data). The results demonstrate that the 1-mg/ml oral solution and the 1-mg tablet are bioequivalent.

Effect of food on the pharmacokinetics of a new hydroxypropyl-beta-cyclodextrin formulation of itraconazole.

STUDY OBJECTIVE: To compare the pharmacokinetics of a single 100-mg oral dose of itraconazole administered as 10 ml of a 10-mg/ml itraconazole solution in hydroxypropyl-beta-cyclodextrin under fasting versus postprandial conditions. DESIGN: Open-label, two-way, randomized, crossover study. SETTING: Janssen Research Foundation, Belgium. PATIENTS: Twelve healthy volunteers. INTERVENTIONS: Blood samples were obtained for pharmacokinetic analyses immediately before dosing and at regular intervals up to 96 hours after each dose. Blood and urine samples were obtained for hematologic, biochemical, and urinary safety analyses at baseline and at the end of the study. MEASUREMENTS AND MAIN RESULTS: The mean peak plasma concentrations of both itraconazole and its active metabolite hydroxy-itraconazole were significantly higher under fasting conditions than under postprandial conditions. The mean times to peak concentration for both the parent compound and its metabolite were significantly shorter under fasting than under nonfasting conditions. The mean areas under the curve (AUC0-infinity and AUC0-24 hrs) were also significantly higher under fasting than under postprandial conditions. CONCLUSIONS: Our findings suggest that the higher bioavailability of this new formulation of itraconazole may be of benefit in seriously ill patients who are not able to ingest adequate quantities of food. The fact that the solution was also well tolerated and was not associated with clinically significant changes in any laboratory value further underscores the potential utility of this dosing form.

Pharmacokinetics of lubeluzole (Prosynap) after single intravenous doses in healthy subjects.

The single-dose pharmacokinetics of lubeluzole were investigated in 2 single-blind, placebo-controlled, dose-escalation studies in healthy male subjects. In the first study, 6 subjects received an intravenous infusion of 2.5, 5, and 10 mg lubeluzole. In the second study, a 15 mg dose of lubeluzole was administered to 6 subjects, of whom 5 also received 20 mg and 2 also 25 mg lubeluzole. Following the infusion, plasma lubeluzole concentrations decayed biphasically, with a mean distribution half-life (t1/2alpha) of 30 to 65 minutes and a mean terminal half-life (t1/2beta) of 15 to 24 hours. The results of the 2 studies indicate that lubeluzole exhibits linear kinetics over the dose range tested in healthy male subjects.

The pharmacokinetics of oral itraconazole in AIDS patients.

To test the hypothesis that absorption of orally administered itraconazole may be reduced in patients with the Acquired Immunodeficiency Syndrome (AIDS), 8 patients with AIDS were given two 100 mg capsules of itraconazole for 15 days. Plasma levels were measured by HPLC hourly for the first 8 h following ingestion, then at 24, 48, 72 and 96 h on days 1, 8 and 15. Peak plasma levels occurred after approximately 4 h. Mean peak plasma concentrations were 446 +/- 196 and 530 +/- 214 ng mL-1 at days 8 and 15. The area under the curve over 24 h (AUC0-24) was 2105 +/- 1241, 7679 +/- 3838 and 8748 +/- 4385 ng mL-1 h for days 1, 8 and 15, respectively. Steady-state was achieved after one week of dosing. There was no evidence of hepatotoxicity and one patient stopped itraconazole due to a rash. It may be concluded that the absorption of oral itraconazole capsules is reduced in AIDS patients, by a factor of approximately 50%, when compared with normal volunteers. AIDS patients may require higher doses of itraconazole than used in non-AIDS patients to achieve comparable plasma levels.

Itraconazole pharmacokinetics in the female genital tract: plasma and tissue levels in patients undergoing hysterectomy after a single dose of 200 mg itraconazole.

Twenty patients who underwent hysterectomy received a single dose of 200 mg itraconazole at different moments before surgery. At the moment of surgery, a urine sample, blood sample and tissue samples of different organs of the female genital tract were collected. Blood levels and tissue levels of itraconazole were measured by means of an HPLC method. Itraconazole blood levels were lower than the corresponding tissue levels in the various organs of the female genital tract. This finding for itraconazole is different from findings with ketoconazole, indicating that itraconazole has a higher affinity for tissue than ketoconazole. Urine levels of itraconazole were virtually undetectable in all samples. None of the patients complained of side-effects, and blood biochemical parameters all remained within the normal limits. The premedication with itraconazole had no effect whatsoever on the induction and maintenance of and recovery from the anaesthesia. No abnormal effects on ECG were observed.