Once-daily Oral Administration Research Articles

Safety, Tolerability, and Pharmacokinetics of ICL670, a New Orally Active Iron‐Chelating Agent in Patients with Transfusion‐Dependent Iron Overload Due to β‐Thalassemia

ICL670 is an orally active representative of a new class of tridentate iron chelator developed for the treatment of blood transfusion-dependent iron overload in chronic anemias. In this randomized, double-blind study, patients with transfusion-dependent beta-thalassemia received single oral doses of ICL670 ranging from 2.5 to 80 mg/kg to investigate its safety, tolerability, and pharmacokinetics and to obtain preliminary information on pharmacodynamic effects. ICL670 was well tolerated, and no safety problems occurred up to 80 mg/kg. A plasma half-life of 11 to 19 hours was found for ICL670, supporting once-daily oral administration. AUC0-24 h and Cmax of ICL670 increased nearly proportionally with the dose. The urinary excretion of ICL670 and its iron complex was less than 0.1% of the dose, and this was in accordance with the expected predominant iron fecal excretion induced by ICL670 (based on preclinical experiments). Notwithstanding, a positive trend toward increased amounts of urinary excreted iron was observed when the AUC0-24 h of ICL670 and the iron complex exceeded specific threshold values at the 40- and 80-mg/kg dose levels.

Atazanavir.

Atazanavir is a novel azapeptide protease inhibitor with high specificity for, and activity against, HIV-1 protease. The resistance profile of atazanavir is distinct, with an I50 L protease substitution appearing to be the signature mutation. Atazanavir was not associated with increases in total cholesterol, low density lipoprotein-cholesterol or triglyceride levels after 108 weeks. Atazanavir has a pharmacokinetic profile that allows for once-daily oral administration. It is a moderate inhibitor of hepatic cytochrome P450 enzymes and interacts with several drugs. In combination with stavudine plus didanosine, atazanavir 200, 400 or 500 mg once daily produced a rapid and sustained reduction from baseline in viral load of 2.57, 2.42 and 2.53 log(10) copies/mL, respectively, in treatment-naive patients after 48 weeks, compared with a decrease of 2.33 log(10) copies/mL with nelfinavir 750 mg three times daily. Nausea was the most clinically relevant adverse event reported in patients receiving atazanavir-based regimens.

Persistent Analgesic Effect of Sustained Release Diclofenac Sodium Preparation on BovineType II Collagen-Induced Arthritis.

As a sustained release preparation of diclofenac sodium (DF-Na), we developed a preparation (SR318B) that was expected to exhibit a persistent analgesic effect by once-daily oral administration. In this study, we investigated the persistence of the analgesic effect of SR318B using female cynomolgus monkeys with arthritis induced by sensitization with bovine type II collagen combined with FreundÕs complete adjuvant. Cynomolgus monkeys in which arthritis was induced to the same severity received oral administration of SR318B (1 mg DF-Na/kg) once daily for 14 days. The mean ellipsoid area of the proximal interphalangeal joints in the monkeys slightly increased before administration on day 3 in the control group. In contrast, the area decreased after day 3 and significantly decreased on day 13 in the SR318B treatment group. The plasma diclofenac (DF) level reached the highest point at 6 hr after administration on day 13, then decreased. The plasma level was lower than the quantification limit 20 hr after administration on both days 0 and 13. In contrast, DF was detected in synovial fluid 24 hr after the initial and final administration. Based on the above findings, SR318B exhibits a persistent analgesic effect on collagen-induced arthritis. While the plasma DF concentration decreased to a level lower than the quantification limit at 20 hr, DF was still detected in the synovial fluid 24 hr after administration. Therefore, the retention of DF in inflammatory regions may play an important role in the analgesic effect.

Weekly dosing with the platelet-derived growth factor receptor tyrosine kinase inhibitor SU9518 significantly inhibits arterial stenosis.

The platelet-derived growth factor (PDGF) ligands and their receptors have been implicated as critical regulators of the formation of arterial lesions after tissue injury. SU9518 (3[5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrol-3-yl]propionic acid) is a novel synthetic indolinone that potently and selectively inhibits the cellular PDGF receptor kinase and PDGF receptor-induced cell proliferation. Inhibition of PDGF receptor phosphorylation in cell-based assays occurs within 5 minutes after drug exposure and persists for >6 hours after drug removal. The pharmacokinetics indicate plasma levels that exceeded the effective concentration required to inhibit the PDGF receptor in cells for up to 8 hours or 7 days after a single oral or subcutaneous administration, respectively. In the rat balloon arterial injury-induced stenosis model, once-daily oral or once-weekly subcutaneous administration of SU9518 reduced intimal thickening of the carotid artery (ratio of neointimal to medial area, 1.94+/-0.38 versus 1.03+/-0.29 [P<0.01] 2.21+/-0.32 versus 1.34+/-0.45 [P<0.01], respectively). These studies provide the rationale to evaluate PDGF receptor tyrosine kinase inhibitors, including inhibitors related to the indolinone, SU9518, for the treatment of arterial restenosis.

Antiviral activity of clevudine [ L-FMAU, (1-(2-fluoro-5-methyl-β, L-arabinofuranosyl) uracil)] against woodchuck hepatitis virus replication and gene expression in chronically infected woodchucks ( Marmota monax)

L-FMAU [1-(2-fluoro-5-methyl-β, L-arabinofuranosyl) uracil] has been shown to be an effective inhibitor of hepatitis B virus (HBV) and duck hepatitis B virus replication in cell culture and duck hepatitis B virus replication in acutely infected Peking ducks. The woodchuck hepatitis virus (WHV) and its natural host, the Eastern woodchuck ( Marmota monax), have been established as a predictive model for the evaluation of antiviral therapies against chronic HBV infection. In this report, the antiviral activity of l-FMAU against WHV replication in chronically infected woodchucks is described. Four weeks of once-daily oral administration of L-FMAU significantly reduced viremia, antigenemia, intrahepatic WHV replication, and intrahepatic expression of woodchuck hepatitis virus core antigen (WHcAg) in a dose-dependent manner. At the highest dose administered (10 mg/kg/d), significant reductions of intrahepatic WHV RNA and covalently closed circular (ccc)WHV-DNA levels also were observed. The reduction in viremia was remarkably rapid at the higher doses of L-FMAU, with greater than 1,000-fold reductions in WHV-DNA serum levels observed after as little as 2 to 3 days of therapy. Following the withdrawal of therapy, a dose-related delay in viremia rebound was observed. At the highest doses used, viremia remained significantly suppressed in at least one half of the treated animals for 10 to 12 weeks' posttreatment. No evidence of drug-related toxicity was observed in the treated animals. L-FMAU is an exceptionally potent antihepadnaviral agent in vitro and in vivo, and is a suitable candidate for antiviral therapy of chronic HBV infection. (H EPATOLOGY 2001;33:254-266)

Studies of the neurotoxicity of oral artemisinin derivatives in mice.

Intramuscular injections of high doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether produce an unusual pattern of selective damage to brain stem centers in experimental mammals, predominantly those involved in auditory processing and vestibular reflexes. We have shown recently in adult Swiss albino mice that parenteral artesunate, a water-soluble derivative, is significantly less neurotoxic than intramuscular artemether in this murine model. Using the same model, in which the drugs were administered daily for 28 days, the neurotoxic potential of the oral drugs was assessed and compared with the parenteral routes of administration. The dose causing neurotoxicity or death in 50% of animals (ED50), was approximately 300 mg/kg/day of oral artemether and artesunate compared to 50 mg/kg/day of intramuscular artemether. Doses of intramuscular artemether > 100 mg/kg/day were uniformly lethal. When oral artemether was given in peanut oil there was an increase in neurotoxicity and mortality compared with the aqueous suspension (P = 0.002), and when the food pellets were coated with artemether in oil, giving relatively constant oral intake, neurotoxicity was further increased; ED50 = 150 mg/kg/day (P = 0.017). These data indicate that once-daily oral administration of artesunate or artemether is relatively safe, presumably because the central nervous system is exposed transiently, whereas constant exposure either from depot intramuscular injection of oil-based drug, or constant oral intake carries relatively greater neurotoxic potential.

Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Tolerability of Metrifonate in Patients with Probable Alzheimer Disease

A randomized, double-blind, placebo-controlled, parallel-group study was undertaken to evaluate the safety and tolerability of a once-daily oral administration of metrifonate in patients with probable mild to moderate Alzheimer disease. Metrifonate was given as a loading dose of 125-225 mg based on weight (2.5 mg/kg) for 2 weeks, followed by a maintenance dose of 50-90 mg based on weight (1.0 mg/kg) for 4 weeks. Twenty-nine patients received metrifonate, and 10 patients received placebo. Metrifonate produced a mean erythrocyte acetylcholinesterase inhibition at the end of treatment of 86.3%. The proportion of patients who experienced at least one adverse event was comparable between the metrifonate (76%) and placebo (80%) groups. Selected adverse events in disfavor of metrifonate (defined as those for which the incidence in the metrifonate and placebo groups differed by at least 10%) were diarrhea, nausea, leg cramps, and accidental injury. Adverse events were predominantly mild in intensity and transient. No severe adverse events were experienced by any patient. The most notable hemodynamic change observed during metrifonate treatment was a clinically insignificant mean decrease in the heart rate (by electrocardiogram) of approximately 9 beats/min, compared with an approximate 3-beats/min decrease for the placebo group. No muscle weakness was observed in this study. No clinically relevant laboratory abnormalities, such as liver toxicity, or changes in exercise tolerance or pulmonary function tests were found with metrifonate treatment. This metrifonate dose provided a high level of acetylcholinesterase inhibition, which was associated in these patients with a favorable safety and tolerability profile. Indeed, the magnitude of the peripheral acetylcholinesterase inhibition is the highest tolerable inhibition level yet observed.

Levofloxacin versus ciprofloxacin versus lomefloxacin in acute pyelonephritis

Objectives. To evaluate, in two randomized, multicenter trials, levofloxacin compared with ciprofloxacin and lomefloxacin for efficacy and safety in treating acute pyelonephritis. Methods. We enrolled a total of 186 patients with bacteriologically proved infection. Of these, 89 patients in both trials combined received levofloxacin 250 mg once daily; 58 received ciprofloxacin 500 mg twice daily in the first trial (double blind); and 39 received lomefloxacin 400 mg once daily in the second trial (open label). Microbiologic response of patients evaluable for microbiologic efficacy was the primary efficacy variable, and clinical response of microbiologically evaluable patients was the secondary efficacy variable in both studies. Results. Escherichia coli was the most prevalent pathogen. At 5 to 9 days after the end of treatment, 95% of uropathogens were eradicated in patients who received levofloxacin compared with 94% in the ciprofloxacin-treated group and 95% in the lomefloxacin-treated group. The clinical cure rate was 92% for levofloxacin in both studies combined, 88% for ciprofloxacin, and 80% for lomefloxacin. Drug-related adverse events were reported by 2% of levofloxacin-treated patients, 8% of ciprofloxacin-treated patients, and 5% of lomefloxacin-treated patients. Conclusions. The once-daily oral administration, proven efficacy, and good tolerability make levofloxacin an excellent choice for empiric treatment of acute pyelonephritis.

Pharmacokinetic study of low- versus high-dose medroxyprogesterone acetate (MPA) in women.

The present study was conducted to compare the pharmacokinetics (PK) of low-dose versus high-dose medroxyprogesterone (MPA) as a once-daily oral administration. Of 32 patients, all women, enrolled in this PK study, 18 received 600 mg MPA daily and 14 received 1200 mg daily. Detailed PK data were obtained on day 1 and after more than 4 weeks of MPA treatment. In addition, multiple data for the minimum steady-state concentration (Css min) were analyzed. The MPA serum concentrations were measured by high-performance liquid chromatography. Wide interpatient variability was found in the PK parameters obtained both on day 1 and after more than 4 weeks. There were no clear relationships between the oral dose and the MPA peak concentration (Cmax), area under the time versus concentration curve (AUC), or mean Css min. Weight gains of 10% or more were demonstrated more frequently in the high-dose group (P < 0.01). Liver dysfunction (n = 5) did not influence the PK of MPA. Five patients demonstrated extremely low AUC and Cmax (< 10 ng/ml) values on day 1. Phenobarbital, dexamethasone and betamethasone were being taken concomitantly with the MPA each by one patient. The serum MPA concentrations were markedly increased after the discontinuation of phenobarbital in that patient, suggesting a drug interaction. At present we cannot recommend the high dose of MPA, except in clinical studies, from a PK or a pharmacodynamic points of view.

Dirithromycin

Dirithromycin is a semisynthetic derivative of erythromycin, a 14-membered ring macrolide antibiotic. The drug is converted during absorption and distribution, to an active metabolite 9-( S)-erythromycylamine, which is the predominant compound found in plasma and extravascular tissues. High tissue concentration of erythromycylamine is achieved after oral doses of dirithromycin, with slow release back into the circulation. 1 The mechanism of action of dirithromycin is like that of erythromycin and other macrolides. These compounds inhibit RNA-dependent protein synthesis. 1–3 It has recently been suggested that all macrolides stimulate dissociation of peptidyl-tRNA from ribosomes during the elongation phase, leading to inhibited protein synthesis. 2 The antimicrobial spectrum of dirithromycin is similar to that of erythromycin, although the drug offers no significant advantage with regard to MIC values. In vitro against Gram-positive isolates, dirithromycin exhibits similar potency to that of clarithromycin, erythromycin, roxithromycin, and clindamycin. In vivo, dirithromycin is active against penicillin-susceptible Staphylococcus aureus, beta-hemolytic streptococci, and Streptococccus pneumoniae. Dirithromycin is as effective as penicillin VK against streptococcal pharyngitis and tonsilitis, and as effective as erythromycin against acute superimposed chronic bronchitis and skin and soft-tissue infections. In comparison with other newer macrolides, dirithromycin has shown similar or lesser in vitro activity. In particular, Haemophilus influenzae, Bacteroides spp., Peptococcus-Peptostreprococcus spp., Clostridium perfringens, Legionella spp., Neisseria gonorrhoeae, and Chlamydia trachomatis were all less sensitive to dirithromycin than azithromycin or clarithromycin. 3,4 Once-daily oral administration of dirithromycin (500 mg) has been demonstrated to be similar in efficacy to erythromycin (250 mg, 4 times daily), each for approximately 7 days, in the treatment of acute bronchitis or acute exacerbations of chronic bronchitis in controlled studies. 1,3 Proven or presumed pathogen eradication rates were 83 and 86% for acute bronchitis patients treated with dirithromycin and erythromycin, respectively. Corresponding bacteriological response rates in acute exacerbations of chronic bronchitis were 75 to 84% with dirithromycin and 75 to 82% with erythromycin. Both agents achieved clinical cure or improvement in over 85% of the patients with either condition. The main advantage of dirithromycin over erythromycin appears to be once-daily administration. Lilly launched dirithromycin in September 1993, in Spain, received approval from the FDA in August 1995, and launched it during October 1995.

Determination of fluconazole concentrations in the prostatic and seminal vesicle fluid (split ejaculate).

The concentrations of fluconazole, a systemic antifungal agent, were determined in the split ejaculate of seven healthy volunteers. Following once-daily oral administration of fluconazole 200 mg over a period of 5 days, the fluconazole levels were determined in ejaculate samples which had been divided into two consecutive fractions upon collection. Simultaneously, a blood sample was drawn for the determination of fluconazole serum levels. It was shown that the fluconazole concentrations determined in both ejaculate fractions corresponded to those found in the serum. As the first fraction of the ejaculate originates in the prostate, the prostatic fluconazole concentrations are likely to be similar to the fluconazole levels found in th ejaculate.

Selection of dose regimens of azithromycin .

The unique pharmacokinetics of azithromycin are characterized by high, sustained tissue concentrations. The concentrations of azithromycin were predicted, following various multiple dose regimens, from concentrations in tonsillar, prostatic, and uterine tissues following single oral doses. Following a five-day treatment regimen (500 mg on day 1, followed by 250 mg on days 2-5), or a three-day regimen (500 mg daily for three days), concentrations of azithromycin in tonsillar tissue, representative of respiratory tract tissues, will continuously be greater than the MICs for key target pathogens (Streptococcus pyogenes, Haemophilus influenzae, Staphylococcus aureus) in infections of the respiratory tract for up to 10 days. Since tissue concentrations above the MICs for infecting organisms were correlated with efficacy in animal models of infection, short treatment regimens consisting of once-daily oral administration of azithromycin should be effective in the treatment of a variety of infections. A single 1 g oral dose will provide concentrations in the uterus and prostate, representing urogenital tissues, above the MIC for Chlamydia trachomatis for approximately 10 days. Thus, this regimen should be effective in the treatment of chlamydial infections of the genital tract.

The U.S. clinical experience with lomefloxacin, a new once-daily fluoroquinolone

Lomefloxacin is a new fluoroquinolone antimicrobial agent that has undergone extensive worldwide clinical evaluation. This report summarizes the safety and efficacy of lomefloxacin in the treatment of uncomplicated urinary tract infections, complicated urinary tract infections, acute exacerbations of chronic bronchitis, and for prophylaxis during urinary tract surgery. The clinical data presented are an overview of all clinical studies conducted in the United States to date. The results have been derived from multiple studies in which patients received lomefloxacin or a comparative agent in either blinded or open-label studies. During the course of the clinical program in the United States, lomefloxacin has been compared with oral norfloxacin, ciprofloxacin, and cefaclor, as well as parenteral cefotaxime. In all instances, the once-daily oral administration of lomefloxacin was either equally effective or statistically significantly superior in clinical and/or bacteriologic efficacy to these comparative agents. In addition, the comparators were administered either two or three times per day, except in the surgical prophylaxis studies, in which single doses of each antibiotic were administered preoperatively. These results attest to the value of the convenience and simplicity of the oral dosing regimen for lomefloxacin. During the course of the clinical program, lomefloxacin was well tolerated, with most adverse events of mild to moderate severity. In general, the incidence of adverse events for patients and subjects receiving lomefloxacin was comparable to that observed in patients treated with comparator drugs. The most common adverse events were related to the gastrointestinal tract (nausea and diarrhea), the skin and appendages (photosensitivity), and the central nervous system (dizziness and headache).

Ursodeoxycholic acid for the treatment of primary sclerosing cholangitis: A 30-month pilot study

We investigated the effects of once-daily oral administration of 10 mg/kg ursodeoxycholic acid (generic name, ursodiol) on elevated serum enzyme activities, bilirubin, cholesterol, bile acids and symptoms in patients with primary sclerosing cholangitis. A 30-mo, open-label, pilot trial was designed to cover four periods: (a) 3 mo of pretreatment observation (period 1), (b) 6 mo on ursodiol (period 2), (c) 3 mo withdrawal of treatment (period 3) and (d) 18 mo of extended retreatment (period 4). Diagnosis was confirmed by cholangiography and liver biopsy specimens. We enrolled 12 patients with persistently elevated pretreatment alkaline phosphatase and gamma-glutamyltransferase levels (at least twice the upper limit of normal), and observed them for a median of 37 mo. Significant reductions in serum total cholesterol levels and in serum enzyme activities indicating cholestasis and hepatocellular injury occurred during ursodiol treatment in both treatment periods 2 and 4 and relapsed with treatment interruption in period 3. Elevated serum bilirubin and symptoms of disabling fatigue, pruritus and diarrhea were improved by ursodiol. Improvements have continued after 2 yr of treatment in 10 patients (1 patient had a transplantation after he relapsed on withdrawal of ursodiol therapy; another died of postoperative complications of colon resection for carcinoma). No other cases of clinical deterioration were observed in the retreatment period. The longer term reductions of alkaline phosphatase, transaminases, bilirubin and cholesterol after 2 yr of treatment were even greater than the initial reductions after 6 mo of treatment. These results justify initiation of larger, controlled clinical trials, with serial morphological evaluations of the liver and biliary tree.

The Effect of a Once-Daily Oral Dose of Nadolol on Intraocular Pressure in Normal Volunteers

We compared the effects of once-daily oral administration of 20 mg and 40 mg of nadolol vs placebo in 40 normal volunteers in a randomized, double-masked trial. Each of 23 women and 17 men (ranging in age from 18 to 50 years) had intraocular pressure, pulse rate, blood pressure, pupil size, amplitude of accommodation, and near point measured immediately before treatment and then at 24 hours, day 8, and day 15 after treatment. Both dosages of nadolol produced significant decreases in intraocular pressure at three hours (P less than .001). Although both dosages decreased intraocular pressure at 24 hours compared with placebo, only the change with the 40-mg dose was significant (P less than .05). Although both dosages produced significant decreases in pulse rate and blood pressure, side effects were minimal.

Time course of plasma drug levels during once-daily oral administration of clomipramine.

Fourteen depressed in-patients were treated with 150 mg clomipramine (CLO) daily, given as one oral dose. Using a gas-chromatographic method, concentrations of CLO and desmethyl clomipramine (DMCLO) were determined in plasma samples taken at frequent intervals during 24 h. The plasma level of each compound 12 h after the dose correlated well with the average value in the same patient, calculated over the whole 24-h period. Levels at other times gave poorer correlations, and at 24 h it was particularly poor. Plasma DMCLO concentrations were usually maximum 4-6 h after the dose. The ratios of maximum to minimum levels averaged only 1.31 +/- 0.15 SD. Peak CLO levels occurred 3 or 4 h after the dose. Maximum; minimum ratios averaged 2.72 +/- 0.73 SD, contrasting with the much smaller fluctuations of plasma nortriptyline (NT) levels observed in patients given this drug once daily. The difference is not due to a shorter half-life of CLO, but to the absorption and/or distribution behaviour of the two drugs. Although not fully understood, this difference between tertiary and secondary amines appears to hold generally among the tricyclic antidepressants.