Pharmacokinetics and Buccal Mucosal Concentrations of a 15 Milligram per Kilogram of Body Weight Total Dose of Liposomal Amphotericin B Administered as a Single Dose (15 mg/kg), Weekly Dose (7.5 mg/kg), or Daily Dose (1 mg/kg) in Peripheral Stem Cell Transplant Patients

The pharmacokinetics and safety of extended-interval dosing of prophylactic liposomal amphotericin B (L-AMB) in peripheral stem cell transplant recipients were evaluated. The patients received L-AMB daily at 1 mg/kg of body weight or weekly at 7.5 mg/kg or received L-AMB as a single dose (15 mg/kg). The buccal mucosal tissue concentrations of L-AMB were measured. Of the 24 patients enrolled, 5 withdrew after the initial dose due to an infusion-related reaction (n = 2) or significant increases in the serum creatinine (Scr) levels (n = 3). Weekly L-AMB dosing (7.5 mg/kg) produced mean plasma concentrations of >0.300 μg/ml for the first 7 days and >0.220 μg/ml for 7 days after the second dose. A single L-AMB dose (15 mg/kg) produced mean plasma concentrations of >0.491 μg/ml for at least 7 seven days. These concentrations are within the range of the MICs reported in the literature for susceptible strains of Candida and are at the lower limits of the MICs for Aspergillus spp. Extended-interval dosing produced buccal mucosal tissue concentrations well in excess of the MICs reported in the literature for susceptible strains of Candida and Aspergillus spp. Infusion-related reactions occurred in 24% of the patients. Baseline and end-of-study Scr, electrolyte (K⁺, Mg²⁺, PO₄), and serum transaminase levels were similar across the dosage groups. Five (31%) patients met the nephrotoxicity definition prior to completion of the study. Patients in the weekly or single-dose groups experienced nephrotoxicity significantly faster than the patients in the daily dosing cohort. A weekly L-AMB dose (7.5 mg/kg) or a single L-AMB dose (15 mg/kg) produced sufficient concentrations in plasma and highly vascular tissue to warrant further studies of the safety, efficacy, and practicality of the weekly prophylactic administration of L-AMB.Amphotericin B (AMB) exhibits concentration-dependent fungicidal activity against many common opportunistic fungal pathogens (19, 20). A dose-fractionation study with a murine disseminated candidiasis model demonstrated that maximization of the maximum drug concentration in plasma (C_max)/MIC ratio optimizes the efficacy of AMB (2). Theoretically, this should enable the intermittent administration of large amounts of AMB, which could make its use by ambulatory patients more practical. However, in practice, maximization of the concentration-dependent activity of AMB deoxycholate is difficult due to its dose-related nephrotoxicity. However, lipid AMB formulations are safer and demonstrate subtle pharmacokinetic differences in disposition from that of AMB deoxycholate, which allows the administration of higher doses. Lipid AMB formulations such as liposomal amphotericin B (L-AMB) should enable clinicians to optimize the pharmacodynamic properties of AMB and facilitate their use by ambulatory patients.Data from studies with neutropenic animals suggest that the administration of a single dose or intermittent doses of L-AMB up to 20 mg/kg of body weight can be employed to prevent or manage infections due to yeasts or molds (1, 22). Higher L-AMB doses produce increased intravascular concentrations, which may facilitate its penetration into certain tissues and which may produce reductions in the fungal burdens in those tissues more marked than those achieved with other AMB formulations (17, 28). In mice, L-AMB administered at 15 mg/kg thrice weekly produced sufficiently high and sustained kidney and spleen concentrations to provide prophylactic efficacy against systemic challenge with a Candida sp. 3 and 6 weeks posttreatment (30). In a murine model, the administration of a single prophylactic L-AMB dose (1, 5, 10, or 20 mg/kg) 7 to 9 days prior to challenge with Candida albicans or Histoplasma capsulatum produced increased L-AMB kidney and spleen concentrations which correlated with dose-dependent increases in efficacy (14).In humans, L-AMB has the pharmacokinetic profile of a small unilamellar vesicle. L-AMB is slowly cleared from the bloodstream; has a long circulation half-life (t_1/2), and achieves a high C_max and a high level of systemic drug exposure (area under the concentration-time curve [AUC]) but has a small volume of distribution (V) (4, 5). L-AMB exhibits a triphasic plasma concentration profile (5-7). The mononuclear phagocytic system (MPS) is primarily responsible for the tissue uptake and distribution of lipid AMB formulations (16, 29). L-AMB is not efficiently cleared by the MPS due to its small particle size distribution (diameter, <100 nm) (11, 12). The incorporation of AMB into a small unilamellar vesicle liposome changes its MPS uptake and alters its distribution and subsequent excretion (5).A nonlinear relationship between the L-AMB dosage and the plasma AUC from time zero to 24 h (AUC_0-24), the plasma AUC from time zero to infinity (AUC_0-∞), and C_max was observed in immunocompromised adults (32). The values of the pharmacokinetic parameters increased following the administration of up to 10 mg/kg/day but declined with subsequent increases in the dosage to 15 mg/kg/day, suggesting an alteration in elimination at higher doses (32). However, the disposition in tissue was not assessed in that study. Liposomal drugs sequestered within tissues of the MPS may not be able to diffuse freely back into the plasma prior to elimination and may be slowly eliminated from those tissue compartments (5, 12). Thus, whether changes in the elimination of L-AMB from the plasma reflect altered elimination or enhanced tissue penetration in humans is unknown.Animal studies have demonstrated the importance of including tissue drug concentrations in the assessment of the pharmacokinetics of L-AMB in plasma (14, 17, 30). However, for technical and ethical reasons, such data from analyses of the pharmacokinetics in humans are often lacking (1, 4).The purpose of the pilot study described here was to investigate the pharmacokinetics and safety of extended-interval dosing of prophylactic L-AMB in medically stable peripheral stem cell transplant (PSCT) recipients. Moreover, by using a readily accessible tissue (buccal mucosal tissue), this study sought to assess the persistence of L-AMB in the tissues of these patients.(Preliminary findings of this work were presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, November 2004, Washington, DC [abstr. A-35].)     

Effect of Food on the Pharmacokinetics and Pharmacodynamics of a Single Oral Dose of Tegoprazan

PurposeTegoprazan is a potassium-competitive acid blocker (P-CAB) that is designed to treat acid-related diseases through a fundamentally different mechanism than that of proton pump inhibitors (PPIs). Because PPIs inhibit only activated parietal cell H⁺/K⁺ adenosine triphosphatase, stimulation of parietal cells by a meal is necessary for optimal results. In contrast, P-CABs can inactivate proton pumps without acid activation and bind to both activated and inactivated adenosine triphosphatase. This study evaluates the effect of food consumption on the pharmacokinetic and pharmacodynamic properties of tegoprazan after a single oral dose in healthy men.MethodsIn this open-label, 2-period crossover study, 24 healthy men were randomized to 1 of 2 treatment sequence groups: administration of tegoprazan under the fasting condition and administration of tegoprazan under the fed condition. The dosing periods of both sequence groups were separated by a washout period of 7 days. At each dosing period, the participants received a single dose of 200 mg of tegoprazan followed by pharmacokinetic and pharmacodynamic analysis.FindingsAfter the oral administration of 200 mg tegoprazan, the C_max was decreased and delayed under the fed condition compared with that of the fasting condition. However, no significant differences were observed in the AUC and the time of gastric acid suppression (inhibition of integrated acidity) during 24 hours.ImplicationsThe pharmacokinetic and pharmacodynamic properties of tegoprazan are independent of food effect; thus, tegoprazan could be administered regardless of the timing of food consumption in patients. ClinicalTrials.gov identifier: NCT01830309.     

Pharmacokinetics of a New Anticonvulsant (CGP 33101) in Epileptic Male Patients and Healthy Male Subjects after Single Ascending Oral Doses of 400--1200 mg

Information on the pharmacokinetic behavior of a new anticonvulsant agent (CGP 33101) was obtained after oral administration of ascending doses to male epileptic patients maintained on existing antiepileptic drug (AED) therapy, as well as to healthy male subjects. Single doses of 400, 800 and 1200 mg were administered to 12 of the 16 epileptic patients participating in the clinical trial and all 3 healthy subjects; the remaining patients received placebo doses on each dosing occasion. The study's primary objectives were to obtain single-dose add-on tolerability information, as well as preliminary pharmacokinetic data for the drug candidate. Either placebo or 400, 800 and 1200 mg of the compound, administered as 200-mg tablets, were coadministered with enzyme-inducing antiepileptic medications to the patients participating in the trial. These AEDs dilantin, tegretol, depakote, mysoline and tranxene) were administered individually or as combination therapy of two or three, with each patient being on the existing therapy for a minimum of 3 weeks prior to receiving the drug candidate (CGP 33101) as an add-on. Three healthy male subjects were included in the study to provide concurrent pharmacokinetic data at equivalent doses, as well as additional safety data in the absence of concomitant medication. Plasma concentrations of the new drug candidate were determined in samples obtained predose through 120-h postdose, with a 5-day washout period between doses. Preliminary pharmacokinetic parameters, such as peak plasma concentrations (C(max), times to peak levels (T(max)), areas under the plasma concentration-time curve (AUC) and terminal half-lives (T(1/2)), were determined in both epileptic patients and healthy subjects following all three doses. The mean T(max) values were similar for all three dose levels in both patients and subjects, indicating that the rate of absorption was comparable. Mean C(max) values increased in a dose-related manner with increasing dose in epileptic patients. The corresponding values showed a dose-proportional relationship in healthy subjects. The relationship between C(max) values and the administered dose did not change in patients or subjects when the data was corrected for dose and/or body weight. After the peak, plasma levels declined, but were still quantifiable in most patients and subjects at 36 h following all three doses. The mean AUC values increased in a dose-proportional manner with increasing dose in healthy subjects. The corresponding mean patient data appeared to increase in a dose-related manner. The relationship between AUC values and size of the administered dose did not change in either patients or subjects when the data was corrected for dose and/or body weight. The terminal elimination half-lives (T(1/2)) were apparently shorter in patients compared to the healthy subjects and were independent of the close administered.     

Safety and Pharmacokinetics of Single Intravenous Dose of MGAWN1, a Novel Monoclonal Antibody to West Nile Virus

West Nile Virus (WNV) is a neurotropic flavivirus that can cause debilitating diseases, such as encephalitis, meningitis, or flaccid paralysis. We report the safety, pharmacokinetics, and immunogenicity of a recombinant humanized monoclonal antibody (MGAWN1) targeting the E protein of WNV in a phase 1 study, the first to be performed on humans. A single intravenous infusion of saline or of MGAWN1 at escalating doses (0.3, 1, 3, 10, or 30 mg/kg of body weight) was administered to 40 healthy volunteers (30 receiving MGAWN1; 10 receiving placebo). Subjects were evaluated on days 0, 1, 3, 7, 14, 21, 28, 42, 56, 91, 120, and 180 by clinical assessments, clinical laboratory studies, electrocardiograms (ECGs), and pharmacokinetic and immunogenicity assays. All 40 subjects tolerated the infusion of the study drug, and 39 subjects completed the study. One serious adverse event of schizophrenia occurred in the 0.3-mg/kg cohort. One grade 3 neutropenia occurred in the 3-mg/kg cohort. Six MGAWN1-treated subjects experienced 11 drug-related adverse events, including diarrhea (1 subject), chest discomfort (1), oral herpes (1), rhinitis (1), neutropenia (2), leukopenia (1), dizziness (1), headache (2), and somnolence (1). In the 30-mg/kg cohort, MGAWN1 had a half-life of 26.7 days and a maximum concentration in serum (C_max) of 953 μg/ml. This study suggests that single infusions of MGAWN1 up to 30 mg/kg appear to be safe and well tolerated in healthy subjects. The C_max of 953 μg/ml exceeds the target level in serum estimated from hamster studies by 28-fold and should provide excess WNV neutralizing activity and penetration into the brain and cerebrospinal fluid (CSF). Further evaluation of MGAWN1 for the treatment of West Nile virus infections is warranted.West Nile Virus (WNV) is a neurotropic enveloped flavivirus. Since 1999, there have been more than 29,000 cases of confirmed symptomatic WNV infection in the United States, which include more than 12,000 cases of West Nile neuroinvasive disease (WNND) and more than 1,100 deaths. WNND is estimated to occur in approximately 1 of 150 infections, and it is likely that as many as 2 million people have been infected by the virus (4, 11, 13, 16, 20). WNV is now the most common cause of epidemic viral encephalitis in the United States, and it will likely remain an important cause of neurological disease for the foreseeable future (5). No effective therapy or vaccine is available for humans.Anecdotal case reports of WNV encephalitis patients who were treated with intravenous immunoglobulin (IVIG) from convalescent WNV-infected persons provide some support for the efficacy of neutralizing antibodies against WNV (2). A placebo-controlled, randomized, double-blind human clinical trial with an IVIG product (Omr-IgG-am), which was sponsored by the Collaborative Antiviral Study Group (CASG), was terminated in December 2006. As of April 2010, no analysis of the data had been published.MGAWN1 is a high-affinity, humanized monoclonal antibody (MAb) that specifically recognizes the E (envelope) protein of WNV (12). MGAWN1 exhibits neutralizing and fusion-inhibitory activity against WNV but exhibits no reactivity or neutralization of closely or distantly related flaviviruses (14). The mechanism of virus neutralization and clearance likely involves the binding of MGAWN1 to cell surface-attached virus particles (12) and the prevention of E protein conformational changes required to release virus core particles from the endosomes into the cytoplasm (22).Pharmacology studies have demonstrated that MGAWN1 is effective both prophylactically and therapeutically in WNV-infected mice and hamsters (8-10, 14). A single dose of MGAWN1 significantly improves survival when administered as late as 5 days postinfection, a time after the establishment of neurological infection. Toxicology studies performed on uninfected rats have revealed no toxicities at single intravenous doses as high as 100 mg/kg of body weight. At 300 mg/kg, minimal to moderate hypertrophy of cells lining the hepatic sinusoids and increased mitotic hepatocytes were noted in female animals at 14 days postinfusion, although no changes in serum chemistry, including liver function test results, were detected. Based on these data, the NOAEL (no-observed-adverse-effect level) was determined to be 100 mg/kg.This phase 1 study evaluated the safety, tolerability, and pharmacokinetics (PK) of single escalating doses of MGAWN1 in healthy subjects.     

Comparison of Pharmacokinetics of Enrofloxacin After Single Oral Bolus and Pulse Dose Administration in Broiler Chicken

Enrofloxacin was administered to commercial broiler chicken of 6 weeks of age at 10 mg kg^?1 as oral bolus and pulse dose to two groups of twelve birds each. Blood was collected at predetermined time interval and plasma samples were analyzed for enrofloxacin concentration by using HPLC. Mean plasma concentration was significantly higher in oral bolus dose up to 2 h and at 48 h. In both the groups enrofloxacin concentration was above 0.30 μg mL^?1 up to 24 h. Pharmacokinetic parameters were calculated by non compartmental analysis which revealed significant increase in AUC_0–∞ (25.35 ± 1.92 vs. 19.66 ± 1.68 μg h mL^?1) and t_1/2β (10.63 ± 0.35 vs. 8.70 ± 0.74 h) in oral bolus dose when compared to pulse dose. There was no significant difference in other pharmacokinetic parameters such as MRT, MAT, V_{d area}/F, V_dss/F, Cl_B/F, C_max and t_max. Hence it can be concluded that enrofloxacin administered to broiler chicken at 10 mg kg^?1 every 24 h as pulse dose will result in better clinical efficacy at par with oral bolus dose.     

Pharmacokinetics of a Single Dose of Azilsartan in Pediatric Patients: A Phase 3, Open-Label,Multicenter Study

Introduction

Azilsartan is an angiotensin II receptor blocker indicated for the treatment of patients with hypertension. The efficacy and safety of azilsartan are established in adults, but have not been evaluated in pediatric patients, nor has its pharmacokinetic profile been determined in pediatric patients.

Methods

In this phase 3, open-label, multicenter study, we investigated the pharmacokinetics and safety of single doses of azilsartan in six Japanese patients with hypertension, aged 9–14 years. The dose of azilsartan was 5 mg for three patients weighing less than 50 kg, with mean body weight at baseline of 27.5 kg, and 10 mg for three patients weighing at least 50 kg, with mean body weight at baseline of 65.9 kg.

Results

Mean maximum plasma concentration (C_max) of azilsartan was 888.3 and 831.3 ng/mL and median time to maximum concentration (T_max) of unchanged azilsartan was 3.0 and 4.0 h, in the 5-mg and 10-mg groups, respectively. Mean areas under the plasma concentration–time curve (AUC) from 0–24 h post-dose (AUC_0–24) and 0 h to infinity (AUC_0–inf) were 6350.3 and 6635.7 ng h/mL, respectively, in the 5-mg group, and 6871.7 and 7433.3 ng h/mL, respectively, in the 10-mg group. Both doses were well tolerated; no treatment-emergent adverse events considered to be related to azilsartan occurred during the study.

Conclusion

Our data suggest that pediatric patients weighing less than 50 kg may have? approximately 2-fold greater exposure to azilsartan than those weighing at least 50 kg at the same dose. Exposure to azilsartan in children weighing at least 50 kg is comparable to that in healthy adults at the same dose.

Trial Registration

ClinicalTrials.gov identifier, NCT02451150.

Funding

Takeda Pharmaceutical Co. Ltd.

     

Safety and Pharmacokinetics of the Anti-Orthopoxvirus Compound ST-246 following a Single Daily Oral Dose for 14 Days in Human Volunteers

ST-246 is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. To this end, a phase 2, double-blind, randomized, placebo-controlled, multicenter trial was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of ST-246 when administered as a single daily oral dose (400 mg or 600 mg) for 14 days in fed adult volunteers. ST-246 was safe and well tolerated, with no deaths or serious adverse events reported during the study. There was a low incidence of treatment-emergent adverse events (TEAEs), the most common of which were mild nausea and headache. There were no clinically significant results from laboratory assessments, vital sign measurements, physical examinations, or electrocardiograms. The PK and dose proportionality of ST-246 were determined. The PK analysis showed that steady state was achieved by day 5 for the ST-246 400-mg treatment group and by day 6 for the 600-mg group. The dose proportionality analysis showed that the 400- and 600-mg ratio of dose-normalized peak drug concentration in plasma (C(max)) and relative exposure for each dosing interval (AUC(τ)) ranged from 80% to 85%. However, the 90% confidence intervals did not include 1.0, so dose proportionality could not be concluded. Overall, ST-246 was shown to be safe, and the PK was predictable. These results support further testing of ST-246 in a multicenter pivotal clinical safety study for licensure application.     

Pharmacokinetics and safety of low-dose submicron indomethacin 20 and 40 mg compared with indomethacin 50 mg

Introduction. Indomethacin is a potent analgesic that, similar to other nonsteroidal anti-inflammatory drugs, is associated with serious dose-related adverse events. There is a need for newer nonsteroidal anti-inflammatory drug products with improved tolerability. Low-dose submicron indomethacin was developed using SoluMatrix Fine Particle Technology? to enable treatment at lower doses than commercially available indomethacin drug products. This study evaluated the pharmacokinetics and safety of submicron indomethacin 20 and 40 mg compared with indomethacin 50-mg capsules. Methods. This was a phase 1, randomized, open-label, 4-period, 4-sequence, single-dose crossover study. Forty healthy volunteers received low-dose submicron indomethacin 20- or 40-mg capsules, or indomethacin 50-mg capsules under fasting or fed conditions. Pharmacokinetic parameters and safety were assessed. Results. Comparable fasting peak plasma levels (mean ± standard deviation) were demonstrated for submicron indomethacin 40 mg (2368.79 ± 631.38 ng/ml) and indomethacin 50 mg (2369.40 ± 969.06 ng/ml). The overall systemic exposure (geometric least squares mean; 95% CI) was > 21% lower for submicron indomethacin 40 mg (6007.71 ng·h/mL; 5585.73–6461.58) compared with indomethacin 50 mg (7646.23 ng·h/ml; 7110.44–8222.40) under fasting conditions. Food delayed the rate but did not affect the extent of indomethacin absorption from submicron indomethacin 40 mg. Submicron indomethacin 40 mg administration resulted in earlier time to peak plasma levels (median 1.67; min–max 0.5–3.5 hours) under fasting conditions compared with indomethacin 50 mg (2.02; 0.5–5.0 hours). Submicron indomethacin 20 and 40 mg were dose proportional and generally well tolerated. Conclusion. Compared with indomethacin 50 mg, submicron indomethacin 40 mg achieved similar peak plasma concentrations, lower systemic exposure, and a faster time to peak plasma concentration, indicating rapid absorption. The current formulation of low-dose submicron indomethacin has recently demonstrated efficacy in 2 phase 3 studies in patients with acute pain following bunionectomy and represents a new, low-dose treatment option for patients with acute pain.     

Safety, Tolerance, and Pharmacokinetics of High-Dose Liposomal Amphotericin B (AmBisome) in Patients Infected with Aspergillus Species and Other Filamentous Fungi: Maximum Tolerated Dose Study

We conducted a phase I-II study of the safety, tolerance, and plasma pharmacokinetics of liposomal amphotericin B (L-AMB; AmBisome) in order to determine its maximally tolerated dosage (MTD) in patients with infections due to Aspergillus spp. and other filamentous fungi. Dosage cohorts consisted of 7.5, 10.0, 12.5, and 15.0 mg/kg of body weight/day; a total of 44 patients were enrolled, of which 21 had a proven or probable infection (13 aspergillosis, 5 zygomycosis, 3 fusariosis). The MTD of L-AMB was at least 15 mg/kg/day. Infusion-related reactions of fever occurred in 8 (19%) and chills and/or rigors occurred in 5 (12%) of 43 patients. Three patients developed a syndrome of substernal chest tightness, dyspnea, and flank pain, which was relieved by diphenhydramine. Serum creatinine increased two times above baseline in 32% of the patients, but this was not dose related. Hepatotoxicity developed in one patient. Steady-state plasma pharmacokinetics were achieved by day 7. The maximum concentration of drug in plasma (C(max)) of L-AMB in the dosage cohorts of 7.5, 10.0, 12.5, and 15.0 mg/kg/day changed to 76, 120, 116, and 105 microg/ml, respectively, and the mean area under the concentration-time curve at 24 h (AUC(24)) changed to 692, 1,062, 860, and 554 microg x h/ml, respectively, while mean CL changed to 23, 18, 16, and 25 ml/h/kg, respectively. These data indicate that L-AMB follows dose-related changes in disposition processing (e.g., clearance) at dosages of >or=7.5 mg/kg/day. Because several extremely ill patients had early death, success was determined for both the modified intent-to-treat and evaluable (7 days of therapy) populations. Response rates (defined as complete response and partial response) were similar for proven and probable infections. Response and stabilization, respectively, were achieved in 36 and 16% of the patients in the modified intent-to-treat population (n = 43) and in 52 and 13% of the patients in the 7-day evaluable population (n = 31). These findings indicate that L-AMB at dosages as high as 15 mg/kg/day follows nonlinear saturation-like kinetics, is well tolerated, and can provide effective therapy for aspergillosis and other filamentous fungal infections.     

Safety, Tolerance, and Pharmacokinetics of a Small Unilamellar Liposomal Formulation of Amphotericin B (AmBisome) in Neutropenic Patients

The safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) administered for empirical antifungal therapy were evaluated for 36 persistently febrile neutropenic adults receiving cancer chemotherapy and bone marrow transplantation. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study which enrolled a total of 8 to 12 patients in each of the four dosage cohorts. Each cohort received daily doses of either 1.0, 2.5, 5.0, or 7.5 mg of amphotericin B in the form of AmBisome/kg of body weight. The study population consisted of patients between the ages of 13 and 80 years with neutropenia (absolute neutrophil count, <500/mm³) who were eligible to receive empirical antifungal therapy. Patients were monitored for safety and tolerance by frequent laboratory examinations and the monitoring of infusion-related reactions. Efficacy was assessed by monitoring for the development of invasive fungal infection. The pharmacokinetic parameters of AmBisome were measured as those of amphotericin B by high-performance liquid chromatography. Noncompartmental methods were used to calculate pharmacokinetic parameters. AmBisome administered as a 1-h infusion in this population was well tolerated and was seldom associated with infusion-related toxicity. Infusion-related side effects occurred in 15 (5%) of all 331 infusions, and only two patients (5%) required premedication. Serum creatinine, potassium, and magnesium levels were not significantly changed from baseline in any of the dosage cohorts, and there was no net increase in serum transaminase levels. AmBisome followed a nonlinear dosage relationship that was consistent with reticuloendothelial uptake and redistribution. There were no breakthrough fungal infections during empirical therapy with AmBisome. AmBisome administered to febrile neutropenic patients in this study was well tolerated, was seldom associated with infusion-related toxicity, was characterized by nonlinear saturation kinetics, and was effective in preventing breakthrough fungal infections.     

Comparison of two reduced-dose regimens of indinavir (600 mg vs 400 mg twice daily) and ritonavir (100 mg twice daily) in healthy volunteers (COREDIR)

OBJECTIVE: To assess the pharmacokinetics and tolerability of reduced dosages of twice daily indinavir (IDV) boosted by low-dose ritonavir (RTV) in healthy volunteers. METHODS: Pharmacokinetics and tolerability of IDV/RTV twice daily (600/100 mg and 400/100 mg) were assessed in a randomized crossover design in 16 healthy volunteers. Each dosage was taken twice daily for 2 weeks before 12 h pharmacokinetics were obtained. RESULTS: Sixteen subjects were included, with a mean age +/- SD of 30 +/- 4 years; seven female, nine male. Fifteen subjects completed the study. After dose reduction of IDV AUC, Cmax and Cmin decreased significantly. In the 400 mg group three out of 15 subjects had IDV levels below 0.10 mg/l vs none in the 600 mg group. All subjects reported mild to moderate side effects throughout the study period, which were more severe in the 600 mg group (mostly renal, dry skin/lips, paresthesias/oral discomfort). In the 600 mg group four subjects reported dysuria and one subject discontinued because of flank pain, whereas two subjects reported dysuria and no subject discontinued in the 400 mg group, respectively. Eight subjects developed crystalluria without a significant difference between both groups. No significant change in serum creatinine was observed. CONCLUSIONS: IDV/RTV 400/100 mg twice daily resulted in significant lower IDV exposure, with three out of 15 subjects revealing Cmin values below the recommended threshold for wild-type virus of 0.10 mg/l. Tolerability, however, was lower in the 600 mg IDV group. Therapeutic drug monitoring in the individual patient appears to be necessary to guarantee appropriate drug levels and simultaneously minimize toxicity.     

Bactericidal activities of DU-6859a and clinafloxacin (CI-960) against staphylococci.

Time killing curves were calculated at concentrations of 2 and 8 times the MICs of DU-6859a and clinafloxacin against six isolates of Staphylococcus aureus. Both quinolones produced a decrease in the log10 CFU per milliliter of > or = 3 within 3 h at 2 and 8 times the MIC for the ciprofloxacin-susceptible isolates and at 8 times the MIC for the ciprofloxacin-resistant isolates; however, only 8 times the MIC of DU-6859a consistently prevented regrowth of all isolates after 24 h of incubation.     

A comparison of preference for and efficacy of tablet formulations of sumatriptan (50 mg and 100 mg), naratriptan (2.5 mg), rizatriptan (10 mg), and zolmitriptan (2.5 mg) in the acute treatment of migraine

Abstract This randomized, multicenter, open-label, five-way crossover study was conducted to assess patients preference for tablet formulations of sumatriptan (50 mg and 100 mg), naratriptan (2.5 mg), rizatriptan (10 mg), and zolmitriptan (2.5 mg) in the acute treatment of migraine and to identify determinants of preference. Patients treated one mild, moderate, or severe migraine with each triptan. The results show that sumatriptan 100 mg was significantly preferred over the random preference rate of 20% (p<0.001) whereas sumatriptan 50 mg, naratriptan, rizatriptan, and zolmitriptan were not. Patients primary reason for preferring a medication was best relief of migraine pain, and the treatment that patients preferred corresponded to the medication that was most likely to confer for them a pain-free response 2 hours postdose. Across all patients, efficacy 2 hours postdose was comparable among triptans with the exception of naratriptan, which was slightly less effective than the other medications (pain-free response 2 hours postdose: 40% sumatriptan 100 mg, 37% sumatriptan 50 mg, 28% naratriptan 2.5 mg, 38% rizatriptan 10 mg, 36% zolmitriptan 2.5 mg). The medications were also similarly well-tolerated. These data demonstrate that information on patients medication preference supplements and does not duplicate data from traditional efficacy measures. Patient preference data are useful in tailoring migraine therapy to the needs of the individual patient.