Urinary Excretion and Bactericidal Activities of a Single Oral Dose of 400 Milligrams of Fleroxacin versus a Single Oral Dose of 800 Milligrams of Pefloxacin in Healthy Volunteers

Twelve healthy volunteers participated in this randomized crossover study to compare the concentrations and recovery levels of fleroxacin and pefloxacin in urine and to assess their bactericidal activities against 12 strains of urinary pathogens with different susceptibilities over a wide range of MICs. The volunteers received a single oral dose of 400 mg of fleroxacin or 800 mg of pefloxacin. The mean cumulative renal excretion of unchanged fleroxacin, N-demethyl-fleroxacin, and N-oxide-fleroxacin accounted for 67, 7, and 6% of the total dose, respectively. The total urinary recovery of pefloxacin and the active metabolite norfloxacin was 34%. In the time-kill and the urinary bactericidal titer (UBT) studies, only the subjects’ urine not supplemented with broth was used. With most tested organisms and both quinolones it took more than 8 h to achieve a reduction in CFU of 99.9% (3 log units). Overall, there was a good correlation between UBTs and MICs for the strains. Against Escherichia coli ATCC 25922 the median UBTs were similar for both antibiotics and at least 1:8 for 96 h; against the E. coli strain for which the MIC was 0.5 μg/ml the UBT was at least 1:4 for 48 h. The UBTs of both drugs against Klebsiella pneumoniae were at least 1:16 for 72 h. The UBTs for Staphylococcus aureus (the MIC for which was 16 μg/ml) of both antibiotics were low, and in some of the samples, no bactericidal titers were observed. UBTs for Proteus mirabilis of pefloxacin are significantly higher than those of fleroxacin. For Pseudomonas aeruginosa the median UBTs were present for the 24-to-48-h interval. The same is true for Enterococcus faecalis. Against Staphylococcus saprophyticus, UBTs were present for at least 48 h with both quinolones. Overall, a single oral dose of 400 mg of fleroxacin exhibits UBTs comparable to those of 800 mg of pefloxacin. Therefore, it may be expected that half of the dose of fleroxacin gives comparable results in the treatment of urinary tract infections; this should be substantiated in comparative clinical trials.     

Urinary Concentrations and Antibacterial Activity of BAL30072, a Novel Siderophore Monosulfactam,against Uropathogens after Intravenous Administration in Healthy Subjects

This annex study to a phase 1 study aimed to correlate urinary concentrations and bactericidal titers (UBTs) of {"type":"entrez-protein","attrs":{"text":"BAL30072","term_id":"359272553","term_text":"BAL30072"}}BAL30072, a novel siderophore monosulfactam, in healthy subjects in order to evaluate which dosage of {"type":"entrez-protein","attrs":{"text":"BAL30072","term_id":"359272553","term_text":"BAL30072"}}BAL30072 should be investigated in a clinical study on complicated urinary tract infection (UTI). Three cohorts of a total of 19 healthy male subjects were included in the add-on study and received the following {"type":"entrez-protein","attrs":{"text":"BAL30072","term_id":"359272553","term_text":"BAL30072"}}BAL30072 dosages. The 1st cohort received 1 g once a day (q.d.) intravenously (i.v.) (1 h) on day 1 and 1 g thrice daily (t.i.d.) on day 2, the 2nd cohort received 2 g q.d. i.v. (1 h) on day 1 and 2 g t.i.d. on day 2, and the 3rd cohort received 1 g q.d. i.v. (4-h infusion) on day 8. Urine was collected up to 24 h after drug administration. UBTs were determined for seven Escherichia coli isolates (three wild type [WT], CTX-M-15, TEM-3, TEM-5, NDM-1), two Klebsiella pneumoniae isolates (WT, KPC), one Proteus mirabilis isolate (WT), and two Pseudomonas aeruginosa isolates (WT, VIM-1 plus AmpC). Urine drug concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The median urinary excretions of {"type":"entrez-protein","attrs":{"text":"BAL30072","term_id":"359272553","term_text":"BAL30072"}}BAL30072 ranged between 38% and 46% (3 cohorts). The median UBTs after i.v. administration of 1 or 2 g q.d. and after 1 or 2 g t.i.d. showed positive UBTs for 24 h after the lowest dosage (1 g q.d.) for 5 of 7 of the Enterobacteriaceae strains and after the higher dosage of 2 g administered i.v. t.i.d. for all strains tested. After i.v. infusion of 1 g over 4 h, positive UBTs were demonstrated for three E. coli strains for up to 12 h, for the K. pneumoniae (KPC) strain for up to 8 h, and for the P. aeruginosa (VIM-1 plus AmpC) strain for up to only 4 h. The minimal bactericidal concentrations (MBCs) of the E. coli (NDM-1) strain and the K. pneumoniae (WT) strain correlated well between broth and urine but did not correlate well for the two P. aeruginosa strains. {"type":"entrez-protein","attrs":{"text":"BAL30072","term_id":"359272553","term_text":"BAL30072"}}BAL30072 exhibits positive UBTs for 24 h even after a dosage of 1 g administered i.v. q.d. for 5 of 7 Enterobacteriaceae strains and after 2 g administered i.v. t.i.d. for all strains except one P. aeruginosa strain (50% of the time). In general, the UBTs correlated well with the MICs of the Enterobacteriaceae but were lower for P. aeruginosa. The clinical efficacy with a dosage regimen of {"type":"entrez-protein","attrs":{"text":"BAL30072","term_id":"359272553","term_text":"BAL30072"}}BAL30072 of 2 g administered i.v. t.i.d. should be evaluated in the treatment of complicated UTI.     

Intravenous Doripenem at 500 Milligrams versus Levofloxacin at 250 Milligrams,with an Option To Switch to Oral Therapy,for Treatment of Complicated Lower Urinary Tract Infection and Pyelonephritis

The prospective, multicenter, double-blind study presented in this report evaluated whether or not intravenous (IV) administration of doripenem, a carbapenem with bactericidal activity against gram-negative and gram-positive uropathogens, is inferior to IV administration of levofloxacin in the treatment of complicated urinary tract infection (cUTI). Patients (n = 753) with complicated lower UTI or pyelonephritis were randomly assigned to receive IV doripenem at 500 mg every 8 h (q8h) or IV levofloxacin at 250 mg q24h. Patients in both treatment arms were eligible to switch to oral levofloxacin after 3 days of IV therapy to complete a 10-day treatment course if they demonstrated significant clinical and microbiological improvements. The microbiological cure rate (primary end point) was determined at the test-of-cure (TOC) visit occurring 5 to 11 days after the last dose of antibiotic. For the microbiologically evaluable patients (n = 545), the microbiological cure rates were 82.1% and 83.4% for doripenem and levofloxacin, respectively (95% confidence interval [CI] for the difference, −8.0 to 5.5%); in the microbiological modified intent-to-treat cohort (n = 648), the cure rates were 79.2% and 78.2%, respectively. Clinical cure rates at the TOC visit were 95.1% in the doripenem arm and 90.2% in the levofloxacin arm (95% CI around the difference in cure rates [doripenem cure rate minus levofloxacin cure rate], 0.2% to 9.6%). Both treatment regimens were generally well tolerated. Doripenem was found not to be inferior to levofloxacin in terms of therapeutics and is now approved for use in the United States and Europe for the treatment of adults with cUTI, including pyelonephritis. As fluoroquinolone resistance increases, doripenem may become a more important option for successful treatment of cUTIs, including treatment of pyelonephritis.Urinary tract infections (UTIs) are the leading cause of gram-negative bacteremia for patients of all ages and can be associated with a high risk of morbidity and mortality, especially in the elderly, for whom they can account for nearly 25% of all infections (2). UTIs are responsible for nearly 7 million office visits and 1 million emergency department visits, which result in 100,000 hospitalizations each year, in the United States alone (2, 22) and account for at least 40% of all nosocomial infections (22, 23). Complicated lower UTIs (cLUTIs) and complicated pyelonephritis occur in patients who have a functionally, metabolically, or anatomically abnormal urinary tract. Unlike the narrow and predictable spectrum of pathogens associated with uncomplicated UTIs, a broad range of bacteria can cause complicated infections, and many are resistant to multiple antimicrobial agents (22). For patients with complicated UTIs (cUTIs) requiring intravenous (IV) antibiotic therapy, empirical treatment with a broad-spectrum antibiotic can help avoid the unnecessary risk and cost of disease progression associated with treatment failure.Fluoroquinolones are indicated for the management of acute uncomplicated UTIs as well as cUTIs and pyelonephritis for adults, but uropathogen resistance to them is increasing (20). The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) surveillance program demonstrated increasing rates of fluoroquinolone resistance in bacterial isolates from U.S. medical centers, especially among Escherichia coli, Enterobacter, Proteus mirabilis, and indole-positive Proteae spp. (17). Resistance to ciprofloxacin and levofloxacin in E. coli reached 21.6% and 20.4%, respectively, of isolates tested in 2005 (16). In the North American Urinary Tract Infection Collaboration Alliance surveillance study, 5.5% and 5.1% of urinary E. coli isolates from outpatients in the United States and Canada were resistant to ciprofloxacin and levofloxacin, respectively (24). Similar results were reported for a cohort in Israel (12). Pseudomonas aeruginosa fluoroquinolone resistance is also problematic, with rates now exceeding 35% (7). As fluoroquinolone resistance increases, alternative therapies will become more important for successful treatment of cUTIs, particularly for patients at risk for infection with fluoroquinolone-resistant pathogens.Doripenem is a broad-spectrum carbapenem that has been approved for use in the United States and Europe for the treatment of adults with cUTIs, including pyelonephritis, and for the treatment of complicated intra-abdominal infections. It has also been approved in Europe for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia. Doripenem is primarily eliminated by the kidneys and is concentrated in the urine (Doripenem package insert; Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ). It has potent in vitro activity against the gram-negative aerobic bacteria commonly encountered in cUTIs, including E. coli, other members of the Enterobacteriaceae, and P. aeruginosa (3, 22). Like other carbapenems, doripenem is resistant to hydrolysis by a variety of β-lactamases, including extended-spectrum β-lactamases (ESBLs). Several in vitro studies have shown that doripenem has greater activity than other carbapenems against recent isolates of key gram-negative pathogens, including ESBL-producing strains of E. coli and P. aeruginosa (8, 10, 11). Moreover, under experimental conditions, doripenem was less likely than other carbapenems to select for carbapenem-resistant mutants of P. aeruginosa (14, 19). This profile makes doripenem an attractive agent for the treatment of cLUTIs and pyelonephritis. Doripenem has moderate activity against Enterococcus faecalis (4, 9), with MIC₉₀ values of 4 to 16 μg/ml, i.e., one dilution lower than ertapenem and meropenem. Most current clinical isolates of Enterococcus faecium are resistant to doripenem.This trial was designed in compliance with Food and Drug Administration guidelines for registration studies to compare the microbiological and clinical cure rates of patients with cUTIs who received at least 3 days of IV doripenem or IV levofloxacin therapy, with an option for patients in both treatment arms to switch from IV therapy to oral levofloxacin if specified favorable clinical and microbiological criteria were satisfied.     

Urinary Excretion and Bactericidal Activities of Gemifloxacin and Ofloxacin after a Single Oral Dose in Healthy Volunteers

In a randomized crossover study, 16 volunteers (8 men, 8 women) received single oral doses of 320 mg of gemifloxacin and 400 mg of ofloxacin on two separate occasions in the fasting state to assess the urinary excretion and urinary bactericidal titers (UBTs) at intervals for up to 144 h. Ofloxacin showed higher concentrations in urine compared with those of gemifloxacin. The median (range) cumulative excretion of gemifloxacin was 29.7% (8.4 to 48.7%) of the parent drug administered, and median (range) cumulative excretion of ofloxacin was 84.3% (46.5 to 95.2%) of the parent drug administered. The UBTs, i.e., the highest twofold dilutions (with antibiotic-free urine as the diluent) of urine that were still bactericidal, were determined for a reference strain and nine uropathogens for which the MICs of gemifloxacin and ofloxacin were as follows: Escherichia coli ATCC 25922, 0.016 and 0.06 microg/ml, respectively; Klebsiella pneumoniae, 0.03 and 0.06 microg/ml, respectively; Proteus mirabilis, 0.125 and 0.125 microg/ml, respectively; Escherichia coli, 0.06 and 0.5 microg/ml, respectively; Pseudomonas aeruginosa, 1 and 4 microg/ml, respectively; Staphylococcus aureus, 0.008 and 0.25 microg/ml, respectively; Enterococcus faecalis, 0.06 and 2 microg/ml, respectively; Staphylococcus aureus, 0.25 and 4 microg/ml, respectively; Enterococcus faecalis, 0.5 and 32 microg/ml, respectively; and Staphylococcus aureus, 2 and 32 microg/ml, respectively. Generally, the UBTs for gram-positive uropathogens were higher for gemifloxacin than for ofloxacin and the UBTs for gram-negative uropathogens were higher for ofloxacin than for gemifloxacin. According to the UBTs, ofloxacin-resistant uropathogens (MICs, >or=4 mg/liter) should also be considered gemifloxacin resistant. Although clinical trials have shown that gemifloxacin is effective for the treatment of uncomplicated urinary tract infections, whether an oral dosage of 320 mg of gemifloxacin once daily is also adequate for the treatment of complicated urinary tract infections has yet to be confirmed.     

Increase in Plasma Concentrations of Geranylgeranoic Acid after Turmeric Tablet Intake by Healthy Volunteers

Geranylgeranoic acid (GGA) is one of the most potent cancer-preventive acyclic retinoids. GGA has been shown to induce cell death in human hepatoma-derived HuH-7 cells. We have recently reported the natural occurrence of GGA and its related compounds in several medicinal herbs such as turmeric, basil, rosehip, cinnamon and others [Shidoji and Ogawa, J. Lipid Res., 45: 1092–1103, 2004]. In the present study, we performed oral administration of turmeric tablets to healthy volunteers in order to investigate bioavailability of natural GGA. By using liquid chromatography/mass spectrometry, authentic GGA was eluted at a retention time of around 18 min as a negative ion of m/z 303.4. With healthy volunteers, plasma GGA was detected prior to the tablet intake and its concentrations were increased at 2 h after its intake and maintained at higher level until 4 h, suggesting an efficient bioavailability of preformed GGA in the turmeric tablets through oral administration. These results indicated that GGA in the turmeric tablet was absorbed as an intact form from intestinal mucosa. The present study provides a clue to conduct a research for cancer preventive roles of GGA in a number of spices.     

Comparison of Oseltamivir and Oseltamivir Carboxylate Concentrations in Venous Plasma,Venous Blood,and Capillary Blood in Healthy Volunteers

Oseltamivir and oseltamivir carboxylate concentrations were measured in venous plasma, venous blood, and capillary blood taken simultaneously from 24 healthy volunteers. Median (range) venous-blood-to-plasma ratios were 1.42 (0.920 to 1.97) for oseltamivir and 0.673 (0.564 to 0.814) for oseltamivir carboxylate. Capillary blood/venous plasma ratios were 1.32 (0.737 to 3.16) for oseltamivir and 0.685 (0.502 to 1.34) for oseltamivir carboxylate. Oseltamivir concentrations in venous and capillary blood were similar. Oseltamivir carboxylate showed a time-dependent distribution between venous and capillary blood.     

Enhanced Bioavailability of Itraconazole in Hydroxypropylβ-Cyclodextrin Solution versus Capsules in Healthy Volunteers

The bioavailabilities and bioequivalences of single 200-mg doses of itraconazole solution and two capsule formulations were evaluated in a crossover study of 30 male volunteers. The two capsule formulations were bioequivalent. The bioavailabilities of the solutions itraconazole and hydroxyitraconazole were 30 to 33% and 35 to 37% greater, respectively, than those of either capsule. However, the maximum concentrations of the drug in plasma (C_max), the times to C_max, and the terminal half-lives were comparable for all three formulations. These data indicate that the bioavailabilities of itraconazole and hydroxyitraconazole are enhanced when administered as an oral solution instead of capsules.     

Evaluation of Urinary Elimination of N-Acetyl-β-Glucosaminidase in Healthy Volunteers Treated with Dibekacin or Gentamicin

The urinary excretion of N-acetyl-β-glucosaminidase was studied in healthy subjects during and after treatment with aminoglycosides. In terms of this parameter dibekacin appeared to be less nephrotoxic than gentamicin.     

盐酸甲氧氯普胺片在健康人体内药动学及生物等效性评价

[目的]评价盐酸甲氧氯普胺片在健康人体内的相对生物利用度及生物等效性.[方法]采用随机、开放、双周期交叉试验设计,24名健康男性受试者分别单剂量口服2×10 mg甲氧氯普胺受试制剂或参比制剂后,在设计的时间点取静脉血,采用高效液相色谱-质谱联用法(HPLC-MS)测定甲氧氯普胺的血浆浓度,计算主要药动学参数.以方差分析方法对主要药动学参数进行均数的差别检验,以双单侧t检验进行生物等效性判定.[结果]受试者分别口服受试制剂和参比制剂后,甲氧氯普胺的主要药动学参数AUC0-24、AUC0-∞、tmax、Cmax、t1/2分别为(184.7±40.1)g/(h·L)和(174.9±36.5)g/(h·L)、(208.6±49.6)g/(h·L)和(189.1±36.9)g/(h·L)、(1.6±0.8)h和(1.2±0.4)h、(24.5±4.3)g/L和(24.4±4.4)g/L、(6.3士2.0)h和(5.0±1.2)h.受试制剂对参比制剂的相对生物利用度为(106.2±12.8)%.[结论]所建立的方法适用于盐酸甲氧氯普胺的人体药动学研究,经方差分析和双向单侧t检验证明,受试制剂与参比制剂为生物等效性制剂.     

Population Pharmacokinetics of Peramivir in Healthy Volunteers and Influenza Patients

Peramivir is an intravenous anti-influenza agent that inhibits viral growth by selectively inhibiting neuraminidase in human influenza A and B viruses. To characterize its pharmacokinetics, a population pharmacokinetic analysis of peramivir was performed using 3,199 plasma concentration data samples from 332 subjects in six clinical studies in Japan and the United States, including studies with renal impairment subjects, elderly subjects, and influenza patients. A three-compartment model well described the plasma concentration data for peramivir, and creatinine clearance was found to be the most important factor influencing clearance. Age and body weight were also found to be covariates for clearance and the volume of distribution, respectively. No difference in pharmacokinetics was found between genders or between Japanese and U.S. subjects. Small differences in pharmacokinetics were observed between uninfected subjects and influenza patients (clearance was 18% higher and the volume of distribution was 6% lower in influenza patients). Monte Carlo simulations indicated that single adjusted doses of 1/3- and 1/6-fold for patients with moderate and severe renal impairment, respectively, would give areas under the curve comparable to those for patients with normal renal function. The population pharmacokinetic model developed for peramivir should be useful for understanding its pharmacokinetic characteristics and for dose adjustment on the basis of renal function.     

Pharmacokinetics and Safety of Enzalutamide in Healthy Chinese Male Volunteers

Purpose

This open-label, single-dose study evaluated the pharmacokinetic profiles of enzalutamide and its major metabolites and the safety of enzalutamide in healthy, Chinese male volunteers.

Multiple-Dose Pharmacokinetics of Ceftibuten in Healthy Adults and Geriatric Volunteers

The steady-state pharmacokinetics of ceftibuten, an orally active cephalosporin were investigated in 12 healthy male volunteers (19--38 years) and in 12 geriatric volunteers (65--76 years). Each received one 200-mg ceftibuten capsule every 12 h on days 1--3 and one capsule in the morning on day 4. Plasma and urine samples were collected at various times on days 1--4 and assayed by high-pressure liquid chromatographic method for ceftibuten and ceftibuten-trans, a conversion product. The T(max) for ceftibuten and ceftibuten-trans occurred at about 2 and 3 h, respectively, in both populations. The C(max) and AUC((0--12 h)) ranged from 10.8 to 12.4 &mgr;g ml(minus sign1) and from 47.5 to 55.1 &mgr;g h ml(minus sign1), respectively, for normal volunteers compared to 12.9--17.5 &mgr;g ml(minus sign1) and 62.3--87.1 &mgr;g h ml(minus sign1), respectively, for geriatric volunteers. The respective values for ceftibuten-trans in normal and geriatric volunteers were 1.3 and 1.3 &mgr;g ml(minus sign1), respectively, and 6.9--8.2 and 5.9--9.8 &mgr;g h ml(minus sign1). At steady state, the C(max) and AUC((0--12 h)) of ceftibuten-trans were about 10--11% and 13--16% those of ceftibuten in normal volunteers and about 8--9% and 9--11% those of ceftibuten, respectively, in geriatric volunteers. The accumulation factor of ceftibuten in normal volunteers was 1.1 as compared to 1.3 in geriatric volunteers. The terminal phase half-life was 2.5 h in healthy volunteers and 3.2 h in geriatric volunteers. Urinary excretion appeared to be the major route of elimination in both populations accounting for more than 90% of the dose recovered in the urine during the dosing interval. The results of this study demonstrate that ceftibuten, 200 mg given twice a day, is safe and well tolerated, is well absorbed, and that steady-state is achieved on days 3 and 4. There is some accumulation in the elderly, but dosage regimen based on age is not warranted.     

A First-in-Human Study To Assess the Safety and Pharmacokinetics of Monoclonal Antibodies against Human Cytomegalovirus in Healthy Volunteers

Human cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal antibodies (LJP538 and LJP539) that bind to and inhibit the function of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. Here, we evaluated the safety, tolerability, and pharmacokinetics of a single intravenous dose of LJP538 or LJP539 or their combination in healthy volunteers. Adverse events and laboratory abnormalities occurred sporadically with similar incidence between antibody and placebo groups and without any apparent relationship to dose. No subject who received antibody developed a hypersensitivity, infusion-related reaction or anti-drug antibodies. After intravenous administration, both LJP538 and LJP539 demonstrated typical human IgG1 pharmacokinetic properties, with slow clearances, limited volumes of distribution, and long terminal half-lives. The pharmacokinetic parameters were linear and dose proportional for both antibodies across the 50-fold range of doses evaluated in the study. There was no apparent impact on pharmacokinetics when the antibodies were administered alone or in combination. CSJ148 and the individual monoclonal antibodies were safe and well tolerated, with pharmacokinetics as expected for human immunoglobulin.     

Serum and Urinary Concentrations of Cyclacillin in Humans

Cyclacillin is a semisynthetic penicillin produced from the penicillin nucleus (6-aminopenicillanic acid) by acylation with 1-aminohexanecarboxylic acid. The absorption and excretion characteristics of cyclacillin were defined in one completely randomized and three three-way crossover experiments. Mean peak serum cyclacillin levels appeared earlier and were fivefold higher than those obtained with equal doses of ampicillin. High serum cyclacillin concentrations were reached at 0.5 h and by 2 h were lower than ampicillin. Serum ampicillin concentrations peaked at 1.5 h, remaining slightly higher than those for cyclacillin for the next 4.5 h. The mean area for the cyclacillin curve was significantly superior to either of the ampicillin formulations. Mean serum concentrations of cyclacillin exhibited a smooth dose-response, approximately doubling in each instance as the dose was doubled from 250 to 500 and from 500 to 1,000 mg. High concentrations of cyclacillin were also demonstrated in urine. Neither ratio of drug to metabolite in the urine nor the percent of excretion was significantly affected by the dose level. Sixty-seven percent of the drug was excreted unchanged, and 17% was excreted as penicilloic acid, with most of the excretion occurring within 6 h of administration. In subjects given 500 mg of cyclacillin (four times daily) for 6 days, 2% of the drug was excreted as 1-aminocyclohexanecarboxylic acid, and approximately 55% (24 to 91%) was unchanged. Neither formation nor excretion of the former was sex dependent.     

盐酸多奈哌齐口腔崩解片人体药物代谢动力学和生物等效性试验

目的采用高效液相色谱-质谱联用法研究盐酸多奈哌齐口腔崩解片的人体药物代谢动力学,并评价其生物等效性。方法 2009年9月-11月对22例健康男性受试志愿者单次交叉口服盐酸多奈哌齐口腔崩解片(试验制剂)和盐酸多奈哌齐普通片(参比制剂),测定给药后不同时间点血浆中多奈哌齐经时血药浓度,采用DAS 2.0软件进行药物代谢动力学参数计算和生物等效性评价。结果受试者单次口服试验制剂与参比制剂后,达峰时间分别为(2.95±1.16)、(3.19±0.98)h,峰浓度分别为(9.98±2.93)、(9.13±2.05)ng/mL,药时曲线下面积(0-t)分别为(470.76±142.64)、(446.57±137.30)ng/mL.h;药时曲线下面积(0-∞)分别为(517.74±169.79)、(489.47±162.13)ng/mL.h。试验制剂与参比制剂的生物等效性结果为104.7%,其90%置信区间为(98.4%,111.4%)。结论盐酸多奈哌齐口腔崩解片与普通片生物等效。     

甲磺酸帕珠沙星注射液在健康人体的药动学及药效学研究

目的:研究甲磺酸帕珠沙星注射液的药代动力学及药效学特点.方法:筛选健康受试者12名,单次及多次静滴甲磺酸帕珠沙星注射液,用反向高效液相色谱-紫外法测定血药浓度及尿药浓度,用DASver1.0软件拟合药代动力学参数.结果:甲磺酸帕珠沙星体内过程符合二室模型;单次给药后的药代动力学参数:Tmax为0.47±0.09 h,Cmax为13.71±1.81 mg/L,AUC0-t为24.60±4.15 mgh/L,T1/2为1.46±0.64 h.Q 12 h静滴帕珠沙星500 mg连续5日,第2、3、4、5日晨测得的谷浓度分别为0.13、0.16、0.17、0.14 mg/L,提示血药浓度已达稳态.末剂给药后的药代动力学参数:Tmax为0.48±0.10 h,Cmax为15.41±1.67 mg/L,AUC0-t为28.42±4.90 mg*h/L,T1/2为1.33±0.49 h,(Css)av为2.34±0.43 mg/L,DF为99.48±0.38%,以上参数与单次给药比较除Cmax外差异均无统计学意义,且累积系数小,说明本品多次给药无体内蓄积.女性和男性受试者主要药动学参数比较均无统计学意义.本品对临床大多数常见致病菌的AUC0～24 h/MIC＞ 100且Cmax/MIC＞8.受试者给药期间未出现严重不良反应.结论:500 mg Q 12 h静滴,在人体内可达到有效血药浓度,可作为临床应用的推荐方案.     

Pharmacokinetics and Pharmacodynamics of Multiple-Dose Intravenous Nemonoxacin in Healthy Chinese Volunteers

This study evaluated the safety and pharmacokinetic/pharmacodynamic profiles of nemonoxacin in healthy Chinese volunteers following multiple-dose intravenous infusion once daily for 10 consecutive days. The study was composed of two stages. In the open-label stage, 500 mg or 750 mg of nemonoxacin (n = 12 each) was administered at an infusion rate of 5.56 mg/min. In the second stage, with a randomized double-blind placebo-controlled design, 500, 650, or 750 mg of nemonoxacin (n = 16 in each cohort; 12 subjects received the drug and the other 4 subjects received the placebo) was given at an infusion rate of 4.17 mg/min. The results showed that, in the first stage, the maximal nemonoxacin concentrations (mean ± SD) at steady state (C_{max_ss}) were 9.60 ± 1.84 and 11.04 ± 2.18 μg/ml in the 500-mg and 750-mg cohorts, respectively; the areas under the concentration-time curve at steady state (AUC_{0–24_ss}) were 44.03 ± 8.62 and 65.82 ± 10.78 μg · h/ml in the 500-mg and 750-mg cohorts, respectively. In the second stage, the nemonoxacin C_{max_ss} values were 7.13 ± 1.47, 8.17 ± 1.76, and 9.96 ± 2.23 μg/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively; the AUC_{0–24_ss} values were 40.46 ± 9.52, 54.17 ± 12.10, and 71.34 ± 17.79 μg · h/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively. No accumulation was found after the 10-day infusion with any regimen. The drug was well tolerated. A Monte Carlo simulation indicated that the cumulative fraction of response of any dosing regimen was nearly 100% against Streptococcus pneumoniae. The probability of target attainment of nemonoxacin therapy was >98% when the MIC of nemonoxacin against S. pneumoniae was ≤1 mg/liter. It is suggested that all of the studied intravenous nemonoxacin dosing regimens should have favorable clinical and microbiological efficacies in future clinical studies. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01944774","term_id":"NCT01944774"}}NCT01944774.)