Pharmacokinetics of intravenous and oral levofloxacin in critically ill adults in a medical intensive care unit

STUDY OBJECTIVE: To characterize the pharmacokinetic disposition of intravenous and oral levofloxacin in critically ill adults. DESIGN: Prospective, open-label study. SETTING: University teaching hospital. PATIENTS: Thirty critically ill patients in a medical intensive care unit (ICU). INTERVENTIONS: All patients received levofloxacin as part of their routine medical care. Pharmacokinetic evaluations were performed in 28 patients receiving intravenous levofloxacin. Ten of these patients subsequently were switched to oral levofloxacin and underwent a second pharmacokinetic evaluation during oral therapy. MEASUREMENTS AND MAIN RESULTS: Mean +/- SD levofloxacin half-life, clearance at steady state, and volume of distribution in all 28 patients were 8.0 +/- 1.7 hours, 134 +/- 35 ml/minute, and 1.2 +/- 0.3 L/kg, respectively Maximum and minimum serum concentrations (Cmax and Cmin) and area under the serum concentration-time curve from 0-24 hours (AUC(0-24)) in patients receiving levofloxacin 500 mg intravenously were 7.5 +/- 0.8 mg/L, 1.0 +/- 0.5 mg/L, and 66.1 +/- 15.7 mg x hour/L, respectively Observed Cmax, Cmin, and time at which maximum concentration was achieved after oral doses of levofloxacin 500 mg were 5.5 +/- 1.1 mg/L, 0.8 +/- 0.4 mg/L, and 1.3 +/- 0.4 hours, respectively. These values were significantly different (p < 0.05) from those observed after intravenous dosing in the same patients; other pharmacokinetic parameters were similar. Statistically significant increases (p < 0.05) in Cmax, Cmin, half-life, and AUC(0-24) were found in critically ill patients administered multiple doses of intravenous levofloxacin compared with historical data from healthy volunteers. CONCLUSIONS: The dosage regimen of intravenous levofloxacin 500 mg once/day appears adequate for most pathogens found in critically ill patients with normal renal function. Less susceptible pathogens may require an increased daily dose for more optimal therapy. Orally administered levofloxacin appears to be well absorbed in selected ICU patients and has pharmacokinetics similar to those of intravenously administered levofloxacin.     

Levofloxacin pharmacokinetics in children

Levofloxacin is a broad-spectrum fluoroquinolone antibiotic with activity against many pathogens that cause bacterial infections in children, including penicillin-resistant pneumococci. To provide dosing guidance for children, 3 single-dose, multicenter pharmacokinetic studies were conducted in 85 children in 5 age groups: 6 months to <2 years, 2 to <5 years, 5 to <10 years, 10 to <12 years, and 12 to 16 years. Each child received a single 7-mg/kg dose of levofloxacin (not to exceed 500 mg) intravenously or orally. Plasma and urine samples were collected through 24 hours after dose. Pharmacokinetic parameters were estimated and compared among the 5 age groups and to previously collected adult data. Levofloxacin absorption (as indicated by C(max) and t(max)) and distribution in children are not age dependent and are comparable to those in adults. Levofloxacin elimination (reflected by t1/2 and clearance), however, is age dependent. Children younger than 5 years of age clear levofloxacin nearly twice as fast (intravenous dose, 0.32+/-0.08 L/h/kg; oral dose, 0.28+/-0.05 L/h/kg) as adults and, as a result, have the total systemic exposure (area under the plasma drug concentration-time curve) approximately one half that of adults. The levofloxacin area under the plasma drug concentration-time curve (dose normalized) in children receiving a single dose of the oral liquid formulation is comparable to that in children receiving the intravenous formulation. To provide compatible levofloxacin exposures associated with clinical effectiveness and safety in adults, children > or =5 years need a daily dose of 10 mg/kg, whereas children 6 months to <5 years should receive 10 mg/kg every 12 hours.     

Pharmacokinetics of Subcutaneous Recombinant Methionyl Human Leptin Administration in Healthy Subjects in the Fed and Fasting States

BACKGROUND: Recombinant methionyl human leptin (r-metHuLeptin) has demonstrated efficacy in improving hormonal and metabolic parameters in leptin-deficient states, and it has been suggested that leptin replacement may reverse metabolic adaptations during weight loss interventions. The pharmacokinetics of subcutaneously administered r-metHuLeptin have been recently published, but whether pharmacokinetic parameters are altered by short-term fasting, adiposity and/or gender has not yet been evaluated. OBJECTIVE: The objective of this study was to characterize pharmacokinetic parameters following subcutaneous r-metHuLeptin administration at doses in the physiological to supra-physiological to pharmacological range in the fed state and during 3-day complete fasting in lean and obese subjects, including both men and women. METHODS: We analysed pharmacokinetic profiles in five lean men, five obese men and five lean women following subcutaneous administration of physiological (0.01 mg/kg), supra-physiological (0.1 mg/kg) and pharmacological (0.3 mg/kg) doses of r-metHuLeptin given once in the fed state and once daily during 3-day complete caloric deprivation (fasting). RESULTS: With r-metHuLeptin administration at 0.01 mg/kg, leptin concentrations ranged up to approximately 7 ng/mL in lean men, approximately 20 ng/mL in obese men and approximately 30 ng/mL in lean women in the fed state. There was a significant effect of 3-day fasting: it decreased baseline leptin concentrations, peak serum concentration (C(max)) and area under the serum concentration-time curve from time zero to infinity (AUC(infinity)) [all p < 0.0001] and increased clearance (p < 0.001), most prominently in lean men (p < 0.0001 across the groups). Administration of r-metHuLeptin at 0.1 mg/kg resulted in leptin concentrations up to approximately 70 ng/mL in lean men, approximately 100 ng/mL in obese men and approximately 150 ng/mL in lean women in the fed state. At this dose, there was a similar effect of fasting on the pharmacokinetic parameters as well as a decrease in the terminal-phase elimination half-life (p = 0.02), consistent with increased clearance, but the effect of fasting was less pronounced overall than with the 0.01 mg/kg dose. With r-metHuLeptin administration at 0.3 mg/kg, leptin concentrations ranged up to approximately 150 ng/mL in lean men, approximately 300 ng/mL in obese men and approximately 400 ng/mL in lean women in the fed state. At this dose, fasting increased clearance to a lesser degree (p = 0.046), mainly in lean men, suggesting that the fasting-induced increase in leptin clearance by the kidneys can plateau. Within each group, the subjects lost approximately 3-4 kg of bodyweight after 3 days of fasting (all p < 0.0001), but the amount and time course of weight loss did not differ according to the dose of r-metHuLeptin administered or the circulating leptin concentrations achieved. CONCLUSIONS: Short-term fasting in healthy individuals results in increased clearance of leptin; this contributes to hypoleptinaemia, which may serve as a signal to increase energy intake in the setting of caloric restriction. Obese individuals with greater energy stores at baseline have a blunted response to the fasting-induced increase in leptin clearance. Also, women have a differential response to fasting, with primarily decreased leptin production rather than increased clearance. These findings and the resulting formulas for calculating doses for r-metHuLeptin administration have important implications for future therapeutic use of r-metHuLeptin in conjunction with hypocaloric diets for the treatment of obesity.     

Pharmacokinetics and pharmacodynamics of intravenous levofloxacin in patients with early-onset ventilator-associated pneumonia

OBJECTIVE: To investigate the pharmacokinetics of levofloxacin and the pharmacokinetic-pharmacodynamic appropriateness of its total body exposure in patients in the intensive care unit (ICU) treated for early-onset ventilator-associated pneumonia (VAP) with intravenous levofloxacin 500mg twice daily. DESIGN: Prospective non-blinded pharmacokinetic-pharmacodynamic study. PARTICIPANTS: Ten critically ill adult patients with normal renal function. METHODS: Blood and urine samples were collected at appropriate times during a 12-hour administration interval at steady state. Levofloxacin concentrations were determined by high-performance liquid chromatography. Clinical and microbiological outcomes were assessed. RESULTS: Levofloxacin pharmacokinetics were only partially comparable with those obtained from literature data for healthy volunteers. Area under the concentration-time curve (AUC(tau)) over the 12-hour dosage interval was about 30-40% lower than in healthy volunteers (33.90 vs 49.60 mg. h/L). The reduced exposure may be due to a greater clearance of levofloxacin (0.204 vs 0.145 L/h/kg [3.40 vs 2.42 mL/min/kg]), leading to a shorter elimination half-life (5.2 vs 7.6 hours). Cumulative urinary excretion during the 12-hour dosage interval confirmed the greater excretion of unchanged drug in these patients compared with healthy subjects (76% vs 68%). Coadministered drugs used to treat underlying diseases (dopamine, furosemide, mannitol) may at least partially account for this enhanced elimination in critically ill patients. Intravenous levofloxacin 500mg twice daily ensured a median C(max)/MIC (maximum plasma concentration/minimum inhibitory concentration) ratio of 102 and a median 24-hour AUC/MIC ratio of 930 SIT(-1). h (inverse serum inhibitory titre integrated over time) against methicillin-sensitive Staphylococcus aureus and Haemophilus influenzae. The overall success rate of the assessable cases was 75% (6/8). Bacterial eradication was obtained in all of the assessable cases (8/8), but a superinfection (Acinetobacter anitratus,Pseudomonas aeruginosa) occurred in three cases. CONCLUSIONS: The findings support the suitability of intravenous levofloxacin 500mg twice daily in the treatment of early-onset VAP in ICU patients with normal renal function. Levofloxacin may represent a valid alternative to non-pseudomonal beta-lactams or aminoglycosides in the empirical treatment of early-onset VAP. However, further larger studies are warranted to investigate its efficacy.     

Intravenous pharmacokinetics, oral bioavailability and dose proportionality of ragaglitazar, a novel PPAR-dual activator in rats

Pharmacokinetics of ragaglitazar (a novel phenoxazine derivative of aryl propanoic acid), a potent insulin sensitizing and lipid-lowering compound was studied in Wistar rats. A single dose of 1, 3 or 10 mg/kg of ragaglitazar was given orally to male rats (n=4 per dose level) to evaluate dose proportionality. In another study, a single intravenous bolus dose of ragaglitazar was given to rats (n=4) at 3 mg/kg dose following administration through the lateral tail vein in order to obtain the absolute oral bioavailability and clearance parameters. Blood samples were drawn at predetermined intervals and the concentration of ragaglitazar in plasma was determined by a validated HPLC method. Plasma concentration versus time data were generated following oral and intravenous dosing and pharmacokinetic analysis was performed using non-compartmental analysis. The results revealed that Cmax and AUC(0-infinity) increased more than proportionally to the administered oral doses. As dose increased in the ratio of 1:3:10, the mean Cmax and AUC(0-infinity) increased in the ratio of 1:3.2:13 and 1:3.2:16, respectively. After intravenous administration the systemic clearance and volume of distribution of ragaglitazar in rats were 139+/-30 ml/h/kg and 463+/-51 ml/kg, respectively (mean+/-SD). Plasma concentrations declined mono-exponentially following intravenous administration and elimination half-life (t1/2) was about 2.6 h and not significantly different (p > 0.05) from the value from oral administration. Mean residence time (MRT) values for ragaglitazar were found to be 4.15+/-0.52 h (3.5 to 4.6 h). Absolute oral bioavailability of ragaglitazar across the doses tested was in the range of 68%-93%. In conclusion, ragaglitazar exhibits promising pharmacokinetic properties in rats.     

左氧氟沙星口服或静脉注射家兔泪液、角膜组织的药动学比较

目的家兔口服或静脉注射(静注)左氧氟沙星后泪液与角膜组织的药动学比较。方法选取54只家兔分成口服组和静注组(n=27),分别口服或静注左氧氟沙星24 mg·kg~(-1),不同时间采集泪液或角膜组织,高效液相色谱法测定药物浓度,3p97软件计算药动学参数。结果口服给药后泪液和角膜组织中左氧氟沙星t_(max)、c_(max)和AUC_(0-t)分别为(0.58±0.20)与(1.00±0.55)h、(34.27±11.69)与(8.51±2.72)μg·g~(-1)、(157.19±32.15)与(22.90±2.63)μg·h·g~(-1);静注后分别为(0.83±0.26)与(0.83±0.26)h、(30·44±3.18)与(6.12±0.71)μg·g~(-1)、(136.72±20.12)与(26.01±5.59)μg·h·g~(-1)。左氧氟沙星口服或静注给药后泪液和角膜组织间药物浓度和药动学参数均无显著差异(P>0.05)。结论左氧氟沙星口服和静注在家兔泪液和角膜组织中药动学参数相似。     

Intranasal Delivery of Topically-Acting Levofloxacin to Rats: a Proof-of-Concept Pharmacokinetic Study

Purpose

To evaluate the potential of levofloxacin intranasal administration as a promising alternative approach to treat local infections such as chronic rhinosinusitis, by delivering drug concentrations directly to the site of infection.

Methods

Drug concentrations were measured in plasma, olfactory bulb and nasal mucosa of anterior (ANM) and posterior regions after intranasal (0.24 mg/kg) and intravenous (10 mg/kg) administration to rats, and pharmacokinetic parameters were compared between routes. For intranasal administration a thermoreversible in-situ gel was used.

Results

Plasma and olfactory bulb exposure to levofloxacin was minimal following intranasal dose, preventing systemic and central nervous system adverse effects. Levofloxacin concentration-time profile in ANM revealed higher concentrations during the first 60 min of the study following intranasal administration than the corresponding ones obtained after intravenous administration. A rapid and continuous decay of levofloxacin concentration in this nasal region was observed after intranasal delivery, resulting in much lower values at the last sampling time-points.

Conclusion

The higher dose-normalized concentrations and pharmacokinetic exposure parameters of levofloxacin in ANM after intranasal administration, demonstrates that intranasal delivery of the formulated gel is, by itself, advantageous for delivering levofloxacin to biophase and thus an attractive approach in management of chronic rhinosinusitis.

     

家兔静脉注射与口服左氧氟沙星后血浆和眼房水药动学比较

目的:比较家兔静脉注射与口服左氧氟沙星后血浆和眼房水药动学.方法:选取54只家兔,分别静脉注射或口服左氧氟沙星24 mg/kg,高效液相色谱法测定血浆和眼房水药物浓度,3p97软件计算药动学参数.结果:静脉注射与口服血浆中左氧氟沙星t1/2分别为(1.42±0.29)h和(2.99 ±0.20)h(P＜0.01);AUC(0-t)分别为(42.56±3.71) μg·h·mL-1和(33.48±2.98)μg·h·mL-1(P＜0.01).房水中左氧氟沙星t1/2分别为(2.53±0.65)h和(2.68±0.70)h;tmax分别为(0.50±0.00)h和(0.67±0.24)h(P＜0.05);Cmax分别为(4.93±0.83)μg/mL和(1.59±0.38) μg/mL(P＜0.01).结论:左氧氟沙星口服给药可在血浆和房水中达较高药物浓度,但静脉注射更为明显,二者有明显差别.     

Comparison of intranasal administration of haloperidol with intravenous and intramuscular administration: a pilot pharmacokinetic study

STUDY OBJECTIVE: To evaluate the pharmacokinetics of haloperidol after intranasal administration compared with intravenous and intramuscular administration, and to evaluate systemic and local tolerance of intranasal administration. DESIGN: Randomized, open-label, three-way crossover study. SETTING: Academic medical center. SUBJECTS: Four healthy volunteers (two men, two women; aged 24-37 yrs). INTERVENTION: Each subject received in a randomized order the following three treatments, with a 2-week washout period between treatments: intravenous haloperidol 2.5 mg (0.5 ml of 5.0 mg/ml) infused over 15 minutes, intramuscular haloperidol 2.5 mg (0.5 ml of 5.0 mg/ml), and intranasal haloperidol 2.5 mg (2.5 mg/0.1-ml spray into a single naris). MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained serially and plasma levels determined. Noncompartmental analysis was used to estimate pharmacokinetic parameters. Physical and nasal examinations and adverse-effect profiles were obtained to assess tolerance. Mean (percent coefficient of variation) haloperidol bioavailability after intranasal administration was 63.8% (24.4%) compared with intravenous administration and 48.6% (29.4%) compared with intramuscular administration. Intranasal administration achieved higher peak levels that occurred more quickly compared with intramuscular administration. Median time to maximum concentration was 15 minutes after the intranasal dose compared with 37.5 and 15 minutes after the intramuscular and intravenous doses, respectively. Subjects had mild-to-moderate systemic adverse effects, all related to an extension of haloperidol's pharmacologic actions. Two of the four subjects complained of mild-tomoderate nasal irritation after the intranasal doses. CONCLUSION: Our results suggest that additional research studies are warranted for further evaluation of intranasal administration of haloperidol. The product provides rapid therapeutic plasma levels and sedation, with only minor and short-lived nasal irritation. These data suggest that intranasal administration of haloperidol, or other antipsychotics with similar potency, could play a role in treating psychiatric emergencies.     

Pharmacokinetics of intravenous busulfan in children prior to stem cell transplantation

AIMS: Intravenous formulations of busulfan have recently become available. Although busulfan is used frequently in children as part of a myeloablative regimen prior to bone marrow transplantation, pharmacokinetic data on intravenous busulfan in children are scarce. The aim was to investigate intravenous busulfan pharmacokinetics in children and to suggest a limited sampling strategy in order to determine busulfan systemic exposure with the minimum of inconvenience and risk for the patient. METHODS: Plasma pharmacokinetics after the first administration was investigated in six children using nonlinear mixed effect modelling. RESULTS: Pharmacokinetics showed little variability and were described adequately with a one-compartment model (population estimates CL,av=0.29 l h(-1) kg(-1); V,av=0.84 l kg(-1); t(1/2)=1.7-2.8 h). Combined with limited sampling and a Bayesian fitting procedure, the model can adequately estimate the systemic exposure to intravenous busulfan, which in children appears to be at the lower end of the adult range. CONCLUSIONS: Busulfan systemic exposure in children during intravenous administration can be estimated adequately with limited sampling and a Bayesian fitting procedure from a one-compartment model. Intravenous busulfan pharmacokinetics in children should be the subject of more research.     

Intrapulmonary pharmacokinetics and pharmacodynamics of high-dose levofloxacin in healthy volunteer subjects

The objective of this study was to determine the plasma and intrapulmonary pharmacokinetic parameters of intravenously administered levofloxacin in healthy volunteers. Three doses of either 750 mg or 1000 mg levofloxacin were administered intravenously to 4 healthy adult subjects (750 mg) to 20 healthy adult subjects divided into five groups of 4 subjects (1000 mg). Standardised bronchoscopy and timed bronchoalveolar lavage (BAL) were performed following administration of the last dose. Blood was obtained for drug assay prior to drug administration and at the time of BAL. Levofloxacin was measured in plasma, BAL fluid and alveolar cells (ACs) using a sensitive and specific combined high-performance liquid chromatographic tandem mass spectrometric technique (HPLC/MS/MS). Plasma, epithelial lining fluid (ELF) and AC pharmacokinetics were derived using non-compartmental methods. The maximum plasma drug concentration to minimum inhibitory concentration ratio (C(max)/MIC(90)) and the area under the drug concentration curve to minimum inhibitory concentration ratio (AUC/MIC(90)) during the dosing interval were calculated for potential respiratory pathogens with MIC(90) values from 0.03 microg/mL to 2 microg/mL. In the 1000 mg dose group, the C(max) (mean+/-standard deviation (S.D.)), AUC(0-8h) and half-life were: for plasma, 9.2+/-1.9 microg/mL, 103.6 microg h/mL and 7.45 h; for ELF, 25.8+/-7.9 microg/mL, 279.1 microg h/mL and 8.10h; and for ACs, 51.8+/-26.2 microg/mL, 507.5 microg h/mL and 14.32 h. In the 750 mg dose group, the C(max) values in plasma, ELF and ACs were 5.7+/-0.4, 28.0+/-23.6 and 34.2+/-18.7 microg/mL, respectively. Levofloxacin concentrations were significantly higher in ELF and ACs than in plasma at all time points. For pathogens commonly associated with community-acquired pneumonia, C(max)/MIC(90) ratios in ELF ranged from 12.9 for Mycoplasma pneumoniae to 859 for Haemophilus influenzae, and AUC/MIC(90) ratios ranged from 139 to 9303, respectively. The C(max)/MIC(90) ratios in ACs ranged from 25.9 for M. pneumoniae to 1727 for H. influenzae, and AUC/MIC(90) ratios ranged from 254 to 16917, respectively. The C(max)/MIC(90) and AUC/MIC(90) ratios provide a pharmacokinetic rationale for once-daily administration of a 1000 mg dose of levofloxacin and are favourable for the treatment of community-acquired respiratory pathogens.     

Tissue pharmacokinetics of levofloxacin in human soft tissue infections

AIMS: The present study addressed the ability of levofloxacin to penetrate into subcutaneous adipose tissues in patients with soft tissue infection. METHODS: Tissue concentrations of levofloxacin in inflamed and healthy subcutaneous adipose tissue were measured in six patients by microdialysis after administration of a single intravenous dose of 500 mg. Levofloxacin was assayed by high-performance liquid chromatography. RESULTS: The mean concentration vs time profile of free levofloxacin in plasma was identical to that in inflamed and healthy tissues. The ratios of the mean area under the free levofloxacin concentration vs time curve from 0 to 10 h (AUC(0,10 h)) in tissue to that in plasma were 1.2 +/- 1.0 for inflamed and 1.1 +/- 0.6 for healthy subcutaneous adipose tissue (mean +/- SD). The mean difference in the ratio of the AUC(tissue) : AUC(plasma) for inflamed and healthy tissue was 0.09 (95% confidence interval -0.58, 0.759, P > 0.05). Interindividual variability in tissue penetration was high, as indicated by a coefficient of variation of approximately 82% for AUC(tissue) : AUC(plasma) ratios. CONCLUSIONS: The penetration of levofloxacin into tissue appears to be unaffected by local inflammation. Our plasma and tissue data suggest that an intravenous dose of 500 mg levofloxacin provides effective antibacterial concentrations at the target site. However, in treatment resistant patients, tissue concentrations may be sub-therapeutic.     

Pharmacokinetics of amiodarone in man

We studied the kinetics of amiodarone in three healthy volunteers after single oral (400 mg) and intravenous (150 mg) doses and in six patients with supraventricular tachycardia. Three patients were studied after the first oral dose (400 mg) and during subsequent therapy (200 mg/day); the other three after 5 mg/kg of amiodarone intravenous. Blood was drawn at intervals for 24 h in patients and up to 32 h (i.v.) and 50 h (p.o.) from healthy volunteers. The drug was measured by high pressure liquid chromatography (HPLC). No difference in kinetic parameters was found between healthy subjects an patients. The pharmacokinetic parameters, calculated on the intravenous data using a two-compartment open model, indicate a very large volume of distribution (9.26-17.17 L/kg in healthy volunteers and 6.88-21.05 L/kg in patients). The elimination half-life ranged from 12.09 to 20.70 h in volunteers and from 11.60 to 19.60 h in patients. Oral absorption was slow an erratic, with fourfold individual variations in systemic bioavailability (22-86%). A slight accumulation of amiodarone was observed in patients under chronic treatment.     

Levofloxacin: a review of its use in the treatment of bacterial infections in the United States

Levofloxacin (Levaquin) is a fluoroquinolone antibacterial agent with a broad spectrum of activity against Gram-positive and Gram-negative bacteria and atypical respiratory pathogens. It is active against both penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae. The prevalence of S. pneumoniae resistance to levofloxacin is <1% overall in the US.A number of randomised comparative trials in the US have demonstrated the efficacy of levofloxacin in the treatment of infections of the respiratory tract, genitourinary tract, skin and skin structures. Sequential intravenous to oral levofloxacin 750mg once daily for 7-14 days was as effective in the treatment of nosocomial pneumonia as intravenous imipenem/cilastatin 500-1000mg every 6-8 hours followed by oral ciprofloxacin 750mg twice daily in one study. In patients with mild to severe community-acquired pneumonia (CAP), intravenous and/or oral levofloxacin 500mg once daily for 7-14 days achieved clinical and bacteriological response rates similar to those with comparator agents, including amoxicillin/clavulanic acid, clarithromycin, azithromycin, ceftriaxone and/or cefuroxime axetil and gatifloxacin. A recent study indicates that intravenous or oral levofloxacin 750mg once daily for 5 days is as effective as 500mg once daily for 10 days, in the treatment of mild to severe CAP. Exacerbations of chronic bronchitis and acute maxillary sinusitis respond well to treatment with oral levofloxacin 500mg once daily for 7 and 10-14 days, respectively.Oral levofloxacin was as effective as ofloxacin in uncomplicated urinary tract infections and ciprofloxacin or lomefloxacin in complicated urinary tract infections. In men with chronic bacterial prostatitis treated for 28 days, oral levofloxacin 500mg once daily achieved similar clinical and bacteriological response rates to oral ciprofloxacin 500mg twice daily. Uncomplicated skin infections responded well to oral levofloxacin 500mg once daily for 7-10 days, while in complicated skin infections intravenous and/or oral levofloxacin 750mg for 7-14 days was at least as effective as intravenous ticarcillin/clavulanic acid (+/- switch to oral amoxicillin/clavulanic acid) administered for the same duration.Levofloxacin is generally well tolerated, with the most frequently reported adverse events being nausea and diarrhoea; in comparison with some other quinolones it has a low photosensitising potential and clinically significant cardiac and hepatic adverse events are rare. CONCLUSION: Levofloxacin is a broad-spectrum antibacterial agent with activity against a range of Gram-positive and Gram-negative bacteria and atypical organisms. It provides clinical and bacteriological efficacy in a range of infections, including those caused by both penicillin-susceptible and -resistant strains of S. pneumoniae. Levofloxacin is well tolerated, and is associated with few of the phototoxic, cardiac or hepatic adverse events seen with some other quinolones. It also has a pharmacokinetic profile that is compatible with once-daily administration and allows for sequential intravenous to oral therapy. The recent approvals in the US for use in the treatment of nosocomial pneumonia and chronic bacterial prostatitis, and the introduction of a short-course, high-dose regimen for use in CAP, further extend the role of levofloxacin in treating bacterial infections.     

Pharmacokinetics/pharmacodynamics of levofloxacin 750 mg once daily in young women with acute uncomplicated pyelonephritis

This pilot study was undertaken to characterise the pharmacokinetics, pharmacodynamics and potential clinical efficacy of levofloxacin 750 mg once daily for 5 days for treatment of women with acute uncomplicated pyelonephritis. Four women diagnosed with acute pyelonephritis were enrolled. Following pre-therapy specimen collection, an initial oral dose of 750 mg levofloxacin was administered. The mean pharmacokinetic parameters for the first dose were: maximum serum concentration (C(max)) 12.5+/-4.7 mg/L (range 5.6-16.0mg/L) (fC(max) 8.8+/-3.3, where f indicates the levofloxacin free or non-protein-bound fraction), area under the serum concentration-time curve (AUC) 85.4+/-14.1 mgh/L (range 66.2-96.8 mgh/L) (fAUC 59.8+/-9.9) and serum half-life (t(1/2)) 6.7+/-0.5h. Mean urine concentrations were 88.0+/-100mg/L at the 0-3 h collection, 307+/-143 mg/L at 3-6 h, 170+/-107 mg/L at 6-12 h and 85+/-8 mg/L at 12-24 h. Mean levofloxacin serum pharmacodynamics for infecting Escherichia coli were: C(max)/minimum inhibitory concentration (MIC) 323+/-185(fC(max)/MIC 226+/-129); and AUC/MIC 2339+/-830(fAUC/MIC 1647+/-579). Mean urine levofloxacin concentration/MIC ratios were: 900+/-1389 for 0-3 h, 12100+/-4950 for 3-6 h, 5922+/-3912 for 6-12 h and 2233+/-1037 for 12-24 h. Levofloxacin eradicated E. coli from the urine by 3-6 h after the first dose. Levofloxacin 750 mg once daily for 5 days has pharmacodynamics that support further evaluation of this regimen for treatment of women with acute uncomplicated pyelonephritis.     

盐酸左氧氟沙星片在健康人体内的药代动力学和 生物等效性研究

目的:研究已上市盐酸左氧氟沙星片在健康中国人体内的生物等效性。方法:48例健康志愿者随机分组,分别在空腹及进食高脂餐后,两周期双交叉单剂量口服盐酸左氧氟沙星片及其参比制剂左氧氟沙星片各500 mg,采用高效液相色谱-串联质谱法测定给药前与给药后48 h内不同时间点的血药浓度,计算主要药代动力学参数,评价生物等效性。结果:在空腹试验中,盐酸左氧氟沙星片及其参比制剂的AUC0~48 h分别为(50.0±8.4)、(48.8±8.6)μg·h·mL^-1,Cmax分别为(6.15±1.42)、(5.98±1.55)μg·mL^-1,tmax分别为(1.19±0.62)、(1.30±0.73)h,t1/2分别为(6.56±1.13)、(6.51±1.14)h^-1,相对生物利用度为(103.0±8.7)%;在餐后试验中,盐酸左氧氟沙星片及其参比制剂的AUC0~48 h分别为(45.4±8.4)、(44.5±8.2)μg·h·mL^-1,Cmax分别为(5.85±1.08)、(6.58±1.89)μg·mL^-1,tmax分别为(1.93±0.72)、(1.82±0.81)h,t1/2分别为(6.69±0.81)、(6.63±0.76)h^-1,相对生物利用度为(102.3±5.3)%。结论:盐酸左氧氟沙星片与其参比制剂具有生物等效性。     

Cocaine pharmacokinetics in men and in women during the follicular and luteal phases of the menstrual cycle.

Preclinical and clinical studies suggest that females may be less vulnerable to cocaine's toxic effects than males. The pharmacokinetics of intravenous cocaine (0.2 and 0.4 mg/kg) were measured in 12 men and 22 women with a history of cocaine abuse, matched with respect to age and body mass index (BMI). Women were studied during the follicular and the luteal phases of the menstrual cycle. There were no differences between men and women in pharmacokinetic measures [peak plasma cocaine levels (Cmax), elimination half-life (T 1/2 min), area under the curve (AUC)] or cardiovascular or subjective effects "high" measures. Heart rate increases were cocaine dose-related (p < .01-.02) and also did not differ between men and women. Cocaine's pharmacokinetic and pharmacodynamic effects were similar in men and women, and in women during the follicular and mid-luteal phases of the menstrual cycle.     

Population pharmacokinetics meta-analysis of recombinant human erythropoietin in healthy subjects

OBJECTIVE: The aim of this analysis was to develop a population pharmacokinetic model to describe the pharmacokinetics of recombinant human erythropoietin (rHuEPO) in healthy subjects, after intravenous and subcutaneous administration over a wide dose range, and to examine the influence of demographic characteristics and other covariates on the pharmacokinetic parameters of rHuEPO. METHODS: Erythropoietin serum concentration data were available from 16 studies comprising 49 healthy subjects who received rHuEPO intravenous doses from 10 to 300 IU/kg, 427 healthy subjects who received rHuEPO subcutaneous doses from 1 to 2400 IU/kg, and 57 healthy subjects who received placebo and where endogenous erythropoietin concentrations were measured. Different pharmacokinetic models were fitted to the dataset using nonlinear mixed-effects modeling software (NONMEM, Version V, Level 1). Several patient covariates were tested in order to quantify the effect on rHuEPO pharmacokinetic parameters. Model evaluation was examined using a posterior predictive check. RESULTS: Erythropoietin showed a diurnal baseline variation of +/-20%, described with a dual cosine model. Disposition was described with a two-compartment model with a small volume of distribution (6L) and parallel linear and nonlinear clearance. Total clearance varied between 0.3 and 0.9 L/h over the concentration range studied. A dual absorption model was used to characterise the rHuEPO absorption from the subcutaneous formulation and consisted of a faster pathway described as a sequential zero- and first-order absorption process and a parallel slower pathway characterised as a zero-order process. The bioavailability of subcutaneous rHuEPO increased from 30% at low doses to 71% at the highest dose of 160 kIU and was described using a hyperbolic model. The most important covariate effects were a decrease in the first-order absorption rate constant (k(a)) with increasing age, an increase in subcutaneous bioavailability with increasing baseline haemoglobin, and a decrease in bioavailability with increasing bodyweight. A posterior predictive check showed no systematic deviation of the simulated data from the observed values. CONCLUSION: The population pharmacokinetic model developed is suitable to describe the pharmacokinetic behaviour of rHuEPO after intravenous and subcutaneous administration in healthy subjects, over a wide dose range.     

中国健康受试者多剂量静脉滴注左氧氟沙星注射液的药物动力学

目的:研究左氧氟沙星注射液多剂量给药在健康人体内的药代动力学.方法:10名健康男性受试者给予左氧氟沙星注射液200mg,注射时间为60min,连续给药7天,其中第1天及第7天给药1次,第2到6天每天给药2次,间隔12h 采用反相高效液相色谱法测定血及尿药浓度.结果:第一次给药的主要药物动力学参数:C_(max)(2.4±0.4)mg/L;AUC_(0-∞)(16.1±1.4)mg·h·L~(-1);T1/3β(6.3±0.3)h.血药浓度于第3天达稳态,稳态后最后一次给药的主要药物动力学参数:C_(ssmax)(2.9±0.4)mg/L;C_(ssmin)(0.71 0.19)mg/L;C_(av)(1.40±0.29)mg/L;AUC_(ss0-12)(17±3)mg·h·L~(-1),T1/2β(6.2±0.8)h.24h内平均尿累积排泄百分率为(88±5)％.累积比为1.20,波动系数为1.30.第一次给药与最后一次给药T1/2β及AUC差异无显著性(P>0.05).整个试验期间,受试者未出现明显的不良反应.结论:左氧氟沙星注射液200mg连续给药7天,药物在体内无明显蓄积.     

Comparative pharmacokinetics and metabolic pathway of gemcitabine during intravenous and intra-arterial delivery in unresectable pancreatic cancer patients

BACKGROUND: To study the pharmacokinetics and clinical outcome of gemcitabine (2'-2'-difluoro-deoxcytidine [dFdC]) during intra-arterial versus intravenous delivery in locally advanced and regionally metastatic pancreatic cancer. PATIENTS AND METHODS: Seven patients with unresectable pancreatic cancer received escalating intra-arterial doses of gemcitabine ranging from 800 to 1400 mg/m2, after selective embolisation of all pancreatic blood supply, except for the tumour-feeding arteries. Four patients received intravenous gemcitabine (control). Venous blood samples at different time intervals were taken throughout 270 minutes for pharmacokinetic analyses of gemcitabine and its inactive metabolite 2'-2'-difluorodeoxyuridine (dFdU). RESULTS: Pharmacokinetic data revealed differences in plasma concentrations between intra-arterial and intravenous delivery routes. The plasma concentration-time curve of gemcitabine during and after cessation of intra-arterial pancreatic target administration through the proximal splenic artery showed a profile with an area under the plasma concentration-time curve from 0 to 270 minutes (intra-arterial 29.0 +/- 0.4 vs intravenous 331.0 +/- 2.7 ng.min/mL; p < 0.0001) and peak plasma concentration (intra-arterial 1.1 +/- 0.2 vs intravenous 7.6 +/- 2.0 ng/mL; p < 0.0001) significantly lower than that for the corresponding systemic intravenous route. A plot of ln (% of dose) versus time showed a bi-compartmentalised metabolic model for intravenous administration of gemcitabine, one indicating rapid conversion of gemcitabine to dFdU, and another at a significantly lower affinity resulting in no conversion. Hence, this could be the main reason why dFdU was not detected in the systemic circulation during pancreatic intra-arterial target delivery. Furthermore, during intravenous administration a pseudo first-order rate constant ( approximately 0.20 min(-)(1)) for in vivo conversion of gemcitabine to dFdU was estimated, indicating a rapid cellular deamination which was not shown in the intra-arterial route. Clinically, one patient had a partial response and six patients had a stable disease after intra-arterial administration of gemcitabine. The median time to disease progression was 4 months and the median overall survival was 5 months. One patient survived for 26 months. No grade III or IV toxicity was documented. CONCLUSION: Intra-arterial administration of gemcitabine has a major advantage related to reduced toxicity as increasing the dose through this administration route will eventually result in pancreatic cellular drug target delivery prior to systemic availability. Despite the low number of patients recruited, the clinical results are encouraging and this approach should be tested in a randomised study.