Shape does matter: short high-concentration exposure minimizes resistance emergence for fluoroquinolones in Pseudomonas aeruginosa.

Objectives: For fluoroquinolones, the area under the free plasma concentration-time curve divided by the MIC (fAUC/MIC) best predicts bacterial killing in mice and outcomes in patients. However, it is unknown whether the shape of the antibiotic concentration profile affects resistance emergence. Our objective was to compare killing and resistance between ciprofloxacin concentration profiles with different shapes at the same fAUC/MIC and identify the durations of ciprofloxacin exposure that minimize resistance emergence.

Population pharmacokinetics of piperacillin at two dose levels: influence of nonlinear pharmacokinetics on the pharmacodynamic profile.

Piperacillin in combination with tazobactam is one of the most commonly used intravenous antibiotics. There is evidence for a possible saturable elimination of piperacillin. Therefore, the saturable elimination and its impact on the choice of optimal dosage regimens were quantified.

An LC-MS/MS procedure for the quantification of naproxen in human plasma: development, validation, comparison with other methods, and application to a pharmacokinetic study.

A sensitive, precise and accurate quantitative LC-MS/MS method for the measurement of naproxen in human plasma was developed and completely validated according to current FDA and EMA guidelines. The new method employs acetonitrile protein precipitation for sample preparation and uses ketoprofen as the internal standard. Suitability of the new assay was assessed in comparison with 36 reported bioanalytical assays and the pharmacokinetic results obtained by the new method were compared to 11 reported studies in humans.

Development and validation of a liquid chromatography/tandem mass spectrometry procedure for the quantification of sunitinib (SU11248) and its active metabolite, N-desethyl sunitinib (SU12662), in human plasma: application to an explorative study.

A sensitive, precise and accurate quantitative liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for the measurement of sunitinib (SU11248) and N-desethyl sunitinib (SU12662) in human plasma was developed and validated. All sample handling was done under strict light protection. The sample preparation method employed acetonitrile protein precipitation using d(5)-SU11248 as an internal standard.

Nonlinear pharmacokinetics of piperacillin in healthy volunteers--implications for optimal dosage regimens.

Aims: (i) To describe the first-order and mixed-order elimination pathways of piperacillin, (ii) to determine the between occasion variability (BOV) of pharmacokinetic parameters and (iii) to propose optimized dosage regimens.

Methods: We performed a five-period replicate dose study in four healthy volunteers. Each subject received 4g piperacillin as a single 5min intravenous infusion in each study period.

Physicochemical and biologic comparability of a biosimilar granulocyte colony-stimulating factor with its reference product.

Background: Development of biosimilars requires physicochemical and biologic characterization to show comparability with a reference product. Zarzio (filgrastim) is a biosimilar recombinant human granulocyte colony-stimulating factor (G-CSF) that has been approved in the EU using Neupogen as its reference product.

Objective: The aim of this study was to compare the drug identity, purity, and bioactivity of Zarzio (300 and 480 μg/0.

Competitive inhibition of renal tubular secretion of ciprofloxacin and metabolite by probenecid.

Aims: Probenecid influences transport processes of drugs at several sites in the body and decreases elimination of several quinolones. We sought to explore extent, time course, and mechanism of the interaction between ciprofloxacin and probenecid at renal and nonrenal sites.

Methods: A randomized, two-way crossover study was conducted in 12 healthy volunteers (in part previously published Clin Pharmacol Ther 1995; 58: 532-41).

Population pharmacokinetic comparison and pharmacodynamic breakpoints of ceftazidime in cystic fibrosis patients and healthy volunteers.

Despite the promising activity of ceftazidime against Pseudomonas aeruginosa and Burkholderia cepacia, there has not yet been a study that directly compared the pharmacokinetics (PK) of ceftazidime in cystic fibrosis (CF) patients and healthy volunteers by population PK methodology. We assessed the population PK and PK/pharmacodynamic (PD) breakpoints of ceftazidime in CF patients and healthy volunteers. Eight CF patients (total body weight [WT] [average +/- standard deviation] = 42.

Development of a new G-CSF product based on biosimilarity assessment.

Background: Zarzio, a new recombinant human granulocyte colony-stimulating factor (filgrastim), was evaluated in healthy volunteers and neutropenic patients in phase I and III studies.

Patients And Methods: Healthy volunteers in randomized, two-period crossover studies received single- and multiple-dose s.c.

Comparison of the pharmacokinetics and pharmacodynamic profile of carumonam in cystic fibrosis patients and healthy volunteers.

Our objectives were to compare the pharmacokinetics (PK) of carumonam, a monobactam, between cystic fibrosis (CF) patients and healthy volunteers and assess its pharmacodynamic profile. We studied 10 adult CF patients and 18 healthy volunteers of similar body size (dose: 2.166 g of carumonam as 15-min intravenous infusion).

Competitive inhibition of renal tubular secretion of gemifloxacin by probenecid.

Probenecid interacts with transport processes of drugs at several sites in the body. For most quinolones, renal clearance is reduced by concomitant administration of probenecid. The interaction between gemifloxacin and probenecid has not yet been studied.

Biosimilarity of HX575 (human recombinant epoetin alfa) and epoetin beta after multiple subcutaneous administration.

Objective: To compare the steady-state pharmacokinetics and pharmacodynamics following multiple subcutaneous administration of a new erythropoiesis stimulating agent (HX575, Binocrit, Sandoz GmbH, Holzkirchen, Germany) with that of epoetin beta (NeoRecormon, Roche Ltd., Welwyn Garden City, UK).

Methods: An open, randomized, parallel group study was conducted in 80 healthy adult males.

Bioequivalence of HX575 (recombinant human epoetin alfa) and a comparator epoetin alfa after multiple intravenous administrations: an open-label randomised controlled trial.

Background: HX575 is a human recombinant epoetin alfa that was approved for use in Europe in 2007 under the European Medicines Agency biosimilar approval pathway. Therefore, in order to demonstrate the bioequivalence of HX575 to an existing epoetin alfa, the pharmacokinetic and pharmacodynamic response to steady state circulating concentrations of HX575 and a comparator epoetin alfa were compared following multiple intravenous administrations.

Methods: An open, randomised, parallel group study was conducted in 80 healthy adult males.

Penetration of antibacterials into bone: pharmacokinetic, pharmacodynamic and bioanalytical considerations.

Antibacterials play a key role in the treatment of bone infections and appropriate surgical prophylaxis. The rate and extent of penetration of antimicrobials into bone has been assessed and shown to be important for successful treatment in numerous studies. However, no recent review or critical evaluation of the analytical techniques is available.

Penetration of moxifloxacin into bone evaluated by Monte Carlo simulation.

Moxifloxacin is a fluoroquinolone with a broad spectrum of activity and good penetration into many tissues, including bone. Penetration of moxifloxacin into bone has not yet been studied using compartmental modeling techniques. Therefore, we determined the rate and extent of bone penetration by moxifloxacin and evaluated its pharmacodynamic profile in bone via Monte Carlo simulation.

Bioequivalence of HX575 (recombinant human epoetin alfa) and a comparator epoetin alfa after multiple subcutaneous administrations.

Aim: To compare the steady-state pharmacokinetics and pharmacodynamics (PK/PD) of two erythropoesis-stimulating agents (ESA), HX575 (Binocrit, Sandoz GmbH, Holzkirchen, Germany), human recombinant epoetin alfa approved as the first biosimilar ESA, and a comparator epoetin alfa, following multiple subcutaneous administrations.

Methods: An open, randomized, parallel group study was conducted in 80 healthy adult males. Subjects were randomized to multiple subcutaneous doses of 100 IU/kg body weight of HX575 or of the comparator epoetin alfa 3 times weekly for 4 weeks.

Inhibition of flucloxacillin tubular renal secretion by piperacillin.

Aims: To explore the extent, time course, site(s), mechanism and possible clinical relevance of the pharmacokinetic (PK) interaction between piperacillin and flucloxacillin.

Methods: A single-dose, randomized, six-way crossover study in 10 healthy volunteers where all subjects received all of the following as 5-min intravenous infusions: (i) 1.5 g piperacillin, (ii) 0.

Evaluation by monte carlo simulation of the pharmacokinetics of two doses of meropenem administered intermittently or as a continuous infusion in healthy volunteers.

Meropenem is a broad-spectrum carbapenem antibacterial agent. In order to optimize levels in plasma relative to the MICs, the ideal dose level and dosage regimen need to be determined. The pharmacokinetics of meropenem were studied in two groups, each comprising eight healthy volunteers who received the following doses: 500 mg as an intravenous infusion over 30 min three times a day (t.

Absence of effect of rufloxacin on theophylline pharmacokinetics in steady state.

Several quinolone antibacterial agents are known to inhibit the metabolism of theophylline, with the potential to cause adverse events due to raised theophylline concentrations during coadministration. A randomized crossover study was therefore conducted with 12 healthy male volunteers (ages, 23 to 34 years; body weight, 64 to 101 kg) to evaluate a possible interaction between rufloxacin and theophylline. Both drugs were administered at steady state.

Effect of probenecid on the distribution and elimination of ciprofloxacin in humans.

Objective: Probenecid-sensitive anion transport systems may be involved in distribution and elimination processes of anionic drugs. The aim of this study was to determine the effect of multiple probenecid treatment on the pharmacokinetic disposition of the zwitterionic fluoroquinolone ciprofloxacin in 12 healthy volunteers.

Methods: A single intravenous dose of 200 mg ciprofloxacin was given with and without multiple oral administration of probenecid in a randomized crossover fashion.

Pharmacokinetics and tissue penetration of tazobactam and piperacillin in patients undergoing colorectal surgery.

The pharmacokinetics of tazobactam and piperacillin in plasma and different tissues after a 30-min intravenous infusion of 4 g of piperacillin and 0.5 g of tazobactam were investigated in 18 patients who underwent elective colorectal surgery. Serial blood samples were collected for up to 6 h after the initiation of the infusion.

Effects of temafloxacin and ciprofloxacin on the pharmacokinetics of caffeine.

A number of quinolone antibacterial agents, particularly enoxacin, pefloxacin, pipemidic acid and ciprofloxacin, are known to decrease the clearance of methylxanthines. The effects of temafloxacin and ciprofloxacin on the pharmacokinetics of caffeine were therefore compared in a 3-way crossover study in 12 healthy young volunteers. Each volunteer received 183mg once-daily doses of caffeine in conjunction with twice-daily placebo, temafloxacin 600mg and ciprofloxacin 750mg in 3 separate phases according to a randomised sequence.

Effect of antacid medication on the pharmacokinetics of temafloxacin.

The effect of an antacid drug (Maalox 70) on the pharmacokinetics of temafloxacin was studied in 12 healthy young volunteers. The study was designed as a randomised open 2-period crossover trial in which temafloxacin was administered alone and with Maalox 70. In both treatments, temafloxacin was administered as a single oral 400mg dose on the morning of day 2.

Effect of cimetidine on the pharmacokinetics of temafloxacin.

Cimetidine, a widely prescribed histamine H2-receptor antagonist, is known to interact with a variety of drugs; consequently, it is important to determine its potential for interaction with any new drug. The interaction between cimetidine and a new quinolone, temafloxacin, has been examined in an open randomised 2-period crossover study in 12 healthy adults. Half the volunteers received cimetidine 400mg 3 times daily for 8 days.

Effects of 2 quinolone antibacterials, temafloxacin and enoxacin, on theophylline pharmacokinetics.

Certain quinolone and naphthyridone antibacterial agents reduce the clearance of theophylline, posing potential clinical risks for patients maintained on this bronchodilator. Whether temafloxacin also affects theophylline pharmacokinetics was assessed in a randomised double-blind 3-way crossover study in 12 healthy volunteers, using placebo and enoxacin as controls. Each volunteer participated in all 3 phases of the study, receiving theophylline plus daily divided doses of temafloxacin 800mg, enoxacin 800mg, or placebo, orally for 7 days.