scholarly journals Clinical Pharmacokinetics of Fosfomycin after Continuous Infusion Compared with Intermittent Infusion: a Randomized Crossover Study in Healthy Volunteers

2020 ◽  
Vol 65 (1) ◽  
pp. e01375-20
Author(s):  
Valentin al Jalali ◽  
Peter Matzneller ◽  
Beatrix Wulkersdorfer ◽  
Scharon Chou ◽  
Soma Bahmany ◽  
...  
Keyword(s):  
Steady State ◽  
Crossover Study ◽  
Healthy Volunteers ◽  
Continuous Infusion ◽  
Intermittent Infusion ◽  
Time Curve ◽  
Clinical Pharmacokinetics ◽  
Clinical Scenarios ◽  
Ringer’S Lactate ◽  
State Concentration

ABSTRACTContinuous infusion (CON) of fosfomycin has been proposed as potentially advantageous in certain clinical scenarios. However, no clinical data on the pharmacokinetics (PK) of fosfomycin after CON are available to date. This study aimed to investigate the PK of fosfomycin after CON and compare it with intermittent infusion (INT) of fosfomycin. A randomized two-way crossover study including 8 healthy male volunteers was performed. Each subject received fosfomycin as INT of 8 g over 30 min every 8 h and, separated by a washout period, as CON of 1 g/h preceded by a loading dose of 8 g over 30 min. PK sampling was performed for 18 and 24 h in the CON and INT groups, respectively. Fosfomycin was generally well tolerated. However, 2 out of 8 subjects (25%) developed thrombophlebitis at the infusion site following CON, which was prevented in the following subjects with a simultaneous coinfusion of Ringer’s lactate. The steady-state maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 to 24 h at steady state (AUCSS,0–24) of fosfomycin after INT were 551.5 ± 67.8 mg/liter and 3,678.5 ± 601.9 h · mg/liter, respectively. CON led to an average steady-state concentration of 183.8 ± 35.9 mg/liter, resulting in a calculated AUCSS,0–24 of 4,411.2 ± 862.4 h · mg/liter, which was 1.2-fold higher than that with INT. CON resulted in a 100% T>MIC (time during which the drug concentration exceeds the MIC) for MICs of ≤128 mg/liter, whereas the %T>MIC for INT was only 44% for an MIC of 128 mg/liter. CON of fosfomycin led to improved PK and PK/pharmacodynamic (PD) determinants in plasma of healthy volunteers. The clinical relevance of these findings remains to be investigated in patients.

scholarly journals Pharmacokinetic Interactions of Maraviroc with Darunavir-Ritonavir, Etravirine, and Etravirine-Darunavir-Ritonavir in Healthy Volunteers: Results of Two Drug Interaction Trials

2011 ◽  
Vol 55 (5) ◽  
pp. 2290-2296 ◽  
Author(s):  
Thomas N. Kakuda ◽  
Samantha Abel ◽  
John Davis ◽  
Julia Hamlin ◽  
Monika Schöller-Gyüre ◽  
...  
Keyword(s):  
Steady State ◽  
Healthy Volunteers ◽  
Potent Inhibitor ◽  
Cytochrome P450 3A ◽  
Short Term ◽  
Two Phase ◽  
Time Curve ◽  
Safety Issues ◽  
Concentration Time ◽  
Crossover Studies

ABSTRACTThe effects of darunavir-ritonavir at 600 and 100 mg twice daily (b.i.d.) alone, 200 mg of etravirine b.i.d. alone, or 600 and 100 mg of darunavir-ritonavir b.i.d. with 200 mg etravirine b.i.d. at steady state on the steady-state pharmacokinetics of maraviroc, and vice versa, in healthy volunteers were investigated in two phase I, randomized, two-period crossover studies. Safety and tolerability were also assessed. Coadministration of 150 mg maraviroc b.i.d. with darunavir-ritonavir increased the area under the plasma concentration-time curve from 0 to 12 h (AUC12) for maraviroc 4.05-fold relative to 150 mg of maraviroc b.i.d. alone. Coadministration of 300 mg maraviroc b.i.d. with etravirine decreased the maraviroc AUC12by 53% relative to 300 mg maraviroc b.i.d. alone. Coadministration of 150 mg maraviroc b.i.d. with etravirine-darunavir-ritonavir increased the maraviroc AUC123.10-fold relative to 150 mg maraviroc b.i.d. alone. Maraviroc did not significantly affect the pharmacokinetics of etravirine, darunavir, or ritonavir. Short-term coadministration of maraviroc with darunavir-ritonavir, etravirine, or both was generally well tolerated, with no safety issues reported in either trial. Maraviroc can be coadministered with darunavir-ritonavir, etravirine, or etravirine-darunavir-ritonavir. Maraviroc should be dosed at 600 mg b.i.d. with etravirine in the absence of a potent inhibitor of cytochrome P450 3A (CYP3A) (i.e., a boosted protease inhibitor) or at 150 mg b.i.d. when coadministered with darunavir-ritonavir with or without etravirine.

scholarly journals Lack of Effect of Zafirlukast on the Pharmacokinetics of Azithromycin, Clarithromycin, and 14-Hydroxyclarithromycin in Healthy Volunteers

1999 ◽  
Vol 43 (5) ◽  
pp. 1152-1155 ◽  
Author(s):  
Kevin W. Garey ◽  
Charles A. Peloquin ◽  
Paul G. Godo ◽  
Anne N. Nafziger ◽  
Guy W. Amsden
Keyword(s):  
Steady State ◽  
Healthy Subjects ◽  
High Performance ◽  
Pharmacokinetic Parameters ◽  
Steady State Concentration ◽  
Open Label ◽  
Time Curve ◽  
Data Analyses ◽  
Concentration Time ◽  
State Concentration

ABSTRACT This randomized, open-label, crossover study was conducted to investigate whether the coadministration of zafirlukast would affect the pharmacokinetics of azithromycin, clarithromycin, or 14-hydroxyclarithromycin (14-OHC). Twelve healthy subjects (six males and six females) received single 500-mg doses of azithromycin and clarithromycin with and without zafirlukast given to a steady-state concentration. Blood was collected prior to all macrolide doses and for 3 and 10 days after each clarithromycin and azithromycin dose, respectively. Serum was assayed for azithromycin, clarithromycin, and 14-OHC concentrations by validated high-performance liquid chromatography assay systems. Data analyses were done by noncompartmental and nonparametric methods. Analysis of the patients indicated that the addition of steady-state concentrations of zafirlukast did not significantly alter the pharmacokinetic parameters of or overall exposure (based on the area under the concentration-time curve) to azithromycin, clarithromycin, and 14-OHC. While zafirlukast is a known inhibitor of CYP3A4, it does not appear to exert a clinically or statistically significant pharmacokinetic effect on azithromycin, clarithromycin, or 14-OHC.

Effect of Steady-State Faldaprevir on Pharmacokinetics of Atorvastatin or Rosuvastatin in Healthy Volunteers: A Prospective Open-Label, Fixed-Sequence Crossover Study

2017 ◽  
Vol 57 (10) ◽  
pp. 1305-1314 ◽  
Author(s):  
Fenglei Huang ◽  
Kristell Marzin ◽  
Rüdiger Koenen ◽  
Klaus Peter Kammerer ◽  
Natalja Strelkowa ◽  
...  
Keyword(s):  
Steady State ◽  
Crossover Study ◽  
Healthy Volunteers ◽  
Open Label ◽  
Fixed Sequence

Pharmacokinetic Comparison of Three Clindamycin Phosphate Dosing Schedules

1987 ◽  
Vol 21 (3) ◽  
pp. 279-281 ◽  
Author(s):  
Raymond J. Townsend ◽  
Robert P Baker
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Crossover Study ◽  
Peak Plasma ◽  
Clindamycin Phosphate ◽  
Time Curve ◽  
Acceptable Alternative ◽  
Male Volunteers

In a randomized, three-way crossover study, six male volunteers received clindamycin phosphate 600 mg iv q6h (treatment A), 600 mg iv q8h (treatment B), or 900 mg iv q8h (treatment C). Plasma clindamycin concentrations were determined periodically for eight hours after achieving steady state. The results indicate that treatment C yielded significantly higher peak plasma clindamycin concentrations than treatments A or B. There were no significant differences in minimum plasma clindamycin concentrations (Cmin) or area under the plasma concentration versus time curve (AUC24) between treatments A and C. However, both treatments A and C yielded significantly greater Cmjn and AUC24 values than treatment B. There were no significant differences among treatments for clindamycin clearance. It is concluded that clindamycin phosphate 900 mg q8h is a pharmacokinetically acceptable alternative to clindamycin phosphate 600 mg q6h.

Pharmacodynamics of RP 59500 (quinupristin-dalfopristin) administered by intermittent versus continuous infusion against Staphylococcus aureus-infected fibrin-platelet clots in an in vitro infection model.

1997 ◽  
Vol 41 (6) ◽  
pp. 1359-1363 ◽  
Author(s):  
M J Rybak ◽  
H H Houlihan ◽  
R C Mercier ◽  
G W Kaatz
Keyword(s):  
Staphylococcus Aureus ◽  
Continuous Infusion ◽  
Bactericidal Activity ◽  
Growth Control ◽  
Intermittent Infusion ◽  
Bacterial Density ◽  
Infection Model ◽  
Time Curve ◽  
Methicillin Resistant

We evaluated the bactericidal activity of RP 59500 (quinupristin-dalfopristin) against fibrin-platelet clots (FPC) infected with two clinical isolates of Staphylococcus aureus, one constitutively erythromycin and methicillin resistant (S. aureus AW7) and one erythromycin and methicillin susceptible (S. aureus 1199), in an in vitro pharmacodynamic infection model. RP 59500 was administered by continuous infusion (peak steady-state concentration of 6 microg/ml) or intermittent infusion (simulated regimens of 7.5 mg/kg of body weight every 6 h (q6h) q8h, and q12h. FPCs were infected with S. aureus to achieve an initial bacterial density of 10(9) CFU/g. Model experiments were run in duplicate over 72 h. Two FPCs were removed from each model at 0, 12, 24, 36, 48, and 72 h, and the bacterial densities (in CFU per gram) were determined and compared to those of growth control experiments. Additional samples were also removed from the model over the 72-h period for pharmacokinetic evaluation. All regimens significantly (P < or = 0.01) decreased bacterial densities in the infected FPCs for both isolates compared to growth controls. This occurred even though MBCs were equal to or greater than the RP 59500 concentrations achieved in the models. There were no significant differences found between the dosing frequencies and levels of killing when examining each isolate separately. However, examination of the residual bacterial densities (CFU per gram at 72 h) and visual inspection of the overall killing effect (killing curve plots over 72 h) clearly demonstrated a more favorable bactericidal activity against 1199 than against the AW7 isolate. This was most apparent when the q8h and the q12h AW7 regimens were compared to all 1199 treatment regimens by measuring the 72-h bacterial densities (P < or = 0.01). Killing (99.9%) was not achieved against the AW7 isolate. However, a 99.9% kill was demonstrated for all dosing regimens against the 1199 isolate. The area under the concentration-time curve from 0 to 24 h was found to be significantly correlated with reduction in bacterial density for the AW7 isolate (r = 0.74, P = 0.04). No resistance was detected during any experiment for either isolate. RP 59500 efficacy against constitutively erythromycin- and methicillin-resistant S. aureus may be improved by increasing organism exposure to RP 59500 as a function of dosing frequency.

scholarly journals Effect of a Nutritional Supplement on Posaconazole Pharmacokinetics following Oral Administration to Healthy Volunteers

2006 ◽  
Vol 50 (5) ◽  
pp. 1881-1883 ◽  
Author(s):  
Angela Sansone-Parsons ◽  
Gopal Krishna ◽  
Angela Calzetta ◽  
David Wexler ◽  
Bhavna Kantesaria ◽  
...  
Keyword(s):  
Oral Administration ◽  
Crossover Study ◽  
Healthy Volunteers ◽  
Maximum Concentration ◽  
Nutritional Supplement ◽  
Healthy Adults ◽  
Time Curve ◽  
Fasted State ◽  
Concentration Time ◽  
Randomized Crossover Study

ABSTRACT We conducted a randomized, crossover study in healthy adults to examine the effects of a nutritional supplement (Boost Plus) on posaconazole pharmacokinetics. In this study, coadministration of posaconazole with Boost Plus increased the maximum concentration of posaconazole in serum and area under the concentration-time curve from 0 to 72 h values 3.4- and 2.6-fold, respectively, compared to those for the fasted state.

scholarly journals Central nervous system effects of alcohol at a pseudo-steady-state concentration using alcohol clamping in healthy volunteers

2009 ◽  
Vol 68 (4) ◽  
pp. 524-534 ◽  
Author(s):  
Remco W. M. Zoethout ◽  
Rik C. Schoemaker ◽  
Lineke Zuurman ◽  
Hans van Pelt ◽  
Albert Dahan ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Steady State ◽  
Healthy Volunteers ◽  
Steady State Concentration ◽  
State Concentration

scholarly journals Pharmacokinetics and Pharmacogenomics of Once-Daily Raltegravir and Atazanavir in Healthy Volunteers

2010 ◽  
Vol 54 (11) ◽  
pp. 4619-4625 ◽  
Author(s):  
Michael Neely ◽  
Laurent Decosterd ◽  
Aurélie Fayet ◽  
Janice Soo Fern Lee ◽  
Ashley Margol ◽  
...  
Keyword(s):  
Steady State ◽  
Healthy Volunteers ◽  
Geometric Mean ◽  
Metabolite Formation ◽  
Time Curve ◽  
Once Daily ◽  
Liquid Chromatography Tandem Mass ◽  
Urine Concentrations ◽  
Multiple Samples

ABSTRACT Atazanavir inhibits UDP-glucuronyl-transferase-1A1 (UGT1A1), which metabolizes raltegravir, but the magnitude of steady-state inhibition and role of the UGT1A1 genotype are unknown. Sufficient inhibition could lead to reduced-dose and -cost raltegravir regimens. Nineteen healthy volunteers, age 24 to 51 years, took raltegravir 400 mg twice daily (arm A) and 400 mg plus atazanavir 400 mg once daily (arm B), separated by ≥3 days, in a crossover design. After 1 week on each regimen, raltegravir and raltegravir-glucuronide plasma and urine concentrations were measured by liquid chromatography-tandem mass spectrometry in multiple samples obtained over 12 h (arm A) or 24 h (arm B) and analyzed by noncompartmental methods. UGT1A1 promoter variants were detected with a commercially available kit and published primers. The primary outcome was the ratio of plasma raltegravir C tau, or concentration at the end of the dosing interval, for arm B (24 h) versus arm A (12 h). The arm B-to-arm A geometric mean ratios (95% confidence interval, P value) for plasma raltegravir C tau, area under the concentration-time curve from 0 to 12 h (AUC0-12), and raltegravir-glucuronide/raltegravir AUC0-12 were 0.38 (0.22 to 0.65, 0.001), 1.32 (0.62 to 2.81, 0.45), and 0.47 (0.38 to 0.59, <0.001), respectively. Nine volunteers were heterozygous and one was homozygous for a UGT1A1 reduction-of-function allele, but these were not associated with metabolite formation. Although atazanavir significantly reduced the formation of the glucuronide metabolite, its steady-state boosting of plasma raltegravir did not render the C tau with a once-daily raltegravir dose of 400 mg similar to the C tau with the standard twice-daily dose. UGT1A1 promoter variants did not significantly influence this interaction.

scholarly journals Effect of combination therapy with ciprofloxacin and clarithromycin on theophylline pharmacokinetics in healthy volunteers.

1996 ◽  
Vol 40 (7) ◽  
pp. 1715-1716 ◽  
Author(s):  
J G Gillum ◽  
D S Israel ◽  
R B Scott ◽  
M W Climo ◽  
R E Polk
Keyword(s):  
Combination Therapy ◽  
Crossover Study ◽  
Healthy Volunteers ◽  
Combination Treatment ◽  
Oral Treatment ◽  
Time Curve ◽  
Real Effect ◽  
Concentration Time ◽  
Beta Error ◽  
Randomized Crossover Study

Five adults completed this four-way randomized crossover study to compare the effects of oral treatment with ciprofloxacin, clarithromycin, and a combination of the two drugs on theophylline pharmacokinetics. The area under the concentration-time curve for theophylline during combination therapy was not different from that for ciprofloxacin alone. Beta error may explain this finding, but any real effect from combination treatment appears to be clinically unimportant.

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