scholarly journals Intrapulmonary pharmacokinetics of azithromycin in healthy volunteers given five oral doses.

1996 ◽  
Vol 40 (11) ◽  
pp. 2582-2585 ◽  
Author(s):  
K M Olsen ◽  
G San Pedro ◽  
L P Gann ◽  
P O Gubbins ◽  
D M Halinski ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
High Performance ◽  
Blood Monocytes ◽  
Epithelial Lining Fluid ◽  
Once Daily ◽  
Drug Concentrations ◽  
Proven Efficacy ◽  
Study Support ◽  
Oral Doses ◽  
Oral Azithromycin

The intrapulmonary pharmacokinetics of oral azithromycin were studied in 25 healthy volunteers, each of whom received an initial dose of 500 mg and then 250 mg once daily for four additional doses. Bronchoscopy, bronchoalveolar lavage, and venipuncture were performed 4, 28, 76, 124, 172, 244, 340, and 508 h after the first dose was administered. Azithromycin concentrations in epithelial lining fluid (ELF), alveolar macrophages, peripheral blood monocytes, and serum were measured by high-performance liquid chromatography. Azithromycin was extensively concentrated in cells and ELF. Drug concentrations in AMs (peak mean +/- standard deviation, 464 +/- 65 micrograms/ml) exceeded 80 micrograms/ml up to 508 h (21 days) following the first dose, while concentrations in PBMs (peak, 124 +/- 28 micrograms/ml) exceeded 20 micrograms/ml up to 340 h (14 days). Azithromycin concentrations in ELF peaked at 124 h (3.12 +/- 0.93 micrograms/ml) and were detectable up to 172 h (7 days), when they were 20 times the concurrent serum concentrations. Although the clinical significance of antibiotic concentrations in these compartments is nuclear, the sustained lung tissue penetration and extensive phagocytic accumulation demonstrated in this study support the proven efficacy of azithromycin administered on a 5-day dosage schedule in the treatment of extracellular or intracellular pulmonary infections.

scholarly journals Comparison of Plasma, Epithelial Lining Fluid, and Alveolar Macrophage Concentrations of Solithromycin (CEM-101) in Healthy Adult Subjects

2012 ◽  
Vol 56 (10) ◽  
pp. 5076-5081 ◽  
Author(s):  
Keith A. Rodvold ◽  
Mark H. Gotfried ◽  
J. Gordon Still ◽  
Kay Clark ◽  
Prabhavathi Fernandes
Keyword(s):  
Steady State ◽  
High Performance ◽  
Healthy Adult ◽  
Plasma Concentrations ◽  
Epithelial Lining ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Once Daily ◽  
Drug Concentrations ◽  
The Mean

ABSTRACTThe steady-state concentrations of solithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL) in 30 healthy adult subjects. Subjects received oral solithromycin at 400 mg once daily for five consecutive days. Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, or 24 h after the last administered dose of solithromycin. Drug concentrations in plasma, ELF, and AM were assayed by a high-performance liquid chromatography-tandem mass spectrometry method. Solithromycin was concentrated extensively in ELF (range of mean [± standard deviation] concentrations, 1.02 ± 0.83 to 7.58 ± 6.69 mg/liter) and AM (25.9 ± 20.3 to 101.7 ± 52.6 mg/liter) in comparison with simultaneous plasma concentrations (0.086 ± 0.070 to 0.730 ± 0.692 mg/liter). The values for the area under the concentration-time curve from 0 to 24 h (AUC0–24values) based on mean and median ELF concentrations were 80.3 and 63.2 mg · h/liter, respectively. The ratio of ELF to plasma concentrations based on the mean and median AUC0–24values were 10.3 and 10.0, respectively. The AUC0–24values based on mean and median concentrations in AM were 1,498 and 1,282 mg · h/L, respectively. The ratio of AM to plasma concentrations based on the mean and median AUC0–24values were 193 and 202, respectively. Once-daily oral dosing of solithromycin at 400 mg produced steady-state concentrations that were significantly (P< 0.05) higher in ELF (2.4 to 28.6 times) and AM (44 to 515 times) than simultaneous plasma concentrations throughout the 24-h period after 5 days of solithromycin administration.

scholarly journals Single-dose intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime in volunteer subjects.

1996 ◽  
Vol 40 (7) ◽  
pp. 1617-1622 ◽  
Author(s):  
J E Conte ◽  
J Golden ◽  
S Duncan ◽  
E McKenna ◽  
E Lin ◽  
...  
Keyword(s):  
Single Dose ◽  
Bronchoalveolar Lavage ◽  
Peak Concentration ◽  
Area Under The Curve ◽  
Lavage Fluid ◽  
Diffusion Method ◽  
Alveolar Cells ◽  
Epithelial Lining Fluid ◽  
Drug Concentrations ◽  
Oral Doses

The intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime were studied in 68 volunteers who received single, oral doses of azithromycin (0.5 g), clarithormycin (0.5 g), ciprofloxacin (0.5 g), or cefuroxime (0.5 g). In subgroups of four subjects each, the subjects underwent bronchoscopy and bronchoalveolar lavage at timed intervals following drug administration. Drug concentrations, including those of 14-hydroxyclarithromycin (14H), were determined in serum, bronchoalveolar lavage fluid, and alveolar cells (ACs) by high-pressure liquid chromatography. Concentrations in epithelial lining fluid (ELF) were calculated by the urea diffusion method. The maximum observed concentrations (mean +/- standard deviation) of azithromycin, clarithromycin, 14H, ciprofloxacin, and cefuroxime in serum were 0.13 +/- 0.07, 1.0 +/- 0.6, 0.60 +/- 0.41, 0.95 +/- 0.32, and 1.1 +/- 0.3 microgram/ml, respectively (all at 6 h). None of the antibiotics except clarithromycin (39.6 +/- 41.1 micrograms/ml) was detectable in ELF at the 6-h bronchoscopy. The movement into and persistence in cells was different for azithromycin and clarithromycin. In ACs azithromycin was not detectable at 6 h, reached its highest concentration at 120 h, and exhibited the greatest area under the curve (7,403 micrograms.hr ml-1). The peak concentration of clarithromycin (181 +/- 94.1 micrograms/ml) was greater and occurred earlier (6 h), but the area under the curve (2,006 micrograms.hr ml-1) was less than that observed for azithromycin. 14H was detectable in ACs at 6 h (40.3 +/- 5.2 micrograms/ml) and 12 h (32.8 +/- 57.2 micrograms/ml). The peak concentration of ciprofloxacin occurred at 6 h (4.3 +/- 5.2 micrograms/ml), and the area under the curve was 35.0 micrograms.hr ml-1. The data indicate that after the administration of a single dose, azithromycin, clarithromycin, and ciprofloxacin penetrated into ACs in therapeutic concentrations and that only clarithromycin was present in ELF. The correlation of these kinetic observations with clinical efficacy or toxicity was not investigated and is unclear, but the data provide a basis for further kinetic and clinical studies.

scholarly journals Pharmacokinetics of Darunavir at 900 Milligrams and Ritonavir at 100 Milligrams Once Daily when Coadministered with Efavirenz at 600 Milligrams Once Daily in Healthy Volunteers

2010 ◽  
Vol 54 (7) ◽  
pp. 2775-2780 ◽  
Author(s):  
Gaik H. Soon ◽  
Ping Shen ◽  
Eu-Leong Yong ◽  
Paul Pham ◽  
Charles Flexner ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Half Life ◽  
Geometric Mean ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Time Curve ◽  
Once Daily ◽  
Drug Concentrations ◽  
Trough Concentrations

ABSTRACT Ritonavir-boosted darunavir with efavirenz may be considered a nucleoside-sparing regimen for treatment-naïve HIV-infected patients. However, the pharmacokinetics of this combination administered once daily have not been studied. We conducted a three-period interaction study with healthy volunteers. The subjects were given darunavir at 900 mg with ritonavir at 100 mg once daily for 10 days. Efavirenz at 600 mg once daily was added for 14 days. Darunavir-ritonavir was then stopped and efavirenz alone was given for 14 days. At the end of each period, blood was taken predosing and for up to 24 h postdosing to measure the drug concentrations. We recruited seven males and five females ages 24 to 49 years and weighing 50 to 83 kg. The darunavir trough concentrations were reduced after efavirenz administration (geometric mean ratio [GMR], 0.43; 90% confidence interval [CI], 0.32 to 0.57]; P < 0.001). The mean darunavir trough concentrations were 1,180 ng/ml (standard deviation, 1,138 ng/ml) after efavirenz administration, but all darunavir trough concentrations were above the 50% effective concentration (EC50) of 55 ng/ml for the wild-type virus. For darunavir, the area under the concentration-time curve from 0 to 24 h (AUC0-24) (GMR, 0.86; 90% CI, 0.75 to 0.97; P = 0.05) and the half-life (GMR, 0.56; 90% CI, 0.49 to 0.65; P < 0.001) were also significantly reduced. The darunavir peak concentrations were not significantly changed (GMR, 0.92; 90% CI, 0.82 to 1.03; P = 0.23). The ritonavir trough concentrations (GMR, 0.46; 90% CI, 0.33 to 0.63; P = 0.001), AUC0-24 (GMR, 0.74; 90% CI, 0.64 to 0.86; P = 0.004), and half-life (GMR, 0.80; 90% CI, 0.75 to 0.86; P < 0.001) were also significantly reduced. The efavirenz half-life was significantly longer when it was coadministered with darunavir-ritonavir than when it was given alone (GMR, 1.66; 90% CI, 1.24 to 2.23; P = 0.01), but there were no differences in the efavirenz trough or peak concentration or AUC0-24 when it was coadministered with darunavir-ritonavir. Efavirenz reduced the trough concentrations of darunavir significantly, but the concentrations remained above the EC50 for the wild-type virus. This regimen should be evaluated with treatment-naïve patients with no preexisting resistance.

scholarly journals Pharmacokinetics of Cefepime during Continuous Renal Replacement Therapy in Critically Ill Patients

2001 ◽  
Vol 45 (11) ◽  
pp. 3148-3155 ◽  
Author(s):  
Rebecca S. Malone ◽  
Douglas N. Fish ◽  
Edward Abraham ◽  
Isaac Teitelbaum
Keyword(s):  
Renal Replacement Therapy ◽  
Continuous Renal Replacement Therapy ◽  
Replacement Therapy ◽  
High Performance ◽  
Hollow Fiber Membrane ◽  
Drug Infusion ◽  
Serum Samples ◽  
Once Daily ◽  
Drug Concentrations ◽  
Elimination Half

ABSTRACT The pharmacokinetics of cefepime were studied in 12 adult patients in intensive care units during continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodiafiltration (CVVHDF) with a Multiflow60 AN69HF 0.60-m2 polyacrylonitrile hollow-fiber membrane (Hospal Industrie, Meyzieu, France). Patients (mean age, 52.0 ± 13.0 years [standard deviation]; mean weight, 96.7 ± 18.4 kg) received 1 or 2 g of cefepime every 12 or 24 h (total daily doses of 1 to 4 g/day) by intravenous infusion over 15 to 30 min. Pre- and postmembrane blood (serum) samples and corresponding ultrafiltrate or dialysate samples were collected 1, 2, 4, 8, and 12 or 24 h (depending on dosing interval) after completion of the drug infusion. Drug concentrations were measured using validated high-performance liquid chromatography methods. Mean systemic clearance (CLS) and elimination half-life (t 1/2) of cefepime were 35.9 ± 6.0 ml/min and 12.9 ± 2.6 h during CVVH versus 46.8 ± 12.4 ml/min and 8.6 ± 1.4 h during CVVHDF, respectively. Cefepime clearance was substantially increased during both CVVH and CVVHDF, with membrane clearance representing 40 and 59% of CLS, respectively. The results of this study confirm that continuous renal replacement therapy contributes substantially to total CLSof cefepime and that CVVHDF appears to remove cefepime more efficiently than CVVH. Cefepime doses of 2 g/day (either 2 g once daily or 1 g twice daily) appear to achieve concentrations adequate to treat most common gram-negative pathogens (MIC ≤ 8 μg/ml) during CVVH or CVVHDF.

Comparison of bronchopulmonary pharmacokinetics of clarithromycin and azithromycin.

1996 ◽  
Vol 40 (10) ◽  
pp. 2375-2379 ◽  
Author(s):  
K B Patel ◽  
D Xuan ◽  
P R Tessier ◽  
J H Russomanno ◽  
R Quintiliani ◽  
...  
Keyword(s):  
High Performance Liquid Chromatography ◽  
High Performance ◽  
Tissue Concentration ◽  
Epithelial Lining ◽  
Assay Sensitivity ◽  
Epithelial Lining Fluid ◽  
Once Daily ◽  
Time Points ◽  
Plasma Pharmacokinetics ◽  
Absolute Concentrations

The bronchopulmonary and plasma pharmacokinetics of clarithromycin (CLA; 500 mg given twice daily for nine doses) or azithromycin (AZ; 500 mg for the first dose and then 250 mg once daily for four doses) were assessed in 41 healthy nonsmokers. Bronchoalveolar lavage was performed at 4, 8, 12, or 24 h after administration of the last dose. The concentrations (mean +/- standard deviation) of CLA, 14-hydroxyclarithromycin, and AZ were measured in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) cells by high-performance liquid chromatography assay. The concentrations of CLA achieved in ELF were 34.02 +/- 5.16 micrograms/ml at 4 h, 20.63 +/- 4.49 micrograms/ml at 8 h, 23.01 +/- 11.9 micrograms/ml at 12 h, and 4.17 +/- 0.29 microgram/ml at 24 h, whereas at the same time points AZ concentrations remained below the limit of assay sensitivity (0.01 microgram/ml) for all but two subjects. The concentrations of CLA in the AM cells were significantly higher than those of AZ at 8 h (703 +/- 235 and 388 +/- 53 micrograms/ml, respectively). However, the ratio of the concentration in AM cells/concentration in plasma was significantly higher for AZ than for CLA for all time points because of the lower concentration of AZ in plasma. These results indicate that while AZ has higher tissue concentration to plasma ratios, as shown by other investigators, the absolute concentrations of CLA in AM cells and ELF are higher for up to 8 and 12 h, respectively, after administration of the last dose.

scholarly journals Pharmacokinetics in Serum and Leukocyte Exposures of Oral Azithromycin, 1,500 Milligrams, Given over a 3- or 5-Day Period in Healthy Subjects

1999 ◽  
Vol 43 (1) ◽  
pp. 163-165 ◽  
Author(s):  
Guy W. Amsden ◽  
Anne N. Nafziger ◽  
George Foulds
Keyword(s):  
Respiratory Tract ◽  
Healthy Volunteers ◽  
Healthy Subjects ◽  
Polymorphonuclear Leukocytes ◽  
Mononuclear Leukocytes ◽  
Drug Concentrations ◽  
Oral Azithromycin ◽  
Relevant Community

ABSTRACT The pharmacokinetics in serum and leukocyte (WBC) exposures of 1,500 mg of oral azithromycin administered as 3-day (500 mg/day, days 1 to 3) and 5-day (500 mg on day 1 and 250 mg/day on days 2 to 5) regimens were compared in 12 healthy volunteers. Serum, polymorphonuclear leukocytes, and mononuclear leukocytes were collected over a 12-day period from the start of each regimen. Results of the study indicate that the exposures of serum and both types of WBCs were similar with both regimens. Drug concentrations in day 12 WBCs were well above the MICs for all relevant community-acquired respiratory tract pathogens. Terminal half-lives in serum obtained by both regimens were essentially equal at 66 h and consistent with past reports. These results indicate that the standard 1,500-mg dose of oral azithromycin can be administered over either 5 or 3 days.

scholarly journals Effects of Gender, AIDS, and Acetylator Status on Intrapulmonary Concentrations of Isoniazid

2002 ◽  
Vol 46 (8) ◽  
pp. 2358-2364 ◽  
Author(s):  
John E. Conte ◽  
Jeffrey A. Golden ◽  
Mari McQuitty ◽  
Juliana Kipps ◽  
Sheila Duncan ◽  
...  
Keyword(s):  
High Performance ◽  
Slow Acetylators ◽  
Dilution Method ◽  
Study Group ◽  
Alveolar Cells ◽  
Entire Study ◽  
Epithelial Lining Fluid ◽  
Once Daily ◽  
Acetylator Status ◽  
Adult Volunteers

ABSTRACT The objective of the present study was to evaluate the effects of gender, AIDS, and acetylator status on the steady-state concentrations of orally administered isoniazid in plasma and lungs. Isoniazid was administered at 300 mg once daily for 5 days to 80 adult volunteers. Subjects were assigned to eight blocks according to gender, presence or absence of AIDS, and acetylator status. Blood was obtained prior to administration of the first dose, 1 h after administration of the last dose, and at the completion of bronchoscopy and bronchoalveolar lavage (BAL), which was performed 4 h after administration of the last dose. The metabolism of caffeine was used to determine acetylator status. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) recovered was calculated by the urea dilution method. Isoniazid concentrations in plasma, BAL fluid, and alveolar cells (ACs) were measured by high-performance liquid chromatography. AIDS status or gender had no significant effect on the concentrations of isoniazid in plasma at 1 or 4 h. Concentrations in plasma at 4 h and concentrations in ELF were greater in slow acetylators than fast acetylators. The concentration in plasma (1.85 ± 1.60 μg/ml [mean ± standard deviation; n = 80]) at 1 h following administration of the last dose was not significantly different from that in ELF (2.25 ± 3.50 μg/ml) or ACs (2.61 ± 5.01 μg/ml). For the entire study group, concentrations in plasma at 1 h were less than 1.0, 2.0, and 3.0 μg/ml for 34.7, 60, and 82.7% of the subjects, respectively; concentrations in ELF were less than 1.0, 2.0, and 3.0 μg/ml in 30 (37.5%), 53 (66.0%), and 58 (72.5%) of the subjects, respectively; and concentrations in ACs were less than 1.0, 2.0, and 3.0 μg/ml in 43 (53.8%), 59 (73.8%), and 65 (81.3%) of the subjects, respectively. The concentrations of orally administered isoniazid in plasma were not affected by gender or the presence of AIDS. The concentrations in plasma at 4 h and the concentrations in ELF, but not the concentrations in ACs, were significantly greater in slow acetylators than fast acetylators. Concentrations in plasma and lungs were low compared to recommended therapeutic concentrations in plasma and published MICs of isoniazid for Mycobacterium tuberculosis. The optimal concentrations of isoniazid in ACs and ELF are unknown, but these data suggest that the drug enters these compartments by passive diffusion and achieves concentrations similar to those found in plasma.

scholarly journals Pulmonary Disposition of Tedizolid following Administration of Once-Daily Oral 200-Milligram Tedizolid Phosphate in Healthy Adult Volunteers

2012 ◽  
Vol 56 (5) ◽  
pp. 2627-2634 ◽  
Author(s):  
Seth T. Housman ◽  
J. Samuel Pope ◽  
John Russomanno ◽  
Edward Salerno ◽  
Eric Shore ◽  
...  
Keyword(s):  
Correction Method ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Once Daily ◽  
Dosing Interval ◽  
Drug Concentrations ◽  
Liquid Chromatography Tandem Mass ◽  
Adult Volunteers

ABSTRACTThis study assessed the pulmonary disposition of tedizolid, an oxazolidinone, in adult volunteers receiving 200 mg of the prodrug tedizolid phosphate orally every 24 h for 3 days to steady state. Plasma samples were collected over the dosing interval, and participants were randomized to undergo bronchoalveolar lavage (BAL) at 2, 6, 12, or 24 h after the last dose. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods followed by compartmental population pharmacokinetics. Penetration was calculated as the area under the concentration-time curve during the dosing interval (AUC0–24) for ELF and AM relative to the free AUC0–24(fAUC0–24) in plasma. The half-life and volume of distribution in plasma were 9.23 ± 2.04 h and 108.25 ± 20.53 liters (means ± standard deviations), respectively. Total AUC0–24in plasma was 25.13 ± 5.78 μg · h/ml. Protein binding was 89.44% ± 1.58%, resulting in a meanfAUC0–24of 2.65 ± 0.72 μg · h/ml in plasma. Mean concentrations (μg/ml) at 2, 6, 12, and 24 h were 9.05 ± 3.83, 4.45 ± 2.18, 5.62 ± 1.99, and 1.33 ± 0.59 in ELF and 3.67 ± 1.02, 4.38 ± 2.18, 1.42 ± 0.63, and 1.04 ± 0.52 in AM. ELF and AM penetration ratios were 41.2 and 20.0. The mean ELF penetration ratio after population analyses was 39.7. This study demonstrates that tedizolid penetrates into ELF and AM to levels approximately 40-fold and 20-fold, respectively, higher than free-drug exposures in plasma.

scholarly journals Pharmacokinetics of Nikkomycin Z after Single Rising Oral Doses

2009 ◽  
Vol 53 (6) ◽  
pp. 2517-2521 ◽  
Author(s):  
David E. Nix ◽  
Robert R. Swezey ◽  
Richard Hector ◽  
John N. Galgiani
Keyword(s):  
High Performance ◽  
Relative Bioavailability ◽  
Time Curve ◽  
Chromatography Method ◽  
Blood Samples ◽  
Drug Concentrations ◽  
Nikkomycin Z ◽  
Group 2 ◽  
Liquid Chromatography Method ◽  
Oral Doses

ABSTRACT Nikkomycin Z is an antifungal drug that inhibits chitin synthase. This agent is under development as an orphan product for treatment of coccidioidomycosis. Safety and pharmacokinetics of nikkomycin Z were evaluated in healthy male subjects following single, rising oral doses ranging from 250 mg to 2,000 mg. A total of 12 subjects were recruited and divided into two groups. Group 1 (n = 6) received two out of three doses of 250 mg, 1,000 mg, or 1,750 mg and a placebo randomly in place of one of the doses. Group 2 (n = 6) received two out of three doses of 500 mg, 1,500 mg, or 2,000 mg and a placebo in place of one of the doses. Subjects were confined to the study unit overnight prior to dosing, and 12 blood samples were collected over 24 h postdosing while subjects were confined. Subjects returned for additional blood samples and safety evaluations at 48 h and 72 h after each dose. There was a 2-week washout period between doses. Plasma drug concentrations were determined using a validated high-performance liquid chromatography method. Nikkomycin Z was absorbed after oral administration, reaching a maximum concentration in serum of 2.21 μg/ml at 2 h postdose and an area under the concentration-time curve from 0 h to infinity of 11.3 μg·h/ml for the 250-mg dose. Pharmacokinetics appeared linear over the range of 250 to 500 mg; however, relative bioavailability was about 62 to 70% for the 1,000-mg dose and 42 to 47% for doses between 1,500 and 2,000 mg. The mean terminal half-life ranged from 2.1 to 2.5 h and was independent of dose. No serious or dose-related adverse events were observed. This study provides a basis for pharmacokinetic simulations and continued studies of nikkomycin Z administered in multiple doses.

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