scholarly journals Safety, toleration, and pharmacokinetics of intravenous azithromycin.

1996 ◽  
Vol 40 (11) ◽  
pp. 2577-2581 ◽  
Author(s):  
D R Luke ◽  
G Foulds ◽  
S F Cohen ◽  
B Levy
Keyword(s):  
Half Life ◽  
Active Drug ◽  
Slow Release ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Concentration Time ◽  
Elimination Half ◽  
The Mean ◽  
Male Subjects

To date, the clinical pharmacology of large intravenous doses of azithromycin has not been described. In the present study, single 2-h intravenous infusions of 1, 2, and 4 g of azithromycin were administered to three parallel groups (in each group, six received active drug and two received placebo) of healthy male subjects. Toleration (assessed by scores of subject-administered visual analog scale tests spanning 0 [good] to 10 [poor]), safety, pharmacokinetics, and serum motilin levels were monitored for up to 240 h after the start of each intravenous infusion. Mean nausea scores of 0.0, 0.0, 1.0, and 0.5 and abdominal cramping scores of 0.0, 0.0, 0.4, and 0.4 for 12-h periods after doses of 0, 1, 2, and 4 g of azithromycin, respectively, suggested that azithromycin was well tolerated. Because of the standardized 1-mg/ml infusates, all subjects in the 4-g dosing group complained of an urgent need to urinate. There were no consistent trends in endogenous motilin levels throughout the study. The maximum concentration of azithromycin in serum (10 micrograms/ml after a 4-g dose) and the area under the concentration-time curve (82 micrograms.h/ml after a 4-g dose) were dose related. The mean pharmacokinetic parameters were an elimination half-life of 69 h, total systemic clearance of 10 ml/min/kg, and a volume of distribution at steady state of 33.3 liters/kg. The pharmacokinetic results suggest that the long half-life of azithromycin is due to extensive uptake and slow release of the drug from tissues rather than an inability to clear the drug. Single intravenous doses of up to 4 g of azithromycin in healthy subjects are generally well tolerated, and quantifiable concentrations may persist in serum for 10 days or more.

scholarly journals Pharmacokinetics of a Fluoronaphthyridone, Trovafloxacin (CP 99,219), in Infants and Children following Administration of a Single Intravenous Dose of Alatrofloxacin

2000 ◽  
Vol 44 (5) ◽  
pp. 1195-1199 ◽  
Author(s):  
John S. Bradley ◽  
Gregory L. Kearns ◽  
Michael D. Reed ◽  
Edmund V. Capparelli ◽  
John Vincent
Keyword(s):  
Volume Of Distribution ◽  
Intravenous Dose ◽  
Pharmacokinetic Parameters ◽  
Single Intravenous Dose ◽  
Average Standard Deviation ◽  
Time Curve ◽  
Concentration Time ◽  
Age Related ◽  
The Mean ◽  
In Infants And Children

ABSTRACT The pharmacokinetics of trovafloxacin following administration of a single intravenous dose of alatrofloxacin, equivalent to 4 mg of trovafloxacin per kg of body weight, were determined in 6 infants (ages 3 to 12 months) and 14 children (ages, 2 to 12 years). There was rapid conversion of alatrofloxacin to trovafloxacin, with an average ± standard deviation (SD) peak trovafloxacin concentration determined at the end of the infusion of 4.3 ± 1.4 μg/ml. The primary pharmacokinetic parameters (average ± SD) analyzed were volume of distribution at steady state (1.6 ± 0.6 liters/kg), clearance (151 ± 82 ml/h/kg), and half-life (9.8 ± 2.9 h). The drug was well tolerated by all children. There were no age-related differences in any of the pharmacokinetic parameters studied. Less than 5% of the administered dose was excreted in the urine over 24 h. On the basis of the mean area under the concentration-time curve of 30.5 ± 10.1 μg · h/ml and the susceptibility (≤0.5 μg/ml) of common pediatric bacterial pathogens to trovafloxacin, dosing of 4 mg/kg/day once or twice daily should be appropriate.

scholarly journals Pharmacokinetics and Distribution over the Blood-Brain Barrier of Zalcitabine (2′,3′-Dideoxycytidine) and BEA005 (2′,3′-Dideoxy-3′-Hydroxymethylcytidine) in Rats, Studied by Microdialysis

1998 ◽  
Vol 42 (9) ◽  
pp. 2174-2177 ◽  
Author(s):  
Natalia Borg ◽  
Lars Ståhle
Keyword(s):  
Protein Binding ◽  
Half Life ◽  
Extracellular Fluid ◽  
Volume Of Distribution ◽  
Time Curve ◽  
Concentration Time ◽  
Water Partition Coefficient ◽  
The Mean ◽  
The Brain

ABSTRACT Microdialysis was applied to sample the unbound drug concentration in the extracellular fluid in brain and muscle of rats given zalcitabine (2′,3′-dideoxycytidine; n = 4) or BEA005 (2′,3′-dideoxy-3′-hydroxymethylcytidine; n = 4) (50 mg/kg of body weight given subcutaneously). Zalcitabine and BEA005 were analyzed by high-pressure liquid chromatography with UV detection. The maximum concentration of zalcitabine in the dialysate (C max) was 31.4 ± 5.1 μM (mean ± standard error of the mean) for the brain and 238.3 ± 48.1 μM for muscle. The time to C max was found to be from 30 to 45 min for the brain and from 15 to 30 min for muscle. Zalcitabine was eliminated from the brain and muscle with half-lives 1.28 ± 0.64 and 0.85 ± 0.13 h, respectively. The ratio of the area under the concentration-time curve (AUC) (from 0 to 180 min) for the brain and the AUC for muscle (AUC ratio) was 0.191 ± 0.037. The concentrations of BEA005 attained in the brain and muscle were lower than those of zalcitabine, withC maxs of 5.7 ± 1.4 μM in the brain and 61.3 ± 12.0 μM in the muscle. The peak concentration in the brain was attained 50 to 70 min after injection, and that in muscle was achieved 30 to 50 min after injection. The half-lives of BEA005 in the brain and muscle were 5.51 ± 1.45 and 0.64 ± 0.06 h, respectively. The AUC ratio (from 0 to 180 min) between brain and muscle was 0.162 ± 0.026. The log octanol/water partition coefficients were found to be −1.19 ± 0.04 and −1.47 ± 0.01 for zalcitabine and BEA005, respectively. The degrees of plasma protein binding of zalcitabine (11% ± 4%) and BEA005 (18% ± 2%) were measured by microdialysis in vitro. The differences between zalcitabine and BEA005 with respect to the AUC ratio (P = 0.481), half-life in muscle (P = 0.279), and level of protein binding (P = 0.174) were not statistically significant. The differences were statistically significant in the case of the half-life in the brain (P = 0.032), clearance (P = 0.046), volume of distribution (P = 0.027) in muscle, and octanol/water partition coefficient (P = 0.019).

scholarly journals Serum bactericidal activities and comparative pharmacokinetics of meropenem and imipenem-cilastatin.

1996 ◽  
Vol 40 (1) ◽  
pp. 105-109 ◽  
Author(s):  
M Dreetz ◽  
J Hamacher ◽  
J Eller ◽  
K Borner ◽  
P Koeppe ◽  
...  
Keyword(s):  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Dose Administration ◽  
Microdilution Method ◽  
Two Compartment Model ◽  
Elimination Half ◽  
Renal Clearances ◽  
The Mean ◽  
Bactericidal Activities

The pharmacokinetics and serum bactericidal activities (SBAs) of imipenem and meropenem were investigated in a randomized crossover study. Twelve healthy male volunteers received a constant 30-min infusion of either 1 g of imipenem plus 1 g of cilastatin or 1 g of meropenem. The concentrations of the drugs in serum and urine were determined by bioassay and high-pressure liquid chromatography. Pharmacokinetic parameters were based on an open two-compartment model and a noncompartmental technique. At the end of infusion, the mean concentrations of imipenem and meropenem measured in serum were 61.2 +/- 9.8 and 51.6 +/- 6.5 mg/liter, respectively; urinary recoveries were 48.6% +/- 8.2% and 60.0% +/- 6.5% of the dose in 12 h, respectively; and the areas under the concentration-time curve from time zero to infinity were 96.1 +/- 14.4 and 70.5 +/- 10.3 mg.h/liter, respectively (P < or = 0.02). Imipenem had a mean half-life of 66.7 +/- 10.4 min; that of meropenem was 64.4 +/- 6.9 min. The volumes of distribution at steady state of imipenem and meropenem were 15.3 +/- 3.3 and 18.6 +/- 3.0 liters/70 kg, respectively, and the mean renal clearances per 1.73 m2 were 85.6 +/- 17.6 and 144.6 +/- 26.0 ml/min, respectively. Both antibiotics were well tolerated in this single-dose administration study. The SBAs were measured by the microdilution method of Reller and Stratton (L. B. Reller and C. W. Stratton, J. Infect. Dis. 136:196-204, 1977) against 40 clinically isolated strains. Mean reciprocal bactericidal titers were measured 1 and 6 h after administration. After 1 and 6 h the median SBAs for imipenem and meropenem, were 409 and 34.9 and 97.9 and 5.8, respectively, against Staphylococcus aureus, 19.9 and 4.4 and 19.4 and 4.8, respectively, against Pseudomonas aeruginosa, 34.3 and 2.2 and 232 and 15.5, respectively, against Enterobacter cloacae, and 13.4 and 2.25 and 90.7 and 7.9, respectively, against Proteus mirabilis. Both drugs had rather short biological elimination half-lives and a predominantly renal route of elimination. Both carbapenems revealed high SBAs against clinically important pathogens at 1 h; meropenem had a higher SBA against E. cloacae and P. mirabilis, and the SBA of imipenem against S. aureus was greater than the SBA of meropenem.

scholarly journals Pharmacokinetics of Intravenous Piperacillin Administration in Patients Undergoing On-Line Hemodiafiltration

2009 ◽  
Vol 53 (8) ◽  
pp. 3266-3268 ◽  
Author(s):  
Kook-Hwan Oh ◽  
Chiweon Kim ◽  
Hankyu Lee ◽  
Hajeong Lee ◽  
Ji Yong Jung ◽  
...  
Keyword(s):  
Standard Deviation ◽  
Total Body Clearance ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Recovery Method ◽  
Elimination Half ◽  
On Line ◽  
The Mean ◽  
Total Body ◽  
Body Clearance

ABSTRACT The pharmacokinetic characteristics of piperacillin sodium were studied in five volunteers undergoing on-line hemodiafiltration (HDF). The subjects were given 2 g of piperacillin sodium intravenously over 1 min and placed on on-line HDF for 4 h starting at 60 min after the piperacillin infusion. Noncompartmental models were employed for estimation of the pharmacokinetic parameters, and intradialytic piperacillin clearance was calculated by the recovery method. The mean volume of distribution and the elimination half-life were 0.27 ± 0.13 liter/kg (mean ± standard deviation) and 1.1 ± 0.6 h, respectively. The total body clearance of piperacillin was 0.19 ± 0.08 liter/h/kg. Piperacillin clearance through on-line HDF was 0.11 ± 0.06 liter/h/kg. The mean serum piperacillin concentration was 4.0 ± 1.9 μg/ml at the end of the 4-h on-line HDF session. The concentration of infused piperacillin recovered in the dialysate was 527 ± 236 mg (26.3% ± 11.8%). We suggest the replacement of 500 mg of piperacillin after each on-line HDF session.

Pharmacokinetics of Once-Daily Ip Gentamicin in Capd Patients

1996 ◽  
Vol 16 (4) ◽  
pp. 379-384 ◽  
Author(s):  
Chai Luan Low ◽  
George R. Bailie ◽  
Anne Evans ◽  
George Eisele ◽  
Richard A. Venezia
Keyword(s):  
Renal Function ◽  
Open Study ◽  
Residual Renal Function ◽  
Volume Of Distribution ◽  
Peritoneal Membrane ◽  
Time Data ◽  
Once Daily ◽  
Concentration Time ◽  
Elimination Half ◽  
The Mean

Objective This study aimed to investigate the pharmacokinetic characteristics of once-daily intraperitoneal (IP) gentamicin in continuous ambulatory peritoneal dialysis (CAPD) patients. Design Prospective, nonrandomized, open study. Setting CAPD outpatient clinic in a teaching hospital. Patients Ten volunteer CAPD patients without peritonitis. Interventions Each patient received a single IP dose of 0.6 mg/kg of gentamicin. Blood and dialysate samples were collected at 0,0.5,1, 2, 3,6 (end of first dwell), and 24 hours after the administration of IP gentamicin. Any urine produced over the 24hour study period was also collected. The dialysate concentration/time data were fitted to a monoexponential curve for all patients. Results The bioavailability was 56±11% over a six hour dwell. The mean serum elimination half-life (t1/2) was 35.8 hours. The volume of distribution was 0.23±0.08 L/kg. Equilibration of gentamicin across the peritoneal membrane was rapid, with a t½ equilibration of 4.5 hours. The peritoneal clearance was 5.74±1.5 mL/min. Patients with residual renal function had significantly higher systemic gentamicin clearances (7.36±1.46 mL/min) than those of anuric patients (4.76±1.08 mL/min, p < 0.024). Conclusion Currently recommended doses of oncedaily IP gentamicin for the treatment of peritonitis may not produce the desired therapeutic serum and dialysate concentrations over 24 hours for effective treatment of peritonitis.

scholarly journals Compartmental Pharmacokinetics and Tissue Drug Distribution of the Pradimicin Derivative BMS 181184 in Rabbits

1998 ◽  
Vol 42 (10) ◽  
pp. 2700-2705 ◽  
Author(s):  
Andreas H. Groll ◽  
Tin Sein ◽  
Vidas Petraitis ◽  
Ruta Petraitiene ◽  
Diana Callender ◽  
...  
Keyword(s):  
Single Dose ◽  
Half Life ◽  
Peak Plasma ◽  
Volume Of Distribution ◽  
Multiple Dosing ◽  
Time Curve ◽  
Dose Administration ◽  
Single Dose Administration ◽  
Elimination Half ◽  
Dose Dependent

ABSTRACT The pharmacokinetics of the antifungal pradimicin derivative BMS 181184 in plasma of normal, catheterized rabbits were characterized after single and multiple daily intravenous administrations of dosages of 10, 25, 50, or 150 mg/kg of body weight, and drug levels in tissues were assessed after multiple dosing. Concentrations of BMS 181184 were determined by a validated high-performance liquid chromatography method, and plasma data were modeled into a two-compartment open model. Across the investigated dosage range, BMS 181184 demonstrated nonlinear, dose-dependent kinetics with enhanced clearance, reciprocal shortening of elimination half-life, and an apparently expanding volume of distribution with increasing dosage. After single-dose administration, the mean peak plasma BMS 181184 concentration (C max) ranged from 120 μg/ml at 10 mg/kg to 648 μg/ml at 150 mg/kg; the area under the concentration-time curve from 0 to 24 h (AUC0–24) ranged from 726 to 2,130 μg · h/ml, the volume of distribution ranged from 0.397 to 0.799 liter/kg, and the terminal half-life ranged from 4.99 to 2.31 h, respectively (P < 0.005 toP < 0.001). No drug accumulation in plasma occurred after multiple daily dosing at 10, 25, or 50 mg/kg over 15 days, although mean elimination half-lives were slightly longer. Multiple daily dosing at 150 mg/kg was associated with enhanced total clearance and a significant decrease in AUC0–24 below the values obtained at 50 mg/kg (P < 0.01) and after single-dose administration of the same dosage (P < 0.05). Assessment of tissue BMS 181184 concentrations after multiple dosing over 16 days revealed substantial uptake in the lungs, liver, and spleen and, most notably, dose-dependent accumulation of the drug within the kidneys. These findings are indicative of dose- and time-dependent elimination of BMS 181184 from plasma and renal accumulation of the compound after multiple dosing.

scholarly journals Pharmacokinetics of Nelfinavir and Efavirenz in Antiretroviral-Naïve, Human Immunodeficiency Virus-Infected Subjects when Administered Alone or in Combination with Nucleoside Analog Reverse Transcriptase Inhibitors

2005 ◽  
Vol 49 (8) ◽  
pp. 3558-3561 ◽  
Author(s):  
Patrick F. Smith ◽  
Gregory K. Robbins ◽  
Robert W. Shafer ◽  
Hulin Wu ◽  
Song Yu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Half Life ◽  
Pharmacokinetic Studies ◽  
Reverse Transcriptase Inhibitors ◽  
Time Curve ◽  
Minimum Concentration ◽  
Concentration Time ◽  
Immunodeficiency Virus ◽  
The Mean

ABSTRACT Pharmacokinetic studies were conducted with human immunodeficiency virus-infected patients receiving efavirenz, nelfinavir, or both agents at weeks 4 and 32. Reductions of 25% and 45% were observed in the mean nelfinavir area under the concentration-time curve and minimum concentration of the drug in serum, and there was a 31% more rapid half-life for patients receiving both drugs compared to patients receiving nelfinavir alone. There were no significant differences in efavirenz pharmacokinetics.

scholarly journals Multiple-Dose Pharmacokinetics and Safety of the New Antifungal Triazole BAL4815 after Intravenous Infusion and Oral Administration of Its Prodrug, BAL8557, in Healthy Volunteers

2006 ◽  
Vol 50 (1) ◽  
pp. 286-293 ◽  
Author(s):  
Anne Schmitt-Hoffmann ◽  
Brigitte Roos ◽  
Jürgen Maares ◽  
Markus Heep ◽  
Jochen Spickerman ◽  
...  
Keyword(s):  
Active Drug ◽  
Volume Of Distribution ◽  
Water Soluble ◽  
Time Curve ◽  
Once Daily ◽  
Routes Of Administration ◽  
Elimination Half ◽  
Constant Rate ◽  
Phase 2 Study ◽  
Multiple Dose Pharmacokinetics

ABSTRACT BAL8557 is the water-soluble prodrug of BAL4815, a new broad-spectrum antifungal. Healthy male subjects were randomly assigned to four treatment cohorts to receive multiple oral doses or multiple 1-h constant-rate intravenous infusions of BAL8557. Loading doses of BAL8557 were equivalent to 100 mg (followed by once-daily maintenance doses of 50 mg) or 200 mg (followed by once-daily maintenance doses of 100 mg) of BAL4815. In each cohort, six subjects received active drug and two subjects received the placebo. Study duration was 21 days (oral) and 14 days (intravenous). All adverse events reported were mild or moderate, except one severe rhinitis event which was not related to trial medication. After both routes of administration, maximum drug concentration observed in plasma (C max) and area under the concentration-time curve (AUC) values of BAL4815 increased proportionally to the administered dose. AUC values reflected a fourfold to fivefold accumulation of active drug in plasma during once-daily dosing, which is in line with the long elimination half-life of BAL4815 determined after the last administration (mean, 84.5 to 117 h). At steady state, the volume of distribution was large and amounted to 308 to 542 liters. Systemic clearance reached only 2.4 to 4.1 liter/h. At the levels obtained in the present study, C max values of 2.56 and 2.55 μg/ml after oral and intravenous administrations, respectively, there was no indication of CYP3A4 induction or inhibition (as revealed by the urinary 6-β-hydroxycortisol/cortisol test). Based on AUC values after oral and intravenous administration, an excellent oral bioavailability can be predicted for BAL4815. Once-daily oral dosing of 50- or 100-mg equivalents of BAL8557 were recently demonstrated to be efficacious in a phase 2 study conducted with patients with esophageal candidiasis. These doses (preceded by adequate loading dose[s]) will be further explored in the treatment of systemic mycoses.

Diet-induced modulation of pharmacokinetics of albendazole in Sahiwal cattle

2015 ◽  
Vol 90 (5) ◽  
pp. 555-560 ◽  
Author(s):  
P.K. Sanyal ◽  
D. Rawte ◽  
A.E. Kerketta ◽  
N.K. Kumbhakar ◽  
D. Kumar ◽  
...  
Keyword(s):  
Half Life ◽  
Maximum Concentration ◽  
Active Metabolite ◽  
Time Curve ◽  
Active Moiety ◽  
Concentration Time ◽  
Elimination Half ◽  
Green Fodder ◽  
Pre Treatment ◽  
Diet Type

AbstractThe influence of diet type and pre-treatment fasting on the kinetic disposition of albendazole was evaluated in Sahiwal heifers following oral and intra-ruminal administration of the drug. The anthelmintically active moiety albendazole sulphoxide appeared early and was eliminated early in cattle offered green fodder, with decreased maximum concentration (Cmax) and area under concentration–time curve (AUC) when the drug was administered both through oral and intra-ruminal routes. Further, the elimination half-life (t½β) revealed significantly increased values for albendazole sulphoxide in cattle administered albendazole through the intra-ruminal route. An increased AUC and t½β is reflective of increased bioavailability of albendazole in animals offered dry fodder. Increased values (P <  0.05) of Cmax, time to Cmax (Tmax), AUC and t½β for albendazole sulphoxide occurred in cattle with a pre-treatment 24-h fast, resulting in its increased bioavailability. Extrapolation of data of the active metabolite albendazole sulphoxide levels in terms of drug–parasite contact revealed increased exposure of parasites to the drug in cattle administered albendazole through the intra-ruminal route and with 24-h pre-treatment fasting.

scholarly journals Induction of theophylline clearance by rifampin and rifabutin in healthy male volunteers.

1996 ◽  
Vol 40 (8) ◽  
pp. 1866-1869 ◽  
Author(s):  
J G Gillum ◽  
J M Sesler ◽  
V L Bruzzese ◽  
D S Israel ◽  
R E Polk
Keyword(s):  
Treatment Phase ◽  
Pharmacokinetic Parameters ◽  
Theophylline Clearance ◽  
Healthy Male ◽  
Time Curve ◽  
Concentration Time ◽  
Male Volunteers ◽  
Hepatic Microsomal Enzyme ◽  
The Mean ◽  
To Receive

Rifampin and rifabutin induce the metabolism of many drugs, which may result in subtherapeutic concentrations and failure of therapy. However, differences between rifabutin and rifampin in potency of induction, and the specific enzymes which are altered, are not clear. This study, involving 12 adult male volunteers, compared the effects of 14-day courses of rifampin and rifabutin on clearance of theophylline, a substrate for the hepatic microsomal enzyme CYP1A2. Subjects were given oral theophylline solution (5 mg/kg of body weight) on day 1 and then randomized to receive daily rifampin (300 mg) or rifabutin (300 mg) on days 3 to 16. Theophylline was readministered as described above on day 15. The first treatment sequence was followed by a 2-week washout period; subjects then received the alternative treatment. Theophylline concentrations were determined for 46 h after each dose, and pharmacokinetic parameters were determined. One subject developed flu-like symptoms while taking rifabutin and withdrew voluntarily. Results from the remaining 11 subjects are reported. Compared with the baseline, the mean area under the concentration-time curve (AUC) (+/- standard deviation) for theophylline declined significantly following rifampin treatment (from 140 +/- 37 to 100 +/- 24 micrograms . h/ml, P <0.001); there was no significant change following rifabutin treatment (136 +/- 48 to 128 +/- 45 micrograms.h/ml). Baseline theophylline AUCs before each treatment phase were not different. A comparison of equal doses of rifampin and rifabutin administered to healthy volunteers for 2 weeks indicates that induction of CYP1A2, as measured by theophylline clearance, is significantly less following rifabutin treatment than it is following rifampin treatment. However, the relative induction potency for other metabolic enzymes remains to be investigated.

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