Pharmacokinetics of Florfenicol in Healthy Pigs and in Pigs Experimentally Infected with Actinobacillus pleuropneumoniae

ABSTRACT A comparative in vivo pharmacokinetic study of florfenicol was conducted in 18 crossbred pigs infected with Actinobacillus pleuropneumoniae following intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration of a single dose of 20 mg/kg. The disease model was confirmed by clinical signs, X rays, pathohistologic examinations, and organism isolation. Florfenicol concentrations in plasma were determined by a validated high-performance liquid chromatography method with UV detection at a wavelength of 223 nm. Pharmacokinetic parameters were calculated by using the MCPKP software (Research Institute of Traditional Chinese Veterinary Medicine, Lanzhou, China). The disposition of florfenicol after a single i.v. bolus was described by a two-compartment model with values for the half-life at α phase (t 1/2α), the half-life at β phase (t 1/2β), the area under the concentration-time curve (AUC0-∞), and the volume of distribution at steady state (V ss) of 0.37 h, 2.91 h, 64.86 μg · h/ml, and 1.2 liter/kg, respectively. The concentration-time data fitted the one-compartment (after i.m.) and two-compartment (after p.o.) models with first-order absorption. The values for the maximum concentration of drug in serum (C max), t 1/2α, t 1/2β, and bioavailability after i.m. and p.o. dosing were 4.00 and 8.11 μg/ml, 0.12 and 3.91 h, 13.88 and 16.53 h, and 122.7 and 112.9%, respectively, for the two models. The study showed that florfenicol was absorbed quickly and completely, distributed widely, and eliminated slowly in the infected pigs, and there was no statistically significant difference between the pharmacokinetic profiles for the infected and healthy pigs.

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Pharmacokinetics of intramuscularly administered aminosidine in healthy subjects.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.5.982 ◽

1997 ◽

Vol 41 (5) ◽

pp. 982-986 ◽

Cited By ~ 12

Author(s):

T P Kanyok ◽

A D Killian ◽

K A Rodvold ◽

L H Danziger

Keyword(s):

Healthy Subjects ◽

Randomized Clinical Trials ◽

Elimination Rate ◽

Pharmacokinetic Parameters ◽

Multiple Drug ◽

Time Data ◽

Time Curve ◽

First Order ◽

Significant Difference

Aminosidine is an older, broad-spectrum aminoglycoside antibiotic that has been shown to be effective in in vitro and animal models against multiple-drug-resistant tuberculosis and the Mycobacterium avium complex. The objective of this randomized, parallel trial was to characterize the single-dose pharmacokinetics of aminosidine sulfate in healthy subjects (eight males, eight females). Sixteen adults (mean [+/- standard deviation] age, 27.6 +/- 5.6 years) were randomly allocated to receive a single, intramuscular aminosidine sulfate injection at a dose of 12 or 15 mg/kg of body weight. Serial plasma and urine samples were collected over a 24-h period and used to determine aminosidine concentrations by high-performance liquid chromatographic assay. A one-compartment model with first-order input, first-order output, and a lag time (Tlag) and with a weighting factor of 1/y2 best described the data. Compartmental and noncompartmental pharmacokinetic parameters were estimated with the microcomputer program WinNonlin. One subject was not included (15-mg/kg group) because of the lack of sampling time data. On average, subjects attained peak concentrations of 22.4 +/- 3.2 microg/ml at 1.34 +/- 0.45 h. All subjects had plasma aminosidine concentrations below 2 microg/ml at 12 h, and all but two subjects (one in each dosing group) had undetectable plasma aminosidine concentrations at 24 h. The dose-adjusted area under the concentration-time curve from 0 h to infinity of aminosidine was identical for the 12- and 15-mg/kg groups (9.29 +/- 1.5 versus 9.29 +/- 2.2 microg x h/ml per mg/kg; P = 0.998). Similarly, no significant differences (P > 0.05) were observed between dosing groups for peak aminosidine concentration in plasma, time to peak aminosidine concentration in plasma, Tlag, apparent clearance, renal clearance, elimination rate constant, and elimination half-life. A significant difference was observed for the volume of distribution (0.35 versus 0.41 liters/kg; P = 0.037) between the 12 and 15 mg/kg dosing groups. Now that comparable pharmacokinetic profiles between dosing groups have been demonstrated, therapeutic equivalency testing via in vitro pharmacokinetic and pharmacodynamic modelling and randomized clinical trials in humans should be conducted.

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Safety, toleration, and pharmacokinetics of intravenous azithromycin.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.11.2577 ◽

1996 ◽

Vol 40 (11) ◽

pp. 2577-2581 ◽

Cited By ~ 48

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.

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Effects of Silymarin on the In Vivo Pharmacokinetics of Simvastatin and Its Active Metabolite in Rats

Molecules ◽

10.3390/molecules24091666 ◽

2019 ◽

Vol 24 (9) ◽

pp. 1666

Author(s):

Ying Li ◽

Yin Wu ◽

Ya-Jing Li ◽

Lu Meng ◽

Cong-Yang Ding ◽

...

Keyword(s):

Active Metabolite ◽

Compartmental Model ◽

Elimination Rate ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Simultaneous Quantification ◽

Concentration Time ◽

Significant Difference ◽

In Vivo Pharmacokinetics

Herein, the effect of silymarin pretreatment on the pharmacokinetics of simvastatin in rats was evaluated. To ensure the accuracy of the results, a rapid and sensitive UPLC–MS/MS method was established for simultaneous quantification of simvastatin (SV) and its active metabolite simvastatin acid (SVA). This method was applied for studying the pharmacokinetic interactions in rats after oral co-administration of silymarin (45 mg/kg) and different concentrations of SV. The major pharmacokinetic parameters, including Cmax, tmax, t1/2, mean residence time (MRT), elimination rate constant (λz) and area under the concentration-time curve (AUC0–12h), were calculated using the non-compartmental model. The results showed that the co-administration of silymarin and SV significantly increased the Cmax and AUC0–12h of SVA compared with SV alone, while there was no significant difference with regards to Tmax and t1/2. However, SV pharmacokinetic parameters were not significantly affected by silymarin pretreatment. Therefore, these changes indicated that drug-drug interactions may occur after co-administration of silymarin and SV.

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Influence of Hypovolemia on the Pharmacokinetics and Electroencephalographic Effect of γ-Hydroxybutyrate in the Rat

Anesthesiology ◽

10.1097/00000542-200211000-00027 ◽

2002 ◽

Vol 97 (5) ◽

pp. 1218-1226 ◽

Cited By ~ 5

Author(s):

Diederik K. Van Sassenbroeck ◽

Peter De Paepe ◽

Frans M. Belpaire ◽

Paul A. Boon ◽

Walter A. Buylaert

Keyword(s):

Blood Pressure ◽

High Performance ◽

Compartment Model ◽

Volume Of Distribution ◽

Control Procedure ◽

Time Data ◽

Time Curve ◽

Concentration Time ◽

Gamma Hydroxybutyrate ◽

Significant Difference

Background Hypovolemia alters the effect of propofol in the rat by influencing the pharmacokinetics and the end organ sensitivity. We now studied the effect of hypovolemia on the anesthetic gamma-hydroxybutyrate (GHB) because in contrast with propofol it increases blood pressure. Methods Thirty-two rats were randomly assigned to undergo moderate hypovolemia or a control procedure. Each rat received either an infusion of sodium-GHB (390 mg x kg(-1) x 5 min(-1)) or the same volume of an equimolar solution of sodium chloride (6.9%). Plasma samples were taken for GHB assay (high-performance liquid chromatography) and the electroencephalography and blood pressure values were recorded. A two-compartment model with Michaelis-Menten elimination was fitted to the concentration-time data and a sigmoid E(max) model to the electroencephalographic effect effect site concentration curve allowing the study of the end organ sensitivity. Results Plasma concentration-time curves and the total volume of distribution in hypovolemic and normovolemic rats were comparable with only small but significant differences in central volume of distribution and the intercompartmental clearance. There was no significant difference either in the distribution from the plasma to the brain (k(e0)) or in the end organ sensitivity (EC50 = 335 +/- 76 microg/ml in control vs. 341 +/- 89 microg/ml in hypovolemic rats). GHB temporarily increased mean arterial pressure in both groups, which cannot be explained by the sodium salt alone. Conclusions Hypovolemia does not influence the overall concentration-time curve of GHB and induces no changes in the electroencephalographic effect of GHB in the rat. This difference with propofol may be due to the fact that it increases blood pressure but also due to its different pharmacokinetic properties.

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Pharmacokinetics of Azithromycin Administered Alone and with Atovaquone in Human Immunodeficiency Virus-Infected Children

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.6.1516 ◽

1999 ◽

Vol 43 (6) ◽

pp. 1516-1519 ◽

Cited By ~ 5

Author(s):

Leock Y. Ngo ◽

Ram Yogev ◽

Wayne M. Dankner ◽

Walter T. Hughes ◽

Sandra Burchett ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Steady State ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Concentration Time ◽

Significant Difference ◽

Immunodeficiency Virus ◽

The Mean ◽

Clinically Significant ◽

To Receive

ABSTRACT To evaluate if atovaquone (ATQ) interacts pharmacokinetically with azithromycin (AZ) in human immunodeficiency virus-infected children, 10 subjects (ages, 4 to 13 years) were randomized in a crossover study to receive AZ (5 mg/kg/day) alone (ALONE) or AZ (5 mg/kg/day) and ATQ (30 mg/kg/day) simultaneously (SIM) prior to receiving AZ and ATQ staggered by 12 h. Despite a lack of significant difference in the mean AZ pharmacokinetic parameters, the steady-state values of AZ’s area under the concentration-time curve from 0 to 24 h and maximum concentration in serum were consistently lower (n = 7 of 7) for the SIM regimen than they were for the ALONE regimen. A larger study will be required to determine if ATQ affects AZ pharmacokinetics and efficacy in a clinically significant manner.

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Determination of Appropriate Weight-Based Cutoffs for Empiric Cefazolin Dosing Using Data from a Phase 1 Pharmacokinetics and Safety Study of Cefazolin Administered for Surgical Prophylaxis in Pediatric Patients Aged 10 to 12 Years

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00082-15 ◽

2015 ◽

Vol 59 (7) ◽

pp. 4173-4180 ◽

Cited By ~ 5

Author(s):

Michael L. Schmitz ◽

Jeffrey L. Blumer ◽

Wes Cetnarowski ◽

Christopher M. Rubino

Keyword(s):

Pediatric Patients ◽

Phase 1 ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Data ◽

Time Data ◽

Surgical Prophylaxis ◽

Open Label ◽

Time Curve ◽

Concentration Time ◽

Few Data

ABSTRACTDespite over 40 years of worldwide usage, relatively few data have been published on the pharmacokinetics of cefazolin in pediatric surgical patients. The primary objectives of this study were to examine the pharmacokinetics and safety of cefazolin in children 10 to 12 years of age (inclusive) receiving 1 or 2 g of cefazolin, based on body weight. This multiple-center, open-label study enrolled pediatric patients electively scheduled for surgical procedures who required cefazolin as part of their routine clinical management. Patients weighing ≥25 to <50 kg received a 1-g dose, and patients weighing ≥50 to ≤85 kg received a 2-g dose. Postdose pharmacokinetic and safety assessments were conducted following drug administration. Cefazolin concentration-time data were analyzed by using both noncompartmental and population pharmacokinetics methods. Monte Carlo simulations were performed to identify appropriate weight-based cutoffs for the dosing of children aged 10 to 17 years of age. Twelve patients were enrolled in this study and provided the requisite pharmacokinetic data. In general, cefazolin was well tolerated. The mean cefazolin terminal elimination half-life, clearance, and area under the concentration-time curve from time zero to infinity in this population were 1.95 h, 0.804 ml/min/kg, and 607 mg · h/liter, respectively. Patients weighing 50 to 60 kg exhibited elevated cefazolin exposures. Observed pharmacokinetic parameters and simulation results indicated that a weight-based cutoff of 60 kg is predicted to provide cefazolin exposure consistent with that observed in normal, healthy adults at recommended doses for surgical prophylaxis. (This study has been registered at ClinicalTrials.gov under registration no. NCT01904357.)

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Pharmacokinetics of an oral VEGF receptor tyrosine kinase inhibitor (PTK787/ZK222584) in patients with myelodysplastic syndrome (MDS): Cancer and Leukemia Group B Study 10105

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.6573 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 6573-6573 ◽

Cited By ~ 2

Author(s):

P. Gupta ◽

A. A. Miller ◽

K. Owzar ◽

D. J. Murry ◽

B. L. Sanford ◽

...

Keyword(s):

Growth Factor ◽

Tyrosine Kinases ◽

Drug Exposure ◽

Kinase Inhibitor ◽

Rank Test ◽

Pharmacokinetic Parameters ◽

Vegf Receptor ◽

Time Data ◽

Time Curve ◽

Concentration Time

6573 Background: Angiogenesis may contribute to the pathophysiology of myelodysplastic syndromes (MDS). PTK787/ZK222584 (PTK/ZK; Novartis and Schering AG) inhibits vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and c-kit receptor tyrosine kinases. Methods: We evaluated early toxicity and pharmacokinetics in a Phase II trial of PTK/ZK in patients with MDS. Patients received PTK/ZK 1,250 mg orally once daily on 28-day courses until disease progression or unacceptable toxicity. A two compartment model with first order absorption and an inducible clearance was fit to serial concentration time data using a MAP Bayesian algorithm as implemented in ADAPT II software. Results: We report preliminary toxicity and pharmacokinetics on 56 of 80 pts enrolled between March 2004 and January 2005. The most common CTC grade ≥2 non-hematological toxicities observed were fatigue, nausea, vomiting, dizziness and ataxia. The initial area under the concentration-time curve (AUCinit) ranged from 25.5–423.1 mg*h/L (mean, 105 mg*h/L). The induced AUC (AUCind) ranged from 8.2–265.3 mg*h/L (mean, 56.2 mg*h/L). There was a significant decrease in drug exposure (Hodges-Lehmann Estimate 45.2 mg*h/L [95% CI=30.5,60.0]; Wilcoxon signed rank test p <0.0001), likely due to CYP3A4 auto-induction. However, there was no statistical correlation between AUCinit and AUCind for individual patients. Because of marked inter-individual heterogeneity observed in AUCinit and AUCind, we examined if drug exposure correlated with toxicity during the first 2 courses. On exploratory analyses, there was no relationship between pharmacokinetic parameters (AUCinit, AUCind or a function of both AUCs) and the occurrence or grade of non-hematological toxicities. Conclusions: Drug exposure declined significantly within 7–14 days after starting treatment with PTK/ZK. In this sample, there was no statistical evidence suggesting that variability in drug exposure was associated with non-hematological toxicities of PTK/ZK in patients with MDS. No significant financial relationships to disclose.

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PHARMACOKINETIC COMPARISON OF MONTELUKAST SODIUM FORMULATIONS AFTER A SINGLE ORAL DOSE IN HEALTHY GUINEA PIGS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2019.v12i2.29279 ◽

2019 ◽

pp. 165-169

Author(s):

NEELAM SINGH ◽

Giriraj T Kulkarni ◽

Yatendra Kumar ◽

GIRIRAJ T KULKARNI

Keyword(s):

Plasma Concentration ◽

Oral Dose ◽

Single Oral Dose ◽

Guinea Pigs ◽

Elimination Rate ◽

Pharmacokinetic Parameters ◽

Time Data ◽

Concentration Time ◽

Montelukast Sodium ◽

Significant Difference

Objective: Pharmacokinetic evaluation of montelukast sodium chronomodulated capsules (sustained-release solid dispersion of drug enclosed in pH-sensitive film-coated hard gelatin shell) and marketed tablets has been carried out in this study. Methods: A single oral dose of prepared capsules and marketed conventional tablets was administered in healthy male Dunkin-Hartley albino guinea pigs. Blood samples were collected at different time intervals and plasma concentration of drug was determined by reversed-phase high-performance liquid chromatography. Different pharmacokinetic parameters were assessed from plasma drug concentration-time profile by one-compartment model, first-order kinetics. Results: Pharmacokinetic parameters such as time to reach maximum concentration, elimination rate constant, elimination half-life, and mean residence time data indicates that drug release from chronomodulated capsules is significantly prolonged with initial release lag time of 3.5–4 h in comparison with marketed conventional tablets. However, maximum drug plasma concentration, area under the concentration-time curve, and apparent volume of distribution values show non-significant difference between capsules and marketed tablets. Conclusion: The findings specified that capsules were providing time controlled delivery of drug at a desired rate for prolonged time, which may be helpful for the prevention of episodic attack of asthma in early morning hours.

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Population Pharmacokinetics of Levofloxacin, Gatifloxacin, and Moxifloxacin in Adults with Pulmonary Tuberculosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01036-07 ◽

2007 ◽

Vol 52 (3) ◽

pp. 852-857 ◽

Cited By ~ 120

Author(s):

Charles A. Peloquin ◽

David Jamil Hadad ◽

Lucilia Pereira Dutra Molino ◽

Moises Palaci ◽

W. Henry Boom ◽

...

Keyword(s):

Plasma Concentrations ◽

University Hospital ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Maximum Plasma ◽

Population Parameter ◽

Time Data ◽

Time Curve ◽

Concentration Time

ABSTRACT The objective of this study was to determine the population pharmacokinetic parameters of levofloxacin, gatifloxacin, and moxifloxacin following multiple oral doses. Twenty-nine patients with tuberculosis at the University Hospital in Vitória, Brazil, participated. Subjects received multiple doses of one drug (levofloxacin, 1,000 mg daily, or gatifloxacin or moxifloxacin, 400 mg daily) as part of a 7-day study of early bactericidal activity. Serum samples were collected over 24 h after the fifth dose and assayed using validated high-performance liquid chromatography assays. Concentration-time data were analyzed using noncompartmental, compartmental, and population methods. The three drugs were well tolerated. Levofloxacin produced the highest maximum plasma concentrations (median, 15.55 μg/ml; gatifloxacin, 4.75 μg/ml; moxifloxacin, 6.13 μg/ml), largest volume of distribution (median, 81 liters; gatifloxacin, 79 liters; moxifloxacin, 63 liters), and longest elimination half-life (median, 7.4 h; gatifloxacin, 5.0 h; moxifloxacin, 6.5 h). A one-compartment model, with or without weight as a covariate, adequately described the data. Postmodeling simulations using median population parameter estimates closely approximated the median values from the original data. Area under the concentration-time curve/MIC ratios for free drug were high. All three quinolones showed favorable pharmacokinetic and pharmacodynamic indices, with the most favorable results in this population being seen with levofloxacin at the comparative doses used.

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Voriconazole Pharmacokinetics and Safety in Immunocompromised Children Compared to Adult Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01731-09 ◽

2010 ◽

Vol 54 (8) ◽

pp. 3225-3232 ◽

Cited By ~ 50

Author(s):

Claudia Michael ◽

Uta Bierbach ◽

Katrin Frenzel ◽

Thoralf Lange ◽

Nadezda Basara ◽

...

Keyword(s):

Pediatric Patients ◽

Fungal Infections ◽

Adult Patients ◽

European Medicines Agency ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Entire Study ◽

Interindividual Variations ◽

Concentration Time ◽

Days Of Therapy

ABSTRACT The aim of this study was to investigate the pharmacokinetics and safety of voriconazole after intravenous (i.v.) administration in immunocompromised children (2 to 11 years old) and adults (20 to 60 years old) who required treatment for the prevention or therapy of systemic fungal infections. Nine pediatric patients were treated with a dose of 7 mg/kg i.v. every 12 h for a period of 10 days. Three children and 12 adults received two loading doses of 6 mg/kg i.v. every 12 h, followed by a maintenance dose of 5 mg/kg (children) or 4 mg/kg (adults) twice a day during the entire study period. Trough voriconazole levels in blood over 10 days of therapy and regular voriconazole levels in blood for up to 12 h postdose on day 3 were examined. Wide intra- and interindividual variations in plasma voriconazole levels were noted in each dose group and were most pronounced in the children receiving the 7-mg/kg dose. Five (56%) of them frequently had trough voriconazole levels in plasma below 1 μg/ml or above 6 μg/ml. The recommended dose of 7 mg/kg i.v. in children provides exposure (area under the concentration-time curve) comparable to that observed in adults receiving 4 mg/kg i.v. The children had significantly higher C max values; other pharmacokinetic parameters were not significantly different from those of adults. Voriconazole exhibits nonlinear pharmacokinetics in the majority of children. Voriconazole therapy was safe and well tolerated in pediatric and adult patients. The European Medicines Agency-approved i.v. dose of 7 mg/kg can be recommended for children aged 2 to <12 years.

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