scholarly journals Modeling Approach To Characterize Intraocular Doripenem Pharmacokinetics after Intravenous Administration to Rabbits, with Tentative Extrapolation to Humans

2012 ◽  
Vol 56 (7) ◽  
pp. 3531-3534 ◽  
Author(s):  
Oudy Semoun ◽  
Sandrine Marchand ◽  
Nicolas Grégoire ◽  
Isabelle Lamarche ◽  
Christophe Adier ◽  
...  
Keyword(s):  
Aqueous Humor ◽  
High Performance ◽  
Vitreous Humor ◽  
Time Curve ◽  
Time Profiles ◽  
Modeling Approach ◽  
New Zealand White Rabbits ◽  
Dosing Regimens ◽  
Sampling Times ◽  
Peripheral Elimination

ABSTRACTThe aim of this study was to determine the penetration of doripenem administered intravenously into the rabbit aqueous and vitreous humors. Nineteen New Zealand White rabbits received a 20-mg dose of doripenem intravenously over 60 min. Specimens of aqueous humor, vitreous humor, and blood were obtained 30 min (n= 5), 1 h (n= 5), 2 h (n= 5), and 3 h (n= 4) after the beginning of the infusion and analyzed by high-performance liquid chromatography (HPLC). A pharmacokinetic (PK) model was developed to fit the experimental data. Doripenem concentrations in aqueous humor were lower than those in plasma ultrafiltrates at all sampling times, with an average aqueous humor-to-plasma ultrafiltrate area under the concentration-time curve ratio estimated as 8.3%. A pharmacokinetic model with peripheral elimination described the data adequately and was tentatively used to predict concentration-versus-time profiles and pharmacokinetic-pharmacodynamic (PK-PD) target attainment in patients under various dosing regimens. In conclusion, systematically administered doripenem does not seem to be a promising approach for the treatment of intraocular infections, especially since it could not be detected in the vitreous humor. However, this study has provided an opportunity to develop a new PK modeling approach to characterize the intraocular distribution of doripenem administered intravenously to rabbits, with tentative extrapolation to humans.

scholarly journals Tissue Distribution oftrans-Resveratrol and Its Metabolites after Oral Administration in Human Eyes

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Shuaishuai Wang ◽  
Zheng Wang ◽  
Shuo Yang ◽  
Tiemei Yin ◽  
Yaoli Zhang ◽  
...  
Keyword(s):  
Oral Administration ◽  
Aqueous Humor ◽  
High Performance ◽  
Limit Of Detection ◽  
Vitreous Humor ◽  
Average Concentration ◽  
Ocular Tissues ◽  
Suitable Amount ◽  
Pars Plana ◽  
Human Eyes

Purpose.This study was performed to measure the concentration oftrans-resveratrol and its three metabolites in human eyes.Methods.The patients who underwent pars plana vitrectomy for rhegmatogenous retinal detachment were included. The participants were orally giventrans-resveratrol-based supplement (Longevinex®). A suitable amount of conjunctiva, aqueous humor, and vitreous humor were obtained during the operation. High-performance liquid chromatography (HPLC) with mass spectrometry (LC/MS/MS) was used to detect the concentration oftrans-resveratrol and its three metabolites in the various samples.Results.The average concentration of resveratrol in the conjunctiva was 17.19 ± 15.32 nmol/g (mean ± SD). The concentration of resveratrol in the aqueous humor was close to the limit of detection, but its metabolites could be quantified. The concentrations of resveratrol metabolites in the aqueous humor can be detected. In the vitreous humor, the average concentration of resveratrol-3-O-sulfate was 62.95 ± 41.97 nmol/L. The sulfate conjugations of resveratrol were recovered in the conjunctiva, aqueous humor, and vitreous humor.Conclusions.Resveratrol and its three metabolites can be detected in the ocular tissues after oral administration. Although the concentration of parent resveratrol was low in the eyes, its metabolites could be detected and may have a role in the treatment of ocular diseases.

scholarly journals Pharmacokinetics and Pharmacodynamics of Anidulafungin for Experimental Candida Endophthalmitis: Insights into the Utility of Echinocandins for Treatment of a Potentially Sight-Threatening Infection

2012 ◽  
Vol 57 (1) ◽  
pp. 281-288 ◽  
Author(s):  
J. L. Livermore ◽  
T. W. Felton ◽  
J. Abbott ◽  
A. Sharp ◽  
J. Goodwin ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
High Performance ◽  
Vitreous Humor ◽  
Dependent Manner ◽  
Time Curve ◽  
Content Type ◽  
Disseminated Candidiasis ◽  
Exposure Response ◽  
Average Patient ◽  
Dose Dependent

ABSTRACTCandidachorioretinitis and endophthalmitis are relatively common manifestations of disseminated candidiasis. Anidulafungin is increasingly used for the treatment of disseminated candidiasis, but its efficacy forCandidaendophthalmitis is not known. A nonneutropenic model of hematogenousCandidaendophthalmitis was used. Anidulafungin at 5, 10, and 20 mg/kg was initiated at 48 h postinoculation. The fungal densities in the kidney and vitreous humor were determined. Anidulafungin concentrations in the plasma and vitreous humor were measured using high-performance liquid chromatography (HPLC). A pharmacokinetic-pharmacodynamic model was used to link anidulafungin concentrations with the observed antifungal effect. The area under the concentration-time curve (AUC) associated with stasis was determined in the both the kidney and the vitreous humor. The results were bridged to humans to identify likely dosages that are associated with significant antifungal activity within the eye. Inoculation ofCandida albicansresulted in logarithmic growth in both the vitreous humor and the kidney. The pharmacokinetics of anidulafungin were linear. There was dose-dependent penetration of the anidulafungin into the vitreous humor. The exposure-response relationships in the kidney and vitreous were completely discordant. AUCs of 270 and 100 were required for stasis in the eye and kidney, respectively. The currently licensed regimen results in an AUC for an average patient that is associated with stasis in the kidney but minimal antifungal activity in the eye. We conclude that anidulafungin penetrates the eye in a dose-dependent manner and that dosages higher than those currently licensed are required to achieve significant antifungal activity in the eye.

scholarly journals Intravitreal, Retinal, and Central Nervous System Foscarnet Concentrations after Rapid Intravenous Administration to Rabbits

2000 ◽  
Vol 44 (3) ◽  
pp. 756-759 ◽  
Author(s):  
Luis F. López-Cortés ◽  
R. Ruiz-Valderas ◽  
M. J. Lucero-Muñoz ◽  
E. Cordero ◽  
M. T. Pastor-Ramos ◽  
...  
Keyword(s):  
High Performance ◽  
Compartment Model ◽  
Vitreous Humor ◽  
Pharmacokinetic Analysis ◽  
Time Curve ◽  
Concentration Time ◽  
Two Compartment Model ◽  
Good Penetration ◽  
Csf Levels ◽  
Pigmented Rabbits

ABSTRACT Retinal, vitreous humor, brain, and cerebrospinal fluid (CSF) foscarnet levels were measured by high-performance liquid chromatography after administration of an intravenous dose of 120 mg/kg of body weight to 32 pigmented rabbits. A pharmacokinetic analysis was done using a two-compartment model. The penetration ratios, defined as ratios of retinal, vitreous humor, brain, and CSF areas under the concentration-time curve from 0 to 2 h were 110% ± 1%, 12.3% ± 0.7%, 118% ± 1%, and 20.2% ± 2.2%, respectively. These results suggest a good penetration of foscarnet into the retinal and brain tissues, reaching higher concentrations than those estimated from vitreous humor and CSF levels.

Parameters of vancomycin pharmacokinetics in postoperative patients with renal dysfunction: comparing the results of a pharmacokinetic study and mathematical modeling

2018 ◽  
pp. 58-64
Author(s):  
G. V. Ramenskaya ◽  
I. E. Shokhin ◽  
M. V. Lukina ◽  
T. B. Andrushishina ◽  
M. A. Chukina ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Renal Dysfunction ◽  
High Performance ◽  
Kidney Injury ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Pharmacokinetic Studies ◽  
Time Curve ◽  
Drug Concentrations ◽  
Dosing Regimens

Mathematical modeling of pharmacokinetic (PK) and pharmacodynamic (PD) parameters essential for establishing correct dosing regimens is an alternative to pharmacokinetic studies (PKS) adopted in the clinical setting. The aim of this work was to compare the values of PK parameters for vancomycin obtained in an actual PKS and through MM in postoperative patients with kidney injury. Our prospective study included 61 patients (47 males and 14 females aged 60.59 ± 12.23 years). During PKS, drug concentrations at steady state Сtrough and Cpeak were measured by high-performance liquid chromatography followed by the calculation of the area under the plasma concentration-time curve AUC24. For mathematical modeling, a single-compartment model was employed; PK parameters were estimated using R 3.4.0. The values of Ctrough measured 48 h after the onset of antibiotic therapy during PKS were significantly lower than those predicted by MM (р = 0.004). In a group of patients with acute kidney injury (AKI), AUC24 measured at the end of treatment was significantly higher than its value predicted by MM (р = 0.011). The probability of achieving the target AUC24 to MIC ratio of over 400 μg•h /ml is higher in the group of patients with Ctrough = 10–15 μg /ml. Our findings confirm that the use of MM in postoperative patients with renal dysfunction is limited and therapeutic drug monitoring should be used instead.

Pharmacokinetics of Azithromycin and Moxifloxacin in Human Conjunctiva and Aqueous Humor During and After the Approved Dosing Regimens

2010 ◽  
Vol 150 (5) ◽  
pp. 744-751.e2 ◽  
Author(s):  
William C. Stewart ◽  
Christopher S. Crean ◽  
Richard C. Zink ◽  
Kurt Brubaker ◽  
Reza M. Haque ◽  
...  
Keyword(s):  
Aqueous Humor ◽  
Dosing Regimens ◽  
Human Conjunctiva

scholarly journals Herb-Drug Interaction betweenEchinacea purpureaand Darunavir-Ritonavir in HIV-Infected Patients

2010 ◽  
Vol 55 (1) ◽  
pp. 326-330 ◽  
Author(s):  
José Moltó ◽  
Marta Valle ◽  
Cristina Miranda ◽  
Samandhy Cedeño ◽  
Eugenia Negredo ◽  
...  
Keyword(s):  
High Performance ◽  
Geometric Mean ◽  
Echinacea Purpurea ◽  
The Body ◽  
Pharmacokinetic Parameters ◽  
Root Extract ◽  
Open Label ◽  
Fixed Sequence ◽  
Time Curve ◽  
Sequence Study

ABSTRACTThe aim of this open-label, fixed-sequence study was to investigate the potential ofEchinacea purpurea, a commonly used botanical supplement, to interact with the boosted protease inhibitor darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy including darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included.E. purpurearoot extract capsules were added to the antiretroviral treatment (500 mg every 6 h) from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on days 0 (darunavir-ritonavir) and 14 (darunavir-ritonavir plus echinacea). Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 with the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 49 (range, 43 to 67) years, and the body mass index was 24.2 (range, 18.7 to 27.5) kg/m2. Echinacea was well tolerated, and all participants completed the study. The GMR for darunavir coadministered with echinacea relative to that for darunavir alone was 0.84 (90% CI, 0.63-1.12) for the concentration at the end of the dosing interval, 0.90 (90% CI, 0.74-1.10) for the area under the concentration-time curve from 0 to 12 h, and 0.98 (90% CI, 0.82-1.16) for the maximum concentration. In summary, coadministration ofE. purpureawith darunavir-ritonavir was safe and well tolerated. Individual patients did show a decrease in darunavir concentrations, although this did not affect the overall darunavir or ritonavir pharmacokinetics. Although no dose adjustment is required, monitoring darunavir concentrations on an individual basis may give reassurance in this setting.

scholarly journals Clinical Pharmacodynamic Index Identification for Micafungin in Esophageal Candidiasis: Dosing Strategy Optimization

2013 ◽  
Vol 57 (11) ◽  
pp. 5714-5716 ◽  
Author(s):  
David R. Andes ◽  
Daniel K. Reynolds ◽  
Scott A. Van Wart ◽  
Alexander J. Lepak ◽  
Laura L. Kovanda ◽  
...  
Keyword(s):  
Dose Level ◽  
Randomized Trials ◽  
Clinical Investigation ◽  
Time Curve ◽  
Content Type ◽  
Dosing Interval ◽  
Concentration Time ◽  
Dosing Regimens ◽  
Dosing Strategy ◽  
Current Report

ABSTRACTEchinocandins exhibit concentration-dependent effects onCandidaspecies, and preclinical studies support the administration of large, infrequent doses. The current report examines the pharmacokinetics/pharmacodynamics of two multicenter, randomized trials of micafungin dosing regimens that differed in both dose level and dosing interval. Analysis demonstrates the clinical relevance of the dose level and area under the concentration-time curve (AUC). Better, although not statistically significant (P= 0.056), outcomes were seen with higher maximum concentrations of drug in serum (Cmax) and large, infrequent doses. The results support further clinical investigation of novel micafungin dosing regimens with large doses but less than daily administration. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00666185 and NCT00665639.)

Comparison of Fluconazole Pharmacokinetics in Serum, Aqueous Humor, Vitreous Humor, and Cerebrospinal Fluid Following a Single Dose and at Steady State

1998 ◽  
Vol 14 (5) ◽  
pp. 459-471 ◽  
Author(s):  
UMAR K. MIAN ◽  
MARTIN MAYERS ◽  
YOGENDER GARG ◽  
QING-FENG LIU ◽  
GIRARD NEWCOMER ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Single Dose ◽  
Steady State ◽  
Aqueous Humor ◽  
Vitreous Humor

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.

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