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1.
Biomed Chromatogr ; 37(12): e5749, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37727118

ABSTRACT

Amphotericin B (AMB) is a polyene macrolide antifungal agent used for treating invasive fungal infections. Liposomal AMB is a lipid dosage form, available as AmBisome, which reduces the toxicity of the drug. A simple HPLC-UV method was developed for the determination of AMB in plasma to study its pharmacokinetic profile in a critical patient receiving AmBisome and treated with extracorporeal replacement therapies. Sample preparation was performed using plasma deproteinization and drug release from liposome by the addition of acetonitrile (ACN)/zinc sulfate and ultrasonication. Chromatographic separation was performed using a C18 column and a mobile phase consisting of phosphate buffer (pH 3.0)/ACN (65/35, v/v). The UV detector was set at 407 nm. The total run time analysis was 23 min. The method was validated according to the standard guidelines and applied to study the pharmacokinetics of AMB in a critical patient. The total run time analysis obtained was shorter than that of the previously reported methods, being useful for therapeutic drug monitoring or pharmacokinetic profile research.


Subject(s)
Amphotericin B , Antifungal Agents , Humans , Amphotericin B/therapeutic use , Amphotericin B/pharmacokinetics , Chromatography, High Pressure Liquid , Antifungal Agents/therapeutic use , Antifungal Agents/pharmacokinetics , Liposomes
2.
Ther Drug Monit ; 41(6): 740-747, 2019 12.
Article in English | MEDLINE | ID: mdl-31136417

ABSTRACT

BACKGROUND: To evaluate the adequacy of different dosing regimens of voriconazole for the prophylaxis of invasive candidiasis and aspergillosis in adult allogeneic stem cell transplant recipients by means of population pharmacokinetic (PK) modelling and simulation. METHODS: Allogeneic stem cell transplant recipients receiving voriconazole were included in this observational study. A population PK model was developed. Three oral voriconazole-dosing regimens were simulated: 200, 300, and 400 mg twice daily. The pharmacodynamic target was defined as fAUC0-24/0.7. A probability of target attainment ≥90% was considered optimal. The cumulative fraction of response was defined as the fraction of patients achieving the pharmacodynamic target when a population of simulated patients is matched with a simulated population of different Candida spp. and Aspergillus spp. The percentage of patients with trough plasma concentrations at steady state (Ctrough) within the reference range (1-5.5 mg/L) was also calculated. RESULTS: A 2-compartment PK model was developed using data from 40 patients, which contributed 237 voriconazole plasma samples, including trough and maximum concentrations. Voriconazole 200, 300, and 400 mg twice daily achieved probability of target attainment ≥90% for minimal inhibitory concentration values ≤0.25, ≤0.38, and ≤0.50 mg/L, respectively. The cumulative fraction of response for A. niger, A. versicolor, and A. flavus increased >10% when increasing voriconazole dose from 200 to 400 mg twice daily (from 72.5% to 89.5% for A. niger; from 77.7% to 88.7% for A. versicolor; and from 82.4% to 94.9% for A flavus). The percentage of patients with Ctrough within the reference range increased 15% when voriconazole dose was increased from 200 to 300 mg twice daily. CONCLUSIONS: The PK simulations in this study suggest that transplant recipients on voriconazole prophylaxis against invasive candidiasis or aspergillosis are likely to achieve the target concentrations associated with the desired treatment outcomes if the maintenance dose is 200 mg twice daily. However, Aspergillus spp. with high minimal inhibitory concentrations could require higher maintenance doses.


Subject(s)
Antifungal Agents/pharmacokinetics , Aspergillosis/microbiology , Candidiasis/microbiology , Stem Cell Transplantation/adverse effects , Voriconazole/pharmacokinetics , Administration, Oral , Adult , Aged , Allografts , Antifungal Agents/administration & dosage , Antifungal Agents/therapeutic use , Aspergillosis/prevention & control , Aspergillus/drug effects , Candida/drug effects , Candidiasis/prevention & control , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Monte Carlo Method , Voriconazole/administration & dosage , Voriconazole/therapeutic use
3.
Biomed Chromatogr ; 33(7): e4529, 2019 Jul.
Article in English | MEDLINE | ID: mdl-30845352

ABSTRACT

Stability studies are necessary in healthcare settings as they facilitate fast, cost-effective and efficient work related to batch manufacturing and availability of supplies. We studied the stability of 1-10 mg/mL mycophenolate mofetil (MMF) in polypropylene 5% dextrose infusion bags prepared from Cellcept® and with a generic brand name (Micofenolato de Mofetilo Accord) at different storage temperatures. To ensure chemical compatibility during preparation, we also tested MMF sorption to the Equashield® closed-system drug transfer device used in this step. For this, a validated stability-indicating high-performance liquid chromatography method was developed for the quantification and identification of MMF in the infusion bags. The analytical selectivity of the assay was determined by subjecting an MMF sample to extreme values of pH, oxidative stress and heat conditions to force degradation. Protected from light, 1-10 mg/mL MMF in infusion polypropylene bags prepared from reconstituted Cellcept® 500 mg or Accord 500 mg in 5% dextrose was stable for at least 35 days when stored at 2-8°C or between -15 and -25°C, and for 14 days when stored at 25°C. MMF loss owing to chemical sorption to the Equashield® closed-system drug transfer device set was negligible.


Subject(s)
Drug Delivery Systems/methods , Glucose/chemistry , Mycophenolic Acid , Polypropylenes/chemistry , Chromatography, High Pressure Liquid , Drug Stability , Mycophenolic Acid/analysis , Mycophenolic Acid/chemistry
4.
Bioanalysis ; 10(7): 461-473, 2018 Apr 01.
Article in English | MEDLINE | ID: mdl-29633862

ABSTRACT

AIM: A simple, rapid, economical and sensitive HPLC-UV method was developed for the simultaneous quantification of ceftolozane and tazobactam in plasma samples. METHODOLOGY: After deproteinization followed by a liquid-liquid back-extraction, the compounds were separated on a C18 column (150 mm × 4.6 mm, 5 µm) with UV-visible detection at 220 nm. The mobile phase consisted of acetonitrile and potassium dihydrogenphosphate buffer at pH 3.0 (8:92, v/v), delivered isocratically at a flow rate of 1.0 ml/min and at a column oven temperature of 30°C. Cefepime was used as an internal standard. RESULTS: Linearity was achieved in the concentration range of 0.50-100.00 µg/ml for ceftolozane and 0.25-50.00 µg/ml for tazobactam. The intra- and interday precision showed good reproducibility with coefficients of variation of less than 9.26% for ceftolozane and 9.62% for tazobactam. CONCLUSION: The sample preparation procedure avoids expensive or time-consuming steps used by other previously published methods. The methodology was validated according to standard guidelines and was used for quantification of ceftolozane and tazobactam in plasma samples from critically ill patients.


Subject(s)
Anti-Bacterial Agents/blood , Cephalosporins/blood , Chromatography, High Pressure Liquid/methods , Penicillanic Acid/analogs & derivatives , Plasma/chemistry , Humans , Penicillanic Acid/blood , Tazobactam
5.
Int J Antimicrob Agents ; 51(1): 115-121, 2018 Jan.
Article in English | MEDLINE | ID: mdl-28666752

ABSTRACT

INTRODUCTION: The study objective was to evaluate the efficacy of different dosages of caspofungin in the treatment of invasive candidiasis and aspergillosis, in relation to the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment, using modelling and Monte Carlo simulations in critically ill adult patients on continuous haemodiafiltration. METHODS: Critically ill adult patients on continuous venovenous haemodiafiltration treated with caspofungin were analysed. A population PK model was developed. Four caspofungin dosing regimens were simulated: the licensed regimen, 70 mg/day, 100 mg/day or 200 mg/day. A PK/PD target was defined as the ratio between the area under the caspofungin concentration-time curve over 24 hours and the minimal inhibitory concentration (AUC/MIC) for candidiasis or the minimal effective concentrations (AUC/MEC) for Aspergillus spp. Target attainment based on preclinical target for Candida and Aspergillus was assessed for different MIC or MEC, respectively. RESULTS: Concentration-time data were described by a two-compartment model. Body-weight and protein concentration were the only covariates identified by the model. Goodness-of-fit plots and bootstrap analysis proved the model had a satisfactory performance. As expected, a higher maintenance dose resulted in a higher exposure. Target attainment was >90% for candidiasis (MIC≤0.06 mg/L) and aspergillosis (MEC≤0.5 mg/L), irrespective of the dosing regimen, but not for C. parapsilosis. Standard regimen was insufficient to reach the target for C. albicans and C. parapsilosis with MIC≥0.1 mg/L. CONCLUSION: The licensed regimen of caspofungin is insufficient to achieve the PK/PD targets in critically ill patients on haemodiafiltration. The determination of MICs will enable dose scheme selection.


Subject(s)
Candidiasis, Invasive/drug therapy , Candidiasis/drug therapy , Echinocandins/administration & dosage , Echinocandins/therapeutic use , Invasive Pulmonary Aspergillosis/drug therapy , Lipopeptides/administration & dosage , Lipopeptides/therapeutic use , Aged , Aged, 80 and over , Antifungal Agents/pharmacology , Aspergillus/drug effects , Candida albicans/drug effects , Candida glabrata/drug effects , Candida parapsilosis/drug effects , Caspofungin , Critical Illness , Female , Hemodiafiltration , Humans , Male , Microbial Sensitivity Tests , Middle Aged
7.
Am J Health Syst Pharm ; 74(13): 1002-1006, 2017 Jul 01.
Article in English | MEDLINE | ID: mdl-28645998

ABSTRACT

PURPOSE: The stability of 0.3-mg/mL tacrolimus ophthalmic solution at different storage temperatures was studied. METHODS: A sterile ophthalmic solution of 0.3 mg/mL tacrolimus was prepared in triplicate under aseptic conditions by diluting tacrolimus in eye drops. Three aliquots of this solution were transferred into polypropylene bottles and stored at 25, 2-8, or -15 to -25 °C. Samples were collected immediately after preparation and at selected time points and assayed in triplicate using high-performance liquid chromatography (HPLC). Samples were also visually examined for macroscopic changes. The 0.3-mg/mL tacrolimus solution was also exposed to acidic treatment and heat to force its degradation and to evaluate the selectivity of the analytic method. The tacrolimus ophthalmic solution was considered stable if at least 90% of the mean initial concentration remained when analyzed by HPLC. RESULTS: When stored at 2-8 °C and between -15 and -25 °C, at least 90% of the initial tacrolimus concentration remained throughout the 85-day study period. There were no significant differences in tacrolimus concentrations between the starting and ending points (p > 0.05). However, when tacrolimus solution was stored at 25 °C, the percentage of the initial tacrolimus concentration remaining had decreased to less than 90% on day 28. CONCLUSION: Tacrolimus diluted to 0.3 mg/mL in eye drop solution was stable for 20 days when stored at 25 °C and for at least 85 days when stored at 2-8 °C or between -15 and -25 °C in polypropylene bottles and protected from light.


Subject(s)
Immunosuppressive Agents/chemistry , Ophthalmic Solutions/chemistry , Tacrolimus/chemistry , Administration, Ophthalmic , Chromatography, High Pressure Liquid/methods , Drug Stability , Drug Storage/methods , Drug Storage/standards , Humans , Immunosuppressive Agents/administration & dosage , Ophthalmic Solutions/analysis , Pharmaceutical Solutions/analysis , Pharmaceutical Solutions/chemistry , Tacrolimus/analysis , Temperature
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