scholarly journals Validation of an HPLC–MS/MS Method for the Determination of Plasma Ticagrelor and Its Active Metabolite Useful for Research and Clinical Practice

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 278
Author(s):  
Jennifer Lagoutte-Renosi ◽  
Bernard Royer ◽  
Vahideh Rabani ◽  
Siamak Davani
Keyword(s):  
Active Metabolite ◽  
Plasma Concentrations ◽  
Antiplatelet Agent ◽  
High Plasma ◽  
Therapeutic Drug ◽  
Routine Practice ◽  
Daily Routine ◽  
Limit Of Quantification ◽  
Wide Range

Ticagrelor is an antiplatelet agent which is extensively metabolized in an active metabolite: AR-C124910XX. Ticagrelor antagonizes P2Y12 receptors, but recently, this effect on the central nervous system has been linked to the development of dyspnea. Ticagrelor-related dyspnea has been linked to persistently high plasma concentrations of ticagrelor. Therefore, there is a need to develop a simple, rapid, and sensitive method for simultaneous determination of ticagrelor and its active metabolite in human plasma to further investigate the link between concentrations of ticagrelor, its active metabolite, and side effects in routine practice. We present here a new method of quantifying both molecules, suitable for routine practice, validated according to the latest Food and Drug Administration (FDA) guidelines, with a good accuracy and precision (<15% respectively), except for the lower limit of quantification (<20%). We further describe its successful application to plasma samples for a population pharmacokinetics study. The simplicity and rapidity, the wide range of the calibration curve (2–5000 µg/L for ticagrelor and its metabolite), and high throughput make a broad spectrum of applications possible for our method, which can easily be implemented for research, or in daily routine practice such as therapeutic drug monitoring to prevent overdosage and occurrence of adverse events in patients.

scholarly journals Determination of venlafaxine and its active metabolite O-desmethylvenlafaxine in human plasma by HPLC fluorescence

2018 ◽  
Vol 31 (2) ◽  
pp. e000010 ◽  
Author(s):  
Shujuan Shen ◽  
Chen Zhang ◽  
Yemeng Mao
Keyword(s):  
Human Plasma ◽  
Active Metabolite ◽  
Plasma Concentrations ◽  
Regression Equation ◽  
Therapeutic Drug ◽  
Dihydrogen Phosphate ◽  
Simple Method ◽  
Column Temperature ◽  
Clinical Detection

BackgroundTherapeutic drug monitoring guides clinical individualised medication by measuring plasma concentration, which could improve the curative effect, avoid drug overdose and reduce the incidence of adverse reactions. At present, there are few reports on the clinical detection of venlafaxine and its active metabolite O-desmethylvenlafaxine. In this paper, the detection method of venlafaxine and O-desmethylvenlafaxine in blood plasma was established, which provides an effective and convenient means for guiding clinical application of medication.AimTo establish a method for determination of venlafaxine and its active metabolite O-desmethylvenlafaxine in human plasma by high-performance liquid chromatography with fluorescence detection.MethodsChromatographic separation was achieved on an Agilent Eclipse XDB-C18 Column (4.6 × 150 mm, 5 µm) with water containing sodium dihydrogen phosphate (0.05 mol/L) and acetonitrile (72:28) as the mobile phases. The following parameters were employed: flow rate 0.5 mL/min, column temperature 30°C, fluorescence excitation wavelength 276 nm and emission wavelength 598 nm.ResultsThe method showed good linearity in the concentration range 10–1000 ng/mL. The regression equation for venlafaxine was R=0.0054C+0.0264, r2=0.99991. The regression equation for O-desmethylvenlafaxine was R=0.0034C+0.0272, r2=0.99969. The intraday and interday precisions (relative SD) were less than 10%, and the quantitative limit was 10 ng/mL.ConclusionWe established a sensitive, specific and simple method for the detection of venlafaxine and O-desmethylvenlafaxine. This method fully meets the needs of clinical trials of venlafaxine and the requirements of relevant guidelines. It provided a reference for the clinical detection of venlafaxine and O-desmethylvenlafaxine plasma concentrations and pharmacokinetic study.

scholarly journals Software for Dosage Individualization of Voriconazole for Immunocompromised Patients

2013 ◽  
Vol 57 (4) ◽  
pp. 1888-1894 ◽  
Author(s):  
William W. Hope ◽  
Michael VanGuilder ◽  
J. Peter Donnelly ◽  
Nicole M. A. Blijlevens ◽  
Roger J. M. Brüggemann ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Cell Transplant ◽  
Multiple Model ◽  
Pharmacokinetic Variability ◽  
Hematopoietic Stem ◽  
Wide Range

ABSTRACTThe efficacy of voriconazole is potentially compromised by considerable pharmacokinetic variability. There are increasing insights into voriconazole concentrations that are safe and effective for treatment of invasive fungal infections. Therapeutic drug monitoring is increasingly advocated. Software to aid in the individualization of dosing would be an extremely useful clinical tool. We developed software to enable the individualization of voriconazole dosing to attain predefined serum concentration targets. The process of individualized voriconazole therapy was based on concepts of Bayesian stochastic adaptive control. Multiple-model dosage design with feedback control was used to calculate dosages that achieved desired concentration targets with maximum precision. The performance of the software program was assessed using the data from 10 recipients of an allogeneic hematopoietic stem cell transplant (HSCT) receiving intravenous (i.v.) voriconazole. The program was able to model the plasma concentrations with a high level of precision, despite the wide range of concentration trajectories and interindividual pharmacokinetic variability. The voriconazole concentrations predicted after the last dosages were largely concordant with those actually measured. Simulations provided an illustration of the way in which the software can be used to adjust dosages of patients falling outside desired concentration targets. This software appears to be an extremely useful tool to further optimize voriconazole therapy and aid in therapeutic drug monitoring. Further prospective studies are now required to define the utility of the controller in daily clinical practice.

Isavuconazole: Case Report and Pharmacokinetic Considerations

Chemotherapy ◽  
2018 ◽  
Vol 63 (5) ◽  
pp. 253-256 ◽  
Author(s):  
Francesco Marchesi ◽  
Corrado Girmenia ◽  
Bianca Maria Goffredo ◽  
Emanuela Salvatorelli ◽  
Atelda Romano ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Plasma Concentrations ◽  
Real Life ◽  
Concomitant Administration ◽  
Invasive Fungal Disease ◽  
High Plasma ◽  
Adult Patients ◽  
Therapeutic Drug ◽  
Hepatic Toxicity ◽  
Maintenance Chemotherapy

Invasive fungal disease (IFD) is one of the major causes of morbidity and mortality in immunocompromised patients. Voriconazole (VCZ) and posaconazole (PCZ) remain the most widely used antifungals for the prophylaxis and treatment of IFD. However, VCZ and PCZ are liable for drug-drug interactions and show a pharmacokinetic variability that requires therapeutic drug monitoring (TDM). Isavuconazole (IVZ) is a newest generation triazole antifungal approved for the treatment of invasive aspergillosis (IA) in adult patients and for the treatment of invasive mucormycosis in adult patients for whom treatment with amphotericin B is inappropriate. In clinical trials, IVZ showed linear pharmacokinetics and little or no evidence for interactions with other drugs. There is only modest evidence on IVZ pharmacokinetics and TDM in real-life settings. Here, we report on IVZ pharmacokinetics in a young adult with Ph chromosome-negative acute lymphoblastic leukemia (ALL) who developed a “probable” IA during induction chemotherapy. The patient was initially treated with VCZ, but she developed a severe hepatic toxicity that was associated to the high plasma levels of VCZ. Therefore, VCZ was discontinued and the patient was switched to IVZ. After a loading dose of IVZ, the patient remained on IVZ for 5 months while also receiving standard maintenance chemotherapy for ALL. At day 65 after the start of IVZ, the patient experienced a significant hepatic toxicity; however, no change in IVZ plasma concentrations was observed in the face of a concomitant administration of many other drugs (cancer drugs, antiemetics, other anti-infectives). Hepatic toxicity resolved after discontinuing maintenance chemotherapy but not IVZ. These results show that (i) IVZ plasma concentrations remained stable throughout and were not affected by concomitant ALL therapy, and (ii) there was no relation between IVZ plasma concentration and hepatic toxicity. Thus, in clinical practice IVZ may not require TDM.

scholarly journals Pharmacokinetic Modeling and Optimal Sampling Strategies for Therapeutic Drug Monitoring of Rifampin in Patients with Tuberculosis

2015 ◽  
Vol 59 (8) ◽  
pp. 4907-4913 ◽  
Author(s):  
Marieke G. G. Sturkenboom ◽  
Leonie W. Mulder ◽  
Arthur de Jager ◽  
Richard van Altena ◽  
Rob E. Aarnoutse ◽  
...  
Keyword(s):  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Mean Squared Error ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Optimal Sampling ◽  
Sampling Strategies ◽  
Wide Range

ABSTRACTRifampin, together with isoniazid, has been the backbone of the current first-line treatment of tuberculosis (TB). The ratio of the area under the concentration-time curve from 0 to 24 h (AUC0–24) to the MIC is the best predictive pharmacokinetic-pharmacodynamic parameter for determinations of efficacy. The objective of this study was to develop an optimal sampling procedure based on population pharmacokinetics to predict AUC0–24values. Patients received rifampin orally once daily as part of their anti-TB treatment. A one-compartmental pharmacokinetic population model with first-order absorption and lag time was developed using observed rifampin plasma concentrations from 55 patients. The population pharmacokinetic model was developed using an iterative two-stage Bayesian procedure and was cross-validated. Optimal sampling strategies were calculated using Monte Carlo simulation (n= 1,000). The geometric mean AUC0–24value was 41.5 (range, 13.5 to 117) mg · h/liter. The median time to maximum concentration of drug in serum (Tmax) was 2.2 h, ranging from 0.4 to 5.7 h. This wide range indicates that obtaining a concentration level at 2 h (C2) would not capture the peak concentration in a large proportion of the population. Optimal sampling using concentrations at 1, 3, and 8 h postdosing was considered clinically suitable with anr2value of 0.96, a root mean squared error value of 13.2%, and a prediction bias value of −0.4%. This study showed that the rifampin AUC0–24in TB patients can be predicted with acceptable accuracy and precision using the developed population pharmacokinetic model with optimal sampling at time points 1, 3, and 8 h.

scholarly journals Determination of Gentamicins C1, C1a, and C2 in Plasma and Urine by HPLC

2000 ◽  
Vol 46 (6) ◽  
pp. 837-842 ◽  
Author(s):  
Nina Isoherranen ◽  
Stefan Soback
Keyword(s):  
Solid Phase Extraction ◽  
Solid Phase ◽  
Preparative Chromatography ◽  
Detector Response ◽  
Therapeutic Drug ◽  
Resonance Spectroscopy ◽  
Pharmacokinetic Studies ◽  
Phase Extraction ◽  
Limit Of Quantification

Abstract Background: Gentamicin is an aminoglycoside antibiotic complex containing gentamicins C1, C1a, and C2. Few methods have been described for analysis of the three gentamicin components separately in biological fluids, and none has been used in pharmacokinetic studies. Determination of the three gentamicins separately may have pharmacokinetic and toxicological implications. The present study describes development of an HPLC method for the analysis of gentamicin C1, C1a, and C2 components in plasma and urine. Methods: The three components were isolated by preparative chromatography and their identities verified by thin-layer chromatography, HPLC, mass spectrometry, nuclear magnetic resonance spectroscopy, and melting point determination. The gentamicins were extracted from the biological matrix by use of Tris buffer and polymer phase solid-phase extraction. Derivatization was carried out in the solid-phase extraction cartridge with 1-fluoro-2,4-dinitrobenzene. The 2,4-dinitrophenyl derivatives were separated with reversed-phase HPLC and quantified by the ultraviolet absorbance at 365 nm. Results: The detector response was linear from the limit of quantification to 50 mg/L for the individual components. The limit of quantification was 0.07 mg/L for gentamicin C1 and 0.1 mg/L for gentamicins C2 and C1a. The recovery of the gentamicin components was 72% from plasma and 98% from urine. The method was validated for human and dog plasma and urine. Conclusions: The method was repeatable and enabled the analysis of gentamicins C1, C1a, and C2 in plasma and urine in concentrations covering the therapeutic range of the drug, thus being suitable for therapeutic drug monitoring and pharmacokinetic studies.

Simultaneous determination of disopyramide and mono-N-dealkyldisopyramide enantiomers in plasma and urine by use of a chiral cellulose-derivative column

1990 ◽  
Vol 36 (7) ◽  
pp. 1300-1304 ◽  
Author(s):  
H Echizen ◽  
K Ochiai ◽  
Y Kato ◽  
K Chiba ◽  
T Ishizaki
Keyword(s):  
Simultaneous Determination ◽  
Active Metabolite ◽  
Signal To Noise Ratio ◽  
Plasma Concentrations ◽  
Internal Standard ◽  
Cellulose Derivative ◽  
Ultraviolet Detection ◽  
Lower Detection ◽  
Relative Errors

Abstract This assay allows simultaneous determination of the enantiomers of both disopyramide and its active metabolite, mono-N-dealkyldisopyramide, in 1 mL of plasma or 0.1 mL of urine within approximately 35 min by HPLC with a chiral cellulose-derivative column and ultraviolet detection. Recoveries for the analytes and the internal standard (racemic verapamil) with an extraction from alkalinized plasma or urine into diethyl ether were greater than 90%. Intra- and interassay CVs for disopyramide enantiomers were less than 5.5% at 2.5 mg/L in plasma and less than 6.5% at 25 mg/L in urine; for mono-N-dealkyldisopyramide enantiomers they were less than 6.3% and less than 8.9%, respectively. Intra- and interassay relative errors for determining these analytes in plasma and urine at 2.5 and 25 mg/L, respectively, ranged from -5.9% to +2.5%. The calibration curves for the respective analytes were linear (r = 0.995 or greater, P less than 0.01) from 0.025 to 5.0 mg/L in plasma and from 0.5 to 10 mg/L in urine. The lower detection limits (signal-to-noise ratio of 3) for S(+)-disopyramide and the other analytes were 0.010 and 0.025 mg/L, respectively. We evaluated clinical applicability of this method by determining steady-state plasma concentrations and urinary excretions of the respective analytes in a pediatric patient being treated with racemic disopyramide.

Is incomplete estradiol suppression during aromatase inhibitor treatment in post-menopausal patients with breast cancer due to insufficient systemic drug concentrations?

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1063-1063
Author(s):  
Daniel Louis Hertz ◽  
Kelley M. Kidwell ◽  
Kelly A Speth ◽  
Christina L Gersch ◽  
Zeruesenay Desta ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Logistic Regression ◽  
Plasma Concentrations ◽  
High Plasma ◽  
Limit Of Quantification ◽  
Drug Concentrations ◽  
Menopausal Women ◽  
Er Positive ◽  
Post Menopausal ◽  
Positive Breast Cancer

1063 Background: Aromatase inhibitors (AI) suppress estrogen biosynthesis and are effective treatments for estrogen receptor (ER)-positive breast cancer. In a prospectively enrolled cohort we observed a subset of post-menopausal women who exhibit high plasma estradiol (E2) concentrations during AI treatment, which could potentially contribute to treatment failure. We tested the hypothesis that incomplete E2 suppression is due to insufficient systemic AI concentrations. Methods: Five hundred post-menopausal women with ER-positive breast cancer were randomized to daily exemestane (Exe) 25 mg or letrozole (Let) 2.5 mg. Plasma E2 was measured using GC/MS/MS (lower limit of quantification (LLOQ) = 1.25 pg/mL) at baseline and after 3 months. Let and Exe plasma concentrations measured after 1 or 3 months were compared with the magnitude of E2 depletion using four complementary statistical procedures to assess associations of drug concentrations with: 1) a binary outcome of E2 suppression below LLOQ (logistic regression), 2) 3-month E2 concentrations (linear regression), 3) absolute change from baseline in E2 concentrations (Spearman correlation), and 4) an ordinal outcome defined by E2: decreased to below LLOQ, decreased but not to LLOQ, stayed the same, or increased from baseline (cumulative logistic regression). Results: 397 patients with E2 and AI concentration measurements were evaluable (Exe n = 199, Let n = 198). Thirty (7.6%) patients (Exe n = 13, Let n = 17) had E2 concentrations above the LLOQ at 3 months (range: 1.42-63.8 pg/mL). Exe and Let concentrations were not associated with achievement of unmeasurable E2 concentrations, on-treatment E2 concentrations, E2 change from baseline, or ordinal groupings of E2 change (all p > 0.05). In a parallel analysis there was no association of estrone-sulfate and drug concentrations (data not shown). Conclusions: Our results suggest that circulating drug concentrations do not explain incomplete E2 suppression in women receiving AI therapy. Additional studies are underway to determine whether age, body mass and genetic variation in the aromatase enzyme influence AI treatment response.

Validation of method for determination total carbon, inorganic carbon and total organic carbon in marine waters

2018 ◽  
Vol 33 (1) ◽  
pp. 199-206
Author(s):  
Karolina Nowogrodzka ◽  
Grażyna Dembska ◽  
Katarzyna Galer-Tatarowicz
Keyword(s):  
Organic Carbon ◽  
Total Carbon ◽  
Marine Waters ◽  
Limit Of Quantification ◽  
Analysis Process ◽  
Wide Range ◽  
Repeatability And Reproducibility ◽  
Marine Institute ◽  
Inorganic And Organic

Validation is a process of setting parameters characterizing the proficiency of actions and limitations of a method and an assessment of its usefulness for particular purposes. As a result, it ensures that the analysis process is carried out in a reliable and precise way and gives reliable results. For the validation process marine water was used, as well as the addition of standard solutions. Uncertainty in the results, limit of quantification, precision, repeatability and reproducibility, recovery and accuracy of the method were obtained. The results of the validation of the method for determination of total inorganic and organic carbon in marine waters are discussed in this paper. For this purpose, a Shimadzu analyser TOC-L was used. The discussed method is based on infrared detection NDIR. A halogen scrubber type B was used for determined the compounds. This allowed the analysis time at the stage of the sample preparation to be shortened. It increased the absorption of salt contained in a sample, as a result of which, the dilution stage could be omitted, and the final result is affected by a smaller error. The method of the validation for determination of total inorganic and organic carbon received accreditation of the Polish Centre for Accreditation and joined a wide range of the analyses carried out in the Laboratory of the Department of Environment Protection of the Marine Institute in Gdańsk.

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