Therapeutic Drug Monitoring of Risperidone Using a New, Rapid HPLC Method: Reappraisal of Interindividual Variability Factors

Caffeine citrate is the drug of choice for the pharmacological treatment of apnea of prematurity. Factors such as maturity and genetic variation contribute to the interindividual variability in the clinical response to caffeine therapy in preterm infants, making the optimal dose administered controversial. Moreover, the necessity for therapeutic drug monitoring (TDM) of caffeine is still worth discussing due to the need to achieve the desired target concentrations as well as concerns about the safety of higher doses. Therefore, we reviewed the pharmacokinetic profile of caffeine in preterm infants, evidence of the safety and efficacy of different doses of caffeine, therapeutic concentration ranges of caffeine and impact of genetic variability on caffeine therapy. Whereas the safety and efficacy of standard-dose caffeine have been demonstrated, evidence for the safety of higher administered doses is insufficient. Thus, preterm infants who lack clinical response to standard-dose caffeine therapy are of interest for TDM when dose optimization is performed. Polymorphisms in pharmacodynamics-related genes, but not in pharmacokinetics-related genes, have a significant impact on the interindividual variability in clinical response to caffeine therapy. For preterm infants lacking clinical response, how to develop individualized medication regimens for caffeine remains to be explored.

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Development and validation of a new HPLC method for valproic acid determination in human plasma and its application to a therapeutic drug monitoring study

Macedonian Pharmaceutical Bulletin ◽

10.33320/maced.pharm.bull.2020.66.01.001 ◽

2020 ◽

Vol 66 (1) ◽

Author(s):

Emrah Dural ◽

Seniha Çelebi ◽

Aslı Bolayır ◽

Burhanettin Çiğdem

Keyword(s):

Valproic Acid ◽

Therapeutic Drug Monitoring ◽

Human Plasma ◽

Drug Monitoring ◽

High Performance ◽

High Standard ◽

Hplc Method ◽

Therapeutic Drug ◽

Recommended Treatment ◽

Monitoring Study

The aim of this study was to develop a new, simple and reliable high performance liquid chromatography (HPLC) method for analysis of valproic acid (VPA) in human plasma and apply to it to a therapeutic drug monitoring study. Also, the relationship between plasma-VPA concentrations and the amount of VPA used by patients was aimed to be evaluated. Plasma samples (0.25 mL) were precipitated with the same volume of acetonitrile and after centrifugation, aliquots were applied to a C18 column (250 mm x 4.6 mm). Mobile phase was prepared with phosphate buffer and acetonitrile (47.5:52.5, v/v). The flow-rate was 1.2 mL/min. Accuracy was between -2.9 and 3.2% and precision was ≤6.6%. Method was specific and sensitive with a detection limit of 2.2 µg/mL and the average recovery was 94.3%. Calibration curve was linear (r2>0.9968) from 10 to 150 µg/mL. Plasma-VPA levels of the epileptic patient population (n=33) treated with VPA between 0.5 and 1.5 g/day were also determined. Patient plasma-VPA concentrations ranged from 2.9 to 166.4 µg/g/mL (56.3±38.8). High RSD% (68.8%) was observed in dose-rated plasma-VPA results. Moreover, VPA plasma levels were found to be outside the recommended treatment range in 30.3% of the patients examined. The procedure described was found to be relatively simple, precise, and applicable for routine therapeutic drug monitoring (TDM) especially in neurology clinics or in toxicology reference laboratories. The high standard deviation (SD) observed in the dose depended plasma-VPA values of the volunteers proved the importance of TDM during the use of this drug. The results showed that for rational drug use, it is important to identify individual polymorphisms in the CYP2C9, CYP2A6 and CYP2B6 subtypes responsible for VPA metabolism, and to rearrange drug doses taking these enzyme activities into account.

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Systematic Therapeutic Drug Monitoring for Linezolid: Variability and Clinical Impact

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00687-17 ◽

2017 ◽

Vol 61 (10) ◽

Cited By ~ 9

Author(s):

Alicia Galar ◽

Maricela Valerio ◽

Patricia Muñoz ◽

Luis Alcalá ◽

Xandra García-González ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Adverse Events ◽

Hospital Mortality ◽

Drug Monitoring ◽

Interindividual Variability ◽

Clinical Impact ◽

Therapeutic Drug ◽

Serum Trough ◽

Trough Levels ◽

Wide Interindividual Variability

ABSTRACT Linezolid serum trough (C min) and peak (C max) levels were determined prospectively in 90 patients. Adequate exposure was defined as a C min of 2 to 8 mg/liter. Therapy was empirical (73.3%) or targeted (26.7%). Wide interindividual variability in linezolid C min levels was recorded (0.1 to 25.2 μg/ml). Overall, 65.5% of the patients had out-of-range, 41.1% had subtherapeutic, and 24.4% had supratherapeutic trough levels. We did not find a correlation between abnormal levels and adverse events, in-hospital mortality, or overall poor outcome.

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Development of a simple HPLC method for determination of carbamazepine in human plasma with application in therapeutic drug monitoring

Toxicology Letters ◽

10.1016/j.toxlet.2015.08.466 ◽

2015 ◽

Vol 238 (2) ◽

pp. S149

Author(s):

C. Tuchilă ◽

E.D. Bîlea ◽

D.L. Baconi

Keyword(s):

Therapeutic Drug Monitoring ◽

Human Plasma ◽

Drug Monitoring ◽

Hplc Method ◽

Therapeutic Drug

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Comparison of a RP-HPLC Method with the Therapeutic Drug Monitoring System TDxfor the Determination of Theophylline in Blood Serum

Analytical Letters ◽

10.1080/00032719308017457 ◽

1993 ◽

Vol 26 (10) ◽

pp. 2127-2142 ◽

Cited By ~ 8

Author(s):

I. N. Papadoyannis ◽

V. F. Samanidou ◽

H. Tsoukali ◽

F. Epivatianou

Keyword(s):

Therapeutic Drug Monitoring ◽

Blood Serum ◽

Monitoring System ◽

Drug Monitoring ◽

Hplc Method ◽

Therapeutic Drug ◽

Rp Hplc ◽

Drug Monitoring System

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A Sensitive Microscale HPLC-UV Method for the Determination of Doxofylline and its Metabolites in Plasma: An Adapted Method for Therapeutic Drug Monitoring in Children

Current Pharmaceutical Analysis ◽

10.2174/1573412914666180611103849 ◽

2019 ◽

Vol 16 (1) ◽

pp. 47-54

Author(s):

Yue-E Wu ◽

Xiu-Fu Wu ◽

Min Kan ◽

Hai-Yan Shi ◽

Meng-Jie Liu ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Pure Water ◽

Internal Standard ◽

Mean Value ◽

Hplc Method ◽

Individual Variability ◽

Small Sample ◽

Therapeutic Drug ◽

Chronic Obstructive

Background: Doxofylline (DXE) is a novel methylxanthine derivative used in the treatment of asthma and Chronic Obstructive Pulmonary Diseases (COPD). Therapeutic Drug Monitoring (TDM) has been proposed in adults, while the adapted analytical method and TDM data are still missing in children. Methods: A highly sensitive and stability indicating High-Performance Liquid Chromatography (HPLC) method of DXE with caffeine as the internal standard, was developed and validated by separating its metabolites, β-Hydroxyethyltheophylline (HPE) and Theophylline (TPE). HPLC separation is achieved on C18 column connected to an ultraviolet detector (276 nm), using acetonitrile and ultra-pure water in a gradient mode of elution at a flow rate of 0.9 mL/min at 25°C. A liquid-liquid extraction method using ethyl acetate was developed with a small sample volume of plasma of 50 μL. Trough concentration was monitored in children receiving DXE therapy. Results: The method was linear over the concentration ranges from 0.4-20 µg/mL for DXE, HPE and TPE, respectively, in plasma. The limits of quantification were 0.4 µg/mL. Intra- and interday coefficients of variation did not exceed 6.5%, and the accuracy ranged from 94.9% to 112.5%. A total of 39 children (mean age of 1.8 years, range: 0.3-5.7 years) were included. The pediatric patients had detectable DXE concentrations with a mean value of 1.78 µg/mL (range from 0.49 to 6.36 µg/mL), and HPE measurable concentrations with a mean value of 0.52 µg/mL (range from 0.40 to 0.82 µg/mL), while the TPE could not be measured in any patient. Conclusion: A sensitive, reliable, and adapted HPLC method has been developed for the simultaneous analysis of DXE and its metabolites in children. The DXE and its metabolites trough concentrations showed large inter-individual variability.

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An Improved HPLC Method for Therapeutic Drug Monitoring of Daunorubicin, Idarubicin, Doxorubicin, Epirubicin, and Their 13-Dihydro Metabolites in Human Plasma

Therapeutic Drug Monitoring ◽

10.1097/00007691-199906000-00022 ◽

1999 ◽

Vol 21 (3) ◽

pp. 367 ◽

Cited By ~ 53

Author(s):

Stefano Fogli ◽

Romano Danesi ◽

Federico Innocenti ◽

Antonello Di Paolo ◽

Guido Bocci ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Human Plasma ◽

Drug Monitoring ◽

Hplc Method ◽

Therapeutic Drug

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Therapeutic Drug Monitoring of Linezolid: a Retrospective Monocentric Analysis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00177-10 ◽

2010 ◽

Vol 54 (11) ◽

pp. 4605-4610 ◽

Cited By ~ 108

Author(s):

Federico Pea ◽

Mario Furlanut ◽

Piergiorgio Cojutti ◽

Francesco Cristini ◽

Eleonora Zamparini ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

High Performance ◽

Drug Exposure ◽

Plasma Concentrations ◽

Hplc Method ◽

Therapeutic Drug ◽

Time Curve ◽

Standard Dosage ◽

Wide Variability

ABSTRACT The objective of the present retrospective observational study carried out in patients receiving a standard dosage of linezolid and undergoing routine therapeutic drug monitoring (TDM) was to assess the interindividual variability in plasma exposure, to identify the prevalence of attainment of optimal pharmacodynamics, and to define if an intensive program of TDM may be warranted in some categories of patients. Linezolid plasma concentrations (trough [C min] and peak [C max] levels) were analyzed by means of a high-performance liquid chromatography (HPLC) method, and daily drug exposure was estimated (daily area under the plasma concentration-time curve [AUC24]). The final database included 280 C min and 223 C max measurements performed in 92 patients who were treated with the fixed 600-mg dose every 12 h (q12h) intravenously (n = 58) or orally (n = 34). A wide variability was observed (median values [interquartile range]: 3.80 mg/liter [1.75 to 7.53 mg/liter] for C min, 14.70 mg/liter [10.57 to 19.64] for C max, and 196.08 mg·h/liter [144.02 to 312.10 mg·h/liter] for estimated AUC24). Linezolid C min was linearly correlated with estimated AUC24 (r 2 = 0.85). Optimal pharmacodynamic target attainment (defined as C min of ≥2 mg/liter and/or AUC24/MIC90 ratio of >80) was obtained in about 60 to 70% of cases, but potential overexposure (defined as C min of ≥10 mg/liter and/or AUC24 of ≥400 mg·h/liter) was documented in about 12% of cases. A significantly higher proportion of cases with potential overexposure received cotreatment with omeprazole, amiodarone, or amlodipine. Our study suggests that the application of TDM might be especially worthwhile in about 30% of cases with the intent of avoiding either the risk of dose-dependent toxicity or that of treatment failure.

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