Prescription and Therapeutic Drug Monitoring Status of Valproic Acid among Patients Receiving Carbapenem Antibiotics: A Preliminary Survey Using a Japanese Claims Database

Abstract Objectives Heat treatment is a convenient measure for pathogens inactivation. The authors investigated the effects of this method on blood concentrations of six commonly therapeutic drugs. Methods Plasma and whole blood were pretreated with or without heating at 56 °C for 30 min, and drug concentrations of vancomycin, methotrexate, valproic acid, digoxin, carbamazepine, and cyclosporine were examined. Results Increased valproic acid levels after plasma heating (63.2 ± 30.2 vs. 62.1 ± 29.8 mg/L, mean recovery 102.0%) and whole blood heating (64.5 ± 30.5 vs. 62.1 ± 29.8 mg/L, mean recovery 104.6%) were observed (both p<0.05), but these differences were not considered clinically important. Recoveries of vancomycin in heat treatments varied widely, with an average and significant decrease of 15.8% in value after whole blood heating (11.7 ± 8.1 vs. 13.7 ± 8.6 mg/L, p<0.05). Conclusions Plasma or whole blood heating at 56 °C for 30 min are feasible in pathogens inactivation during monitoring methotrexate, valproic acid, digoxin, carbamazepine, and cyclosporine. However, such pretreatment seems inappropriate in monitoring vancomycin concentrations. Those results highlight the need for caution when applying heat treatment for pathogens inactivation in therapeutic drug monitoring.

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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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