The scientific and practical substantiation of the therapeutic drug monitoring procedure: validation of the analytical method of valproic acid measurement




therapeutic drug monitoring, validation, laboratory method, narrow therapeutic index drugs, valproic acid


The need for careful therapeutic drug monitoring (TDM) arises for measurement of drugs with a narrow therapeutic index (NTIDs), as well as for assuring their safe and controlled replacement with generics. In particular, this category includes anti-epileptic drugs, which use is associated with the range of issues during the management of therapy effectiveness and safety. One of these examples is valproic acid, which therapeutic concentrations vary greatly depending on the individual patient. The need to substantiate the choice and control of individual optimal dosing regimen of drugs, as well as to provide the rational use of generic NTIDs, determines the relevance of the introduction of TLM in the routine practice of standardized medical care for certain categories of patients, and it requires appropriate scientific and practical justification.

Aim. To provide the scientific and practical substantiation of the procedure of TDM by validation of the laboratory method for determining the concentration of valproic acid in the blood plasma.

Materials and methods. Analytical, statistical and biological methods were used in the study. Measurement of valproic acid concentration in a standardized sample of the blood plasma was performed by the photometric method using reagents produced by SIEMENS, Inc., USA and the control serum “Chemical control, level1” produced by Bio-Rad, Inc., USA. Measurements were made by a Siemens Bio Dimension RxL Max automatic biochemical analyzer.

Results. The limits of intra-laboratory reproducibility by the factor of the laboratory assistant have been estimated as R = 3.25. The assessment of the repeatability and reproducibility of the method by the time factor and in different concentration ranges has shown the absence of gross errors and statistically significant differences in the measurements. It has been found that in the range of 73.8 ± 110 µg/ml valproic acid concentration values determined by this method using the Siemens Dimension RxL Max device can be considered accurate and reliable. The linearity of this method within the range of the concentrations measured has been also proven; it confirms the possibility of its use for measuring the concentration of valproic acid in the blood plasma.

Conclusions. The scientific and practical substantiation obtained is necessary for the proper implementation of TDM in the process of providing medical care to particular categories of patients to optimize the individual dosing regimen of NTIDs. In addition, validation of the TDM method allows using it for assuring the safe and controlled generic replacement of NTIDs. The results of the work can be used in the process of further improvement and development of new analytical methods for TDM of valproic acid, as well as other NTIDs.

Author Biographies

V. Ye. Dobrova, National University of Pharmacy

Doctor of Pharmacy (Dr. habil), professor of the Department of Clinical Pharmacology and Clinical Pharmacy

O. S. Popov, National University of Pharmacy

Candidate of Medicine (Ph.D.), teaching assistant of the Department of Clinical Pharmacology and Clinical Pharmacy

S. V. Misiurova, National University of Pharmacy

Candidate of Pharmacy (Ph.D.), associate professor of the Department of Clinical Pharmacology and Clinical Pharmacy


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Laboratory diagnostics