Therapeutic Drug Monitoring of Valproic Acid in Patients with Monotherapy at Steady State

Document Type : Original Article


1 Department of Neurology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Pharmacodinamy & Toxicology, Pharmaceutical Research Center & School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Medicinal Chemistry, Pharmaceutical Research Center & School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

4 Department of Psychiatry, Faculty of Medicine, Psychiatric Research Center, Ebn-sina Hospital, Mashhad University of Medical Sciences, Mashhad, Iran


The role of therapeutic drug monitoring (TDM) in patient care has grown rapidly since its introduction three decades ago. The aim of present study was to evaluate the possible relationship between serum levels and the clinical response of valproic acid (VPA).
Materials and Methods
In the present study we evaluated a homogeneous group of adult patients receiving VPA monotherapy. A total of 18 epileptic patients who fulfilled inclusion and exclusion criteria were entered this prospective study. Steady state trough plasma concentration was determined by fluorescence polarization immunoassay (FPIA). The correlation between therapeutic response and VPA serum concentration was evaluated.
Mean VPA dose and mean total VPA plasma concentrations were 8.35±1.49 mg/kg/day and 50.40±4.18 pg/ml respectively. Mean VPA clearance was 8.84±4.43 (ml/kg/h). Plasma levels within the therapeutic range were found in 33% of epileptic patients. Plasma levels were below the therapeutic range in 67% of study population. Of patients 75% and 17% with sub-therapeutic levels achieved complete control and partial control respectively.
Poor correlation was found between the plasma concentration of VPA and its therapeutic effects. Therefore, this study showed that TDM of VPA will be useful only when individuals are non-responsive to treatment or vulnerable to adverse reactions with standard doses.


1.Joerger M, Schellens JH, Beijnen JH. Therapeutic drug monitoring of non-anticancer drugs in cancer patients. Methods Find Exp Clin Pharmacol 2004; 26:531-545.
2.Eilers R. Therapeutic drug monitoring for the treatment of psychiatric disorders. Clinical use and cost effectiveness. Clin Pharmacokinet 1995; 29:442-450.
3.Reith DM, Andrews J, McLaughlin D. Valproic acid has temporal variability in urinary clearance of metabolites. Chronobiol Int 2001; 18:123-129.
4.Evans WE, Schentag JJ, Jasko WJ. Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. 3rd ed. Lippincott Williams & Wilkins; 1992.
5.DeVane CL. Pharmacokinetics, drug interactions, and tolerability of valproate. Psychopharmacol Bull 2003; 37:25-42.
6.Lagace DC, O'Brien WT, Gurvich N, Nachtigal MW, Klein PS. Valproic acid: How it works. Or not. Clin Neurosci Res 2004; 4:215-225.
7.Fattore C, Messina S, Battino D, Croci D, Mamoli D, Perucca E. The influence of old age and enzyme inducing comedication on the pharmacokinetics of valproic acid at steady-state: A case-matched evaluation based on therapeutic drug monitoring data. Epilepsy Res 2006; 70:153-160.
8.Jiang Z, Zhang J, Liao HM, Tang JW, Peng QL. Influence of age, body weight and dose on sodium valproate plasma concentrations in children with epilepsy. Zhongguo Dang Dai Er Ke Za Zhi 2008; 10:325-328.
9.Perucca E, Aldenkamp A, Tallis R, Kramer G. Role of valproate across the ages. Treatment of epilepsy in the elderly. Acta Neurol Scand Suppl 2006; 184:28-37.
10.Sharma S, Joshi S, Mukherji S, Bala K, Tripathi CB.Therapeutic Drug Monitoring: Appropriateness and Clinical Utility in Neuropsychiatry Practice. Am J Ther 2008 (In Press).
11.Gidal BE, Pitterle ME, Spencer NW, Maly MM. Relationship between valproic acid dosage, plasma concentration and clearance in adult monotherapy patients with epilepsy. J Clin Pharm Ther 1995; 20:215-519.