A Theoretical Method for Normalizing Total Serum Valproic Acid Concentration in Hypoalbuminemic Patients

Abstract

Abstract. In patients with hypoalbuminemia, the total serum concentration of valproic acid may offer poor clinical information; however, very few clinical laboratories routinely analyze the free concentration of the drug. The aim of this study was to design a procedure to normalize the total concentration of valproic acid according to the level of serum albumin and using previously published free fraction values. In 121 adult patients, with albumin levels of 18 -41 g / L, the total concentration of valproic acid was normalized using the derived equation: C N = a H C H / 6.5, where a H is the free fraction of the drug corresponding to the patient's particular albuminemia and C H is the total concentration of valproic acid. The value of 6.5 corresponds to the free fraction of the drug for a serum albumin of 42 g / L (percentile 50 of the reference range). For total concentrations lower than 75 mg / L, the predicted normalized valproic acid concentrations were reasonably concordant with the observed normalized concentrations calculated using the data from a protein-binding study. In a significant number of cases, subtherapeutic concentrations of the drug became therapeutic and even supratherapeutic when corrected according to the albumin levels. Furthermore, cases with therapeutic drug concentrations frequently became supratherapeutic when normalized. The limitations and clinical aplications of the proposed formula for normalizing the total concentration of valproic acid are presented. It is concluded that it may be useful for the posological management of hypoalbuminemic patients when the free concentration of the drug is not available, and decisions have to be made based on the total serum concentration.

Impact of Hypoalbuminemia on Voriconazole Pharmacokinetics in Critically Ill Adult Patients

“…Similar formulas were developed previously to estimate unbound concentrations of phenytoin and valproic acid, two antiepileptic drugs with high PPB (above 70%) based on plasma albumin concentrations (27,28), as total measured plasma concentrations could not always explain adverse events seen in patients (37)(38)(39)(40)(41).…”

“…However, in these studies, the drugs that were the subject of debate were mostly drugs with linear pharmacokinetics. The influence of hypoalbuminemia on protein binding characteristics of antimicrobial agents was demonstrated in critically ill patients (15,16) for highly protein-bound drugs (PPB above 70%) (16) such as ceftriaxone (PPB, Ϯ95%) (19), flucloxacilline (PPB, above 90%) (15), carbamazepine (PPB, 70% to 80%) (54), phenytoin (PPB, Ϯ90%) (28,55,56), and valproic acid (PPB, 80% to 90%) (27,57). For drugs with low to moderate PPB (30 to 70%) and linear pharmacokinetics, changes in PPB have little consequence in clinical practice, as small increases in unbound drug concentrations are immediately metabolized and eliminated (16).…”

“…These formulae are applied in daily clinical practice, the formula for valproic acid being the Hermida Tutor formula (27) and that for phenytoin being the Sheiner Tozer or Winter-Tozer formula (28,29), as both drugs are characterized by high PPB and saturated metabolism. This renders patients with hypoalbuminemia prone to toxicity even with total measured concentrations within the reference interval (30).…”

Non-convulsive status epilepticus in adults - an overview

“…The substance leads to the production of ammonia (sometimes dramatically exacerbated by the presence of a mitochondrial urea-cycle enzyme defect like ornithyl-carbamoyl-transferase deficiency) which should be closely controlled after fast loading; levels of ammonia up to 70 μmol (normal 7-34) usually were well tolerated, whereas levels >90 μmol may lead to substantial obtundation which warrants for a dose reduction [239][240][241]. During i/v therapy for SE, levels of free (unbound) VPA should be monitored, because this fraction (normally 10-15%) rises overproportionally in the case of high doses and hypoalbuminaemia [242,243] and may induce toxicity (sedation, elevated liver enzymes, low platetelet count, reversible parkinsonism, pancreatitis) [244][245][246]. The use of VPA in patients with intracranial bleedings is questionable because of the various effects of VPA on platelet number and function as well as on several clotting factors [247,248].…”

Determinación del nivel de dosis del ácido valproico e influencia de los fármacos inductores y no inductores enzimáticos en pacientes voluntarios de la ciudad de Mérida, Venezuela

“…Se menciona que existe una escasa correlación entre la dosis administrada y las concentraciones séricas del ácido valproico debido a su elevada unión a las proteínas plasmáticas, por lo que los cambios en la fracción libre del fármaco no son proporcionales al aumento de la dosis (16) . Hermida y Tutor proponen en pacientes con hipoalbuminemia el empleo de una ecuación para determinar la fracción libre del ácido valproico (H): Hα = Concentración libre (CF)/ Concentración total del fármaco (CH) (22) . Hay medicamentos que desplazan al valproato de su unión proteica, lo que lleva a un aumento de la fracción libre del fármaco e incluso un cambio de las vías metabólicas del valproato (9) .…”