Be. Gidal et al., RELATIONSHIP BETWEEN VALPROIC ACID DOSAGE, PLASMA-CONCENTRATION AND CLEARANCE IN ADULT MONOTHERAPY PATIENTS WITH EPILEPSY, Journal of clinical pharmacy and therapeutics, 20(4), 1995, pp. 215-219
Significant variability has been reported in the plasma concentration-
dose relationship for the anticonvulsant compound valproic acid (VPA).
Several factors may contribute to this observed variability, includin
g heterogeneous patient populations of children and adults, polytherap
y, and timing of plasma concentration sampling. To optimally determine
the relationship between trough VPA plasma concentration and dose, we
evaluated a homogeneous group of adult ambulatory patients with epile
psy receiving VPA monotherapy. Furthermore, we sought to evaluate whet
her a relationship existed between VPA dosage and plasma clearance for
both total and unbound or free drug. Steady-state trough plasma conce
ntrations were determined in thirty-two patients. Mean VPA dose was 22
.8 +/- 10.3 mg/kg/day. Mean total and unbound VPA plasma concentration
s were 97.9 +/- 34.9 and 13.2 +/- 10.6 mu g/ml, respectively, Signific
ant correlations between VPA dose and total and unbound plasma concent
rations were found (r = 0.82 and r = 0.85, P less than or equal to 0.0
01, respectively). Significant relationships were also observed betwee
n VPA dose and clearance. A positive correlation was noted for dose an
d total plasma clearance (r = 0.61, P less than or equal to 0.001), wh
ile an inverse correlation existed between dose and unbound VPA plasma
clearance (r = 0.51, P < 0.01). Although a statistically significant
correlation does exist between VPA dosage and both total and unbound p
lasma concentrations, significant interpatient variability still remai
ns even under 'optimal' therapeutic drug monitoring conditions.