Every-12-hour administration of extended-release divalproex in patients with epilepsy: impact on plasma valproic acid concentrations.
Extended-release divalproex sodium (divalproex-ER) biopharmaceutics after every-12-hour (q12h) administration was compared with that of once-daily divalproex-ER and conventional divalproex given every 6 hours (q6h) in a multiple-dose (14-day), randomized, three-period crossover design study in 24 patients with epilepsy concomitantly receiving enzyme-inducing antiepileptic medication(s). Plasma valproic acid (VPA) minimum concentration (Cmin) for divalproex-ER q12h was higher than the once-daily divalproex-ER Cmin (P=0.043). Once-daily divalproex-ER Cmin values were not different from those for divalproex q6h, suggesting that adequate trough steady-state concentrations are maintained with once daily dosing, despite enzyme-inducing comedication. The degree of peak-trough fluctuation (DFL, calculated as (Cmax-Cmin)/Cavg) in VPA concentration was less with both q12h (35.2% less) and once-daily (16.9% less) divalproex-ER regimens compared with q6h divalproex (P0.024). The DFL for divalproex-ER dosed as a q12h regimen was 22% less than that for once-daily divalproex-ER (P=0.02). The DFL in VPA concentration with divalproex-ER can be minimized with once-daily administration and more so with q12h administration, compared with conventional enteric-coated divalproex taken q6h.
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. ronald.reed@abbott.com
Ronald C
RC
Reed
Sandeep
S
Dutta
John H
JH
Cavanaugh
Charles
C
Locke
G Richard
GR
Granneman
D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D001682:Biological Availability; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D013810:Therapeutic Equivalency; D014635:Valproic Acid / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics
D000927:Anticonvulsants; D003692:Delayed-Action Preparations; D014635:Valproic Acid