What Is the Best Strategy for Converting from Twice-Daily Divalproex to a Once-Daily Divalproex ER Regimen? : Examinations and Answers via Computer Simulations.
OBJECTIVE
To examine if, during conversion from conventional divalproex to once-daily divalproex extended-release (ER) tablets, plasma valproic acid (VPA) concentrations in the first 48 hours after conversion are maintained within the accepted therapeutic range (50-100 mg/L).


METHODS
Four distinct 12-hourly (q12h) divalproex to once-daily divalproex ER conversion strategies were explored: immediate, delayed, stepwise and mixed conversion. These strategies were each used in simulations for hypothetical adult patients being treated under different conditions: monotherapy (uninduced, at 1500 mg/day divalproex ER) and polytherapy on enzyme-inducing co-medications (induced, at 3000 and 4500 mg/day divalproex ER).


RESULTS
The proportion of uninduced patients expected to have minimum VPA concentrations (C(min)) >50 mg/L was 90% for immediate, 83% for stepwise and 82% for mixed-conversion strategies; only 52% undergoing a delayed-conversion strategy had C(min) >50 mg/L. More importantly, 33% of induced patients under-going delayed conversion to 3000 mg/day divalproex ER maintained an adequate VPA C(min). Maximum VPA concentrations (C(max)) attained after conversion to divalproex ER are unlikely to rise beyond the steady-state C(max) observed with divalproex q12h regimens with any conversion strategy tested in uninduced or induced patients. Marked perturbation in VPA concentration is not likely when converting to once-daily divalproex ER 'all-at-once' 12 hours after the last divalproex q12h dose. Stepwise and mixed-conversion strategies do not offer any advantage; delayed conversion may produce a large drop in VPA concentration.


CONCLUSIONS
An ideal conversion strategy for q12h divalproex to once-daily divalproex ER appears to be an immediate conversion 12 hours after the last divalproex q12h dose; it causes the least perturbation in plasma VPA, even for patients required to take high divalproex ER doses.
Reed
Ronald C
RC
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois, USA.
Dutta
Sandeep
S