Divalproex Conversion: 1000mg BID to Extended-Release Dosing
When converting from divalproex 1000mg BID (2000mg total daily dose) to divalproex extended-release (ER) taken once nightly, increase the total daily dose by 8-20% to compensate for the lower bioavailability of the ER formulation, which means using 2250mg ER once daily at night. 1, 2
Dose Calculation and Rationale
The 8-20% Increase Requirement
- The extended-release formulation has approximately 89% bioavailability compared to the delayed-release formulation, requiring a dose increase of approximately 12% (calculated as 1.0/0.89) to achieve comparable plasma exposure 2
- Since ER dosage strengths (250mg and 500mg tablets) don't allow for exact 12% increments, an 8-20% higher daily dose should be used when converting 1, 2, 3
- For your current 2000mg total daily dose, an 8-20% increase translates to 2160-2400mg daily 1, 2
Practical Dosing Recommendation
- Use 2250mg ER once daily (nine 250mg tablets or four 500mg + one 250mg tablet), which represents a 12.5% increase and falls within the recommended 8-20% range 1, 2, 3
- This dose achieves equivalent 24-hour area under the curve (AUC) exposure compared to your current 1000mg BID regimen 1, 2, 3
Pharmacokinetic Advantages of ER Formulation
Concentration Profile Benefits
- ER formulation produces 42-48% lower peak-to-trough fluctuation in valproic acid plasma concentrations compared to the delayed-release formulation 3
- Maximum concentration (Cmax) is significantly lower with ER (approximately 21% lower), reducing risk of concentration-related adverse effects 2, 3
- Minimum concentration (Cmin) is maintained at comparable or slightly higher levels, preserving therapeutic efficacy 2, 3
Monitoring Considerations
- When dosing ER once nightly (e.g., 8 PM), blood samples drawn 12-15 hours later (8-11 AM) will show concentrations 18-25% higher than true trough values 4
- For accurate trough monitoring with evening dosing, wait 18-21 hours after the dose (2-5 PM blood draw), which yields values only 3-13% above trough 4
- The predose trough concentration with ER consistently represents the lowest concentration during the dosing interval, unlike delayed-release formulations where absorption lag time and multiple daily doses complicate interpretation 1
Important Clinical Considerations
Common Pitfalls to Avoid
- Do not use equal total daily doses when converting to ER—this results in only 89% bioavailability and subtherapeutic exposure 1, 2
- Avoid blood sampling 3-15 hours after an ER dose, as this captures peak concentrations that are not representative of steady-state trough levels 4
- The ER formulation's lower bioavailability is consistent across different meal conditions and prior dosing frequencies of delayed-release formulation 2
Expected Clinical Benefits
- Once-daily dosing improves medication adherence compared to twice-daily regimens 1
- Lower peak concentrations may reduce dose-related adverse effects such as tremor, sedation, and gastrointestinal symptoms 1, 3
- More stable plasma concentrations throughout the 24-hour period provide consistent therapeutic effect 1, 3