Ronald C. Reed

Distinct absorption characteristics of oral formulations of valproic acid/divalproex available in the United States

Five oral formulations of valproic acid (VPA)/divalproex sodium are approved and commonly used in the US for treatment of epilepsy, mania/bipolar disorder and migraine prophylaxis. These formulations have unique pharmacokinetic and formulation characteristics and are designed to treat distinct patient populations. We compared the absorption characteristics of all five oral VPA/divalproex formulations currently available in the US. Plasma VPA concentration-time profiles, following single oral dose (250mg) administration of five VPA/divalproex formulations under fasting conditions, from three pharmacokinetic studies in healthy subjects (N=9-15 each) were compared. The five VPA/divalproex formulations demonstrated marked absorption differences. The rate of absorption, as characterized by maximum concentration (C(max)) and time to C(max) (T(max)), may be rank-ordered as: VPA syrup (34.2mg/L, 0.9h)>VPA capsule (31.4mg/L, 2.2h)>divalproex sodium sprinkle capsule (20.7mg/L, 4.0h; lag-time congruent with1h) congruent withdivalproex sodium enteric-coated delayed-release tablet (26.0mg/L, 3.4h; lag-time congruent with2h)>divalproex sodium extended-release (divalproex-ER) tablet (11.8mg/L, 19.7h). Divalproex-ER had approximately 11% lower exposure (AUC). The comparable AUC across the five formulations, when corrected for bioavailability differences, demonstrates that formulation primarily affects the drug-release and in vivo absorption of VPA. Only divalproex-ER demonstrated true sustained-release characteristics.

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.

Comparative Absorption Profiles of Divalproex Sodium Delayed-Release versus Extended-Release Tablets—Clinical Implications

Background: The distinct absorption characteristics of the conventional enteric-coated, delayed-release (DR) and the novel extended-release (ER) divalproex sodium formulations are not well recognized. Objective: To quantitatively and qualitatively differentiate the absorption characteristics of divalproex-DR and -ER formulations. Methods: Healthy volunteers (N = 28) received single 1000 mg doses of divalproex-DR and divalproex-ER tablets in a crossover fashion. Noncompartmental and compartmental analyses were used to estimate valproic acid (VPA) pharmacokinetics from the plasma concentration–time profiles determined from intensive blood sampling over 48 hours. Results: VPA was not absorbed from divalproex-DR in the first 2 hours (absorption lag-time) after dosing. After VPA release in the intestine, approximately 63% of the dose was absorbed in less than 1 hour, that is, 2.9 hours (mean absorption time) from dosing. Maximum concentration (Cmax) was achieved approximately 4 hours after dosing. VPA absorption was complete (~93% of dose) within 3 absorption half-lives (~4.5 h) post-absorption lag-time, that is, 6–7 hours from dosing. In contrast, VPA absorption from divalproex-ER starts immediately after administration, initially at a modest rate, followed by slow and extended absorption at a constant rate for more than 20 hours; VPA concentrations at 1 and 2 hours were 28% and 40% of Cmax. Approximately 53% of the dose was absorbed within 12 hours (mean absorption time); complete absorption occurred over more than 20 hours without any dose dumping. Conclusions: When antihypertensive treatment options are clinically equivalent, prescribers may first consider using a verapamil SR–based strategy, especially in patients with CAD who have no history of depression. VPA absorption from enteric-coated divalproex-DR is rapid following a lag-time of approximately 2 hours and is complete within 6–7 hours of dosing. In contrast, VPA absorption from divalproex-ER starts immediately after administration, but occurs at a slow, approximately constant rate over more than 20 hours.

Once-daily dosing is appropriate for extended-release divalproex over a wide dose range, but not for enteric-coated, delayed-release divalproex: Evidence via computer simulations and implications for epilepsy therapy

Divalproex sodium extended-release (divalproex-ER), administered once-daily, maintains plasma valproic acid (VPA) concentrations for 24h, whereas enteric-coated, delayed-release divalproex sodium (divalproex) requires multiple-daily doses to do the same. We hypothesize that a once-daily divalproex regimen should not be administered to epilepsy patients requiring high total daily doses, e.g., 35.6-56 mg/kg/day, due to the potential for high (>125 mg/L) maximum VPA concentrations (C(max)). We examined the impact of once-daily dosing, divalproex vs. divalproex-ER, on steady-state plasma VPA concentration-time profiles at commonly used doses in monotherapy (uninduced) and polytherapy (hepatic enzyme-induced) virtual adult patients. Only the 1125 mg once-daily divalproex dose had mean C(max)<100mg/L; >or=2000 mg produced mean C(max)>or=125 mg/L. Mean divalproex C(min) was approximately 50 mg/L at two of four doses tested, whereas mean ER C(min) was >73 mg/L at all doses tested. Once-daily divalproex peak-trough fluctuation was 4.4-6.2-fold greater than once-daily divalproex-ER. We predict that excursions beyond the conventional recommended VPA plasma concentration range will commonly occur with high total mg daily doses (>or=2000 mg) of enteric-coated divalproex, if dosed once-daily, potentially producing clinical toxicity. This divalproex formulation should not be dosed once-daily at high total mg daily doses due to this risk. Divalproex-ER is the appropriate formulation for administration on a once-daily basis, especially if large total mg/day doses are required for the control of seizure activity.

A Multiphasic Absorption Model Best Characterizes Gastrointestinal Absorption of Divalproex Sodium Extended‐Release Tablets

D sodium extended-release (divalproex-ER) tablet is a novel once-daily formulation that offers the potential advantages of improved medication adherence, increased patient convenience, and easier titration to maximum effective dose while possibly reducing the risk of side effects (by reducing peaktrough fluctuations in plasma concentrations). Divalproex-ER is based on hydrophilic matrix technology; drug release is controlled primarily by erosion of a water-soluble polymer (hydroxypropylmethyl cellulose) from the matrix. We have previously quantified the mean input absorption rate parameter value for valproic acid (VPA) from orally administered divalproex-ER as 0.0431 mg/h/mg dose, representing a pseudo zero-order absorption rate from this formulation. Closer inspection of this VPA absorption profile from divalproex-ER revealed that our characterization could be optimized. In particular, we needed to distinguish this formulation’s true absorption characteristics that cannot be characterized by simple absorption models (eg, firstand zero-order) and several atypical absorption models (mixed zeroand first-order, Weibull function, timeand/or gastrointestinal [GI]-location-dependent, exponential, and several other absorption models) that have been proposed for other drugs or formulations. The purpose of this investigation was to expand our initial observations and more fully characterize, using a unique model, the absorption characteristics and single-dose pharmacokinetics of divalproex-ER tablets.

Does It Really Matter When a Blood Sample for Valproic Acid Concentration is Taken Following Once-daily Administration of Divalproex-er?

Divalproex sodium extended-release (divalproex-ER) is a novel formulation intended for once-daily oral administration, either morning or evening. Questions have risen concerning the optimal time for obtaining a blood sample for valproic acid (VPA) concentration in relation to the dose. Trough sampling is easily achieved just before a morning daily dose, but the best time to sample after an evening daily dose is unclear, because collecting a blood sample 21 to 24 hours later may be limited by the operational hours of the laboratory. This investigation provides practical guidance regarding blood sample timing. Steady-state plasma VPA concentration-time profiles from 5 published divalproex-ER studies (healthy subjects and epilepsy patients) were analyzed. The concentration-time profile for each subject/patient was expressed as a percentage of his/her trough concentration and summary statistics computed. Typically, when taking divalproex-ER once daily in the morning, a blood sample collected 21 to 24 hours later is expected to have a concentration within 3% of the trough value. Conversely, for divalproex-ER dosed once-daily in the evening, for example 8 PM, a blood draw 12 to 15 hours later (ie, 8 to 11 AM) will give a plasma VPA concentration value that is 18% to 25% higher, on average, than the trough value. However, waiting longer, (for example 18 to 21 hours, ie 2 to 5 PM) will result in concentration values that are merely 3% to 13% higher than trough values, which may provide acceptable information for monitoring purposes. The greatest deviation from trough VPA concentration occurs around the peak, that is 3 to 15 hours after a once-daily divalproex-ER dose; sampling during this time period is recommended only if a clinical need exists to test for a higher VPA concentration. Despite the apparent smoothness of the VPA concentration-time profile after a once-daily divalproex-ER dose, the timing of the blood sample does matter and impacts the proper interpretation of the VPA concentration.

Comment from Dorothée G.A. Kasteleijn-Nolst Trenité, Edouard Hirsch, Ronald C. Reed, Bassel Abou-Khalil, and Bernd Schmidt on: How predictive are photosensitive epilepsy models as proof of principle trials for epilepsy?

In this interesting paper, the authors have successfully quantified the predictive capabilities of the single-blind, Phase IIa photosensitivity model. Most importantly, their conclusion stresses that potential AEDs showing suppression of the pathological generalized epileptogenic reaction to Intermittent Photic Stimulation (IPS) also show efficacy in phase III double-blind placebo-controlled AED trials of both partial and generalized epilepsies. This is not surprising since photosensitivity (the photoparoxysmal EEG response, PPR) can occur in all different types of epilepsies. We would, however, like to put two main issues that are addressed in the Discussion section into a broader perspective and give advice for future proof of principle (PoP) intrapatient photosensitivity studies based on what we have learned so far from all trials, including those referred to by Yuen and Sims.