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Keywords:

  • dissolution;
  • steady-state serum concentration;
  • sustained-release formulation;
  • valproic acid

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Abstract  Recently a new sustained-release formulation of valproic acid has been developed in Japan. The sustained-release mechanism of the new formulation was different from the conventional formulation. The aim of the present study was to compare the pharmacokinetic characteristics of valproic acid in two sustained-release formulations. Different sustained-release formulations of valproic acid (Depakene R and Selenica R) were administered in a randomized cross-over fashion in repeated doses in 24 psychiatric patients. After ≥4 weeks administration of valproic acid once daily, blood samples were taken just before (0 h) and 8, 12, 24 h after the morning dose. Blood sampling was performed in the same manner in the same patients 4 weeks after switching from one to the other formulation of valproic acid. Serum concentrations of valproic acid at 0 h (50.7 ± 19.4 vs 44.9 ± 21.8 μg/mL, P < 0.05) and 24 h (52.3 ± 19.54 vs 6.2 ± 22.2 μg/mL, P < 0.05) were significantly higher during Selenica R than during Depakene R treatment, whereas the serum concentration of valproic acid at 8 h (49.7 ± 19.2 vs 62.4 ± 25.6 μg/mL, P < 0.01) was significantly lower during Selenica R treatment than during Depakene R treatment. Serum concentrations of valproic acid at 12 h were not different. The present study demonstrated that steady-state serum concentrations were different because of the different dissolution profiles. When a prescription for valproic acid is switched from one drug to the other, prescribers should be aware that the therapeutic drug monitoring data are not consistent.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Successful long-term treatment of patients with epilepsy requires selection of an appropriate anti-epileptic regimen, optimal dosing and patient compliance.1 Recent advances in the choice of treatment options are transforming the global management of these patients.1 Although the achievement of seizure freedom remains the primary goal of any anti-epileptic treatment, issues associated with drug acceptability and tolerability, and with quality of life have gained increasing attention as major determinants of ultimate therapeutic success.1,2 Sustained-release formulations of anti-epileptic drugs can be very helpful in achieving treatment objectives. Stable serum levels without marked peak-to-trough fluctuations, reduced frequency of dosing and the possibility of dosing flexibility may all improve compliance, patient satisfaction and ultimately quality of life.3–5

Valproic acid has been widely used in the last decade and is now considered a relatively safe and effective anticonvulsant agent.6 Recently, several investigators have proposed its use in the treatment of anxiety, alcoholism and mood disorders.7,8 Valproic acid is characterized by dose-limited absorption, non-linear plasma protein binding, and multiple metabolic pathways of elimination.6,9,10 Once absorbed, valproic acid is largely bound to plasma proteins and has a relatively small volume of distribution. Its concentration incerebrospinal fluid is approximately one-tenth that in plasma and is directly correlated with the concentration found in tears.10 At therapeutic doses, valproic acid half-life varies from 10 to 20 h in adults, while it is significantly shorter (6–9 h) in children.6,10 Valproic acid undergoes extensive liver metabolism.10,11 Numerous metabolites have been positively identified and there is reasonable evidence that several of them contribute to its pharmacological and toxic actions.10,11

Valproic acid is available in different dosage forms for parenteral and oral use. All available oral formulations are almost completely bioavailable, but they differ in dissolution characteristics and absorption rates. The sustained-release formulation (Depakene R, Kyowa Hakko Kogyo Co. Ltd, Tokyo, Japan) can therefore be given once or twice daily.12,13 The tablet core consists of a matrix structure that is covered with the sustained-released membrane. The elution of valproic acid is controlled as the substance passes through the core of the matrix structure and further through the sustained-released membrane (Fig. 1).

image

Figure 1. Cross-section of the slow-release Depakene R and Selenica R tablets.

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Recently another sustained-release formulation containing 200 mg valproic acid (Selenica R, Nikken Chemicals Co. Ltd, Tokyo, Japan) has been developed and available in Japan.14 Selenica R has a double-coating system that provides a mechanism that is different from the conventional sustained-release formulation (Fig. 1). We therefore compared the pharmacokinetic parameters in two formulations of valproic acid in psychiatric patients.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

The Ethics Committee of Hirosaki University School of Medicine approved this study protocol, and written informed consent was been obtained from each participant before any examinations.

The subjects were 24 patients (15 male, nine female) receiving valproic acid, who were diagnosed as having bipolar disorders and schizophrenia. The mean (and range) of age and bodyweight were 51 years (21–68 years) and 58 kg (38–98 kg), respectively. Twelve patients received valproic acid at 08.00 hours in the conventional sustained-release formulation, Depakene R, for at least 4 weeks, and the other 12 patients received the valproic acid at 08.00 hours in the new sustained-release formulation, Selenica R for at least 4 weeks. Co-administered medications were as follows: risperidone (n = 10), olanzapine (n = 8), haloperidol (n = 4), zotepine (n = 3), levomepromadine (n = 3), lithium (n = 2), flunitrazepam (n = 12), brotizolam (n = 8), diazepam (n = 5), biperiden (n = 7), and sennoside (n = 13). These medications were fixed throughout the study period. After ≥4 weeks of administration, blood sampling (5 mL each) was performed just before and 8, 12 and 24 h after administration. The sustained-release formulation of valproic acid administered to the patients was switched to the other type. Four weeks after the switching, blood sampling (5 mL each) was performed in the same way. Clinical global impression (CGI) score for patient psychiatric condition was monitored at blood sampling.15 There was no difference between administration days of Depakene R and Selenica R.

The serum samples were frozen and kept at −20°C until analysis. Serum concentrations of valproic acid were quantified with enzyme immunoassay (EIA). The detection limit was 1.0 μg/mL. The inter- and intra-assay coefficient of variation (CV) for plasma concentrations of valproic acid were <5.5% for all quality control concentrations.

Pharmacokinetic parameters were determined on a non-compartment model with WinNonLin software (Pharsight, Cary, NC, USA). Apparent volume of distribution (Vd/F), absorption constant (Ka), elimination constant (Ke), lag time (Tlag) were calculated as first parameters. Area under the drug concentration–time curve (AUC), apparent clearance (CL/F), time to peak concentration (Tmax), peak concentration (Cmax), peak concentration at steady state (Cssmax) and minimum concentration at steady state (Cssmin) were estimated as second parameters.

Statistical analysis was performed by the use of repeated measures of anova in SPSS (SPSS, Chicago, IL, USA). Post-hoc analysis was done using Bonferroni correction with paired t-test. All tests were two-tailed and were considered to be statistically significant for < 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

There were no patients who had an adverse event after switching valproic acid formulation. Daily change in serum concentration of valproic acid during treatments with Depakene R and Selenica R are shown in Fig. 2. Serum concentrations of valproic acid at 0 h (44.9 ± 21.8 vs 50.7 ± 19.4 μg/mL, P < 0.05) and 24 h (46.2 ± 22.2 vs 52.3 ± 19.5 μg/mL, P < 0.05) during Depakene R treatment were significantly lower than those during Selenica R treatment (Fig. 2). Serum concentration of valproic acid at 8 h (62.4 ± 25.6 vs 49.7 ± 19.2 μg/mL, P < 0.01) during Depakene R treatment was significantly higher than the concentration during Selenica R treatment (Fig. 2). However, no difference was found in steady-state serum concentration of valproic acid at 12 h (62.4 ± 25.6 vs 49.7 ± 19.2 μg/mL, n.s.; Fig. 2).

image

Figure 2. Steady-state serum concentration–time curves after repeated oral doses of Depakene R and Selenica R. Error bars indicate SD. (○), Depakene R; (●), Selenica R. *P < 0.05, **P < 0.01.

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The results of pharmacokinetics parameters simulated by the Pharmacokinetic Analysis program (WinNonLin) are shown in Table 1. The Tlag (1.3 ± 1.4 vs 6.8 ± 1.6 h, P < 0.001) and Tmax (9.4 ± 2.2 vs 15.8 ± 2.1 h, P < 0.001) during Selenica R treatment were significantly later than during Depakene R treatment. No difference in the estimated Cssmax and Cssmin were found between the two formulations (Table 1).

Table 1.  Estimated pharmacokinetic parameters in patients receiving repeated doses of valproate in two sustained-release formulations (n = 24)
ParametersDepakene R (mean ± SD)Selenica R (mean ± SD)P
  1. AUC (0–∞), area under the curve from 0 to infinity; Cl/F, apparent total clearance; Cmax, peak concentration; Cssmax, peak concentration in the steady state; Cssmin, trough concentration in the steady state; Ka, absorption constant; Ke, elimination constant; Tlag, lag time; tmax, time to peak concentration in serum; Vd/F, apparent volume of distribution.

Vd/F (L)5.45 ± 0.597.22 ± 2.14<0.01
Ka (1/h)0.092 ± 0.0630.068 ± 0.026<0.05
Ke (1/h)0.075 ± 0.0220.073 ± 0.026NS
T lag (h)1.3 ± 1.46.8 ± 1.6<0.001
AUC (h·μg/mL)1334 ± 5311305 ± 467NS
CL/F (L/h)0.50 ± 0.320.49 ± 0.26NS
Tmax (h)9.4 ± 2.215.8 ± 2.1<0.001
Cmax (μg/mL)43 ± 2346 ± 19NS
Cssmax (μg/mL)65 ± 2060 ± 20NS
Cssmin (μg/mL)35 ± 1231 ± 11NS

There was no difference in CGI scores between Depakene R and Selenica R (3.9 ± 1.2 vs 4.0 ± 1.3, n.s.).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Bioequivalence is an important component of the development of anti-epileptic drugs.16 Development of new formulations after the original testing of any drug requires demonstration that the compounds are therapeutically equivalent and additional efficacy studies may not be required. Sustained-release formulations may reduce toxicity with a lower maximum blood concentration (Cmax) and improve efficacy with a higher minimum blood concentration (Cmin). Obtaining an equivalent AUC while slowing gastrointestinal transit and avoiding food effects and dose dumping among a population with epilepsy with individual variability requires extensive engineering of the formulation.16

The results of the preliminary study using a single oral dose showed no differences in Cmax or AUC of valproic acid between the new and conventional formulations,17 suggesting that these two formulations are bioequivalent. However, absorption speed, that is, Tlag, and hence Tmax were very different between the two formulations in the single oral dose study. These findings suggest that valproic acid dissolved from the Depakene R tablet appears earlier in the blood and brain than that from the Selenica R tablet. Thesefindings resulted from the different mechanisms of the sustained release between Depakene R and Selenica R, namely, the elution of valproic acid in Depakene R is controlled in such a way that the substance passes through the core of a matrix structure and further through the sustained-released membrane, while Selenica R has a mixed membrane composed of ethylcellulose and methacrylate copolymer-l (Fig. 1).14

The result of a repeated-dose study in psychiatric patients showed significant differences in steady-state serum concentration of valproic acid at 0, 8 or 24 h after administration. Steady-state serum concentrations at 0 and 24 h during Selenica R were higher than those during Depakene R, while the steady-state serum concentration at 8 h during Selenica R was lower than during Depakene R. The difference may be explained by the difference in Tlag, and hence Tmax, observed in the single-dose study and the difference in dissolution. As a result, the fluctuation of serum valproic acid concentration in the steady state during Selenica R is shifted to 5–6 h later compared with Depakene R. Because blood sampling for therapeutic drug monitoring (TDM) of valproic acid is generally recommended just before administration, previous therapeutic drug monitoring data are not available when a sustained-release preparation is switched to another formulation. Simulation curve of serum concentration of valproic acid in the steady state including Cssmax and Cssmin from 1-point sampling data should be available for TDM.

In contrast, no changes in the mental status of psychiatric patients were observed between Selenica R treatment and Depakene R treatment in the present study. This is explained by similar exposure (AUC) in the two formulations. Thus, when a sustained-release preparation is switched to another formulation, the inconsistency of TDM data does not necessarily mean alternation in clinical response.

Many medications were concomitantly administered with valproic acid in Selenica R and Depakene R formulations. However, it is unlikely that the difference in the two formulations led to the significant difference in the results of the present study because co-administered medications were fixed throughout the study period.

Steady-state serum concentrations of valproic acid in the present study were slightly lower than the therapeutic concentration for epilepsy. If doses are escalated up to therapeutic levels, we concluded that the significant difference of TDM data does not necessarily mean alternation in clinical response, because the drug Cssmax or exposure (AUC) in the two formulations probably associated with pharmacodynamic action are not different.

In order to improve compliance, a small tablet is preferable for patients, particularly for children. The size of the current commercial once-a-day controlled-release tablet is as follows: Depakote Tablet (Abbott Laboratories, Abbott Park, IL, USA; containing 500 mg divalproex sodium), 0.9 × 1.9 cm, 1.0 g; Depakene R 200 mg Tablet, 0.66 × 1.06 cm, 0.52 g; and Selenica R 200 mg Tablet, 0.50 × 0.92 cm, 0.25 g. From the point of view of easy swallowing, Selenica R Tablet may have the advantage.

In conclusion, the present study demonstrated that steady-state serum concentrations of valproic acid were different because of the different dissolution profiles. When drug prescription for valproic acid is switched from one drug to the other, prescribers should know that TDM data are not consistent.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

None of the authors and their institutes has any conflicts of interest. This study was supported by a grant from the Hirosaki Research Institute for Neurosciences, Health and Labour Sciences Research Grants (Research on Psychiatric and Neurological Diseases and Mental Health) (H18-kokoro-002) and Grants-in-Aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology (18591270 and 16109006).

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES
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