[Slow release versus immediate release oxcarbazepine in difficult-to-treat focal epilepsy: a multicenter, randomized, open, controlled, parallel group phase III study]. / Retardiertes vs. schnell freisetzendes Oxcarbazepin bei therapierefraktärer fokaler Epilepsie : Eine offene multizentrische, randomisierte kontrollierte Studie.

BACKGROUND: The aim of the study was an assessment of the tolerability and efficacy of slow release oxcarbazepine (OXC-MR) versus immediate release OXC (OXC-IR) after forced titration in patients with focal epileptic seizures with and without secondary generalization who had previously not become seizure-free under OXC-IR with or without concomitant antiepileptic drugs. The primary study variable was to assess the maximum tolerated dosage with OXC-MR and OXC-IR. PATIENTS AND METHODS: This was designed as a multicenter, randomized, open, controlled, parallel group phase III study. After randomization patients received OXC-MR or OXC-IR for a study period of 26 days. The initial dosage of 900 mg, 1,200 mg or 1,500 mg OXC was increased every 5 days by 300 mg up to a maximum daily dosage of 2,700 mg. In cases of intolerable adverse events dosage could be reduced by 150 mg 2 days after an increase. Adverse events and executive abilities were assessed with the questionnaire "Adverse Event Profile plus" and with the Epitrack® test protocol. Serum concentrations of OXC and its active metabolite were measured in a part of the patient group. RESULTS: The 71 patients (54% male, age: 19-70 years) enrolled in the study were randomized. The maximum mean daily OXC dosage at the end of the study period was 1,950 mg with OXC-MR and thus statistically significantly higher than in OXC-IR group (1,650 mg, p = 0.022). The number of causally related adverse events was lower in the OXC-MR group (n = 104 versus n = 138 with OXC-IR) and CNS-related adverse events such as dizziness, tremor, somnolence and headache occurred significantly less often with OXC-MR (OXC-MR 65.7%, OXC-IR 88.9%, p = 0.01). Fluctuations of serum concentrations of the active metabolite were less pronounced under the OXC-MR regimen. CONCLUSIONS: Due to better tolerability OXC-MR allowed higher maintenance dosages to be reached than OXC-IR. In spite of a higher mean daily dosage adverse events and especially CNS-related adverse events occurred less often than with OXC-IR.

Pharmacokinetic characteristics of a new multiple unit sustained release formulation of sodium valproate.

AIM: Two bioavailability studies were conducted in healthy male volunteers to determine the absorption characteristics of a new dosage form of sodium valproate consisting of sustained release pellets in a hard gelatine capsule. SUBJECTS, MATERIAL AND METHODS: To obtain first data on the in vivo behavior of the new multiple unit formulation a single dose pilot study in comparison with an oral solution was performed in 6 volunteers. Following the pilot study the pharmacokinetics were investigated versus a conventional enteric-coated tablet after multiple dosing in 18 volunteers. The volunteers were administered either a single or multiple dose of 300 mg sodium valproate. In both studies a wash-out period of at least 1 week elapsed between the periods. Valproic acid was determined from serum by gas chromatography at intervals suitable for obtaining concentration time curves for both regimens. RESULTS: The results of the pilot study showed that the valproate concentration in serum following administration of the new sustained release capsule increased smoothly and a longer lasting plateau was observed as compared with the solution. The average maximum serum valproate concentration of 12.5 microg/ml (sustained release capsule) and 24.3 microg/ml (solution) appeared at 9.3 h and 0.58 h after dosing. The extent of valproate absorption as reflected in the AUC data for each formulation was equivalent for the new sustained release capsule and reference formulation (AUC0-infinity: 369 +/- 88.9 and 339 +/- 76.2 microg/ml x h). Data obtained after multiple dose administration provided an indication of the consistency of valproate absorption from each dosage form. The time concentration profiles following twice daily administration of 300 mg sodium valproate in the multiple dose study showed that the extent parameters for absorption of valproate (AUC(8tau9tau) = 842 +/- 166 microg/ml x h) are equivalent with the enteric-coated preparation (AUC(8tau9tau) = 823 +/- 139 microg/ml x h). However, the fluctuation of the new sustained release formulation (PTF(8tau9tau) = 0.33 +/- 0.09) is about only one third of the fluctuation observed with the enteric-coated formulation (PTF(8tau9tau) = 0.88 +/- 0.22) when administered twice daily. CONCLUSION: These data indicate that the new sustained release capsule possesses desirable absorption characteristics in a form that allows twice daily or even once daily dosing and therefore improves patient compliance.

Study on the dose proportionality of the pharmacokinetics of sustained release sodium valproate.

OBJECTIVE: A bioavailability study using three different doses was designed to assess the dose proportionality of a new multiple-unit sustained release formulation of sodium valproate. SUBIECTS AND METHODS: The study was performed using an open, three-period, randomized, crossover design. Twelve healthy male volunteers received on three occasions single oral doses of either 100 mg, 150 mg and 300 mg of a sustained release sodium valproate formulation. A wash-out period of at least 7 days elapsed between the administrations. Valproic acid was determined in serum by gas chromatography with flame-ionization detector. RESULTS: After administration of single doses of 100 mg, 150 mg and 300 mg sodium valproate the population mean curves reached their maxima of 4.3 microg/ml, 6.8 microg/ml and 12.8 microg/ml at 9 h, 9 h and 10 h, respectively. The geometric means of AUC0-tz and AUC0-infinity as well as Cmax related to each other approximately according to the expected ratios of 0.33:0.5:1. Point estimates and 90% confidence intervals for the ratios of geometric means of dose-normalized parameters (AUC0-tz, AUC0-infinity, Cmax) were included by the acceptance range of 80-125%. There were no differences in tmax as shown by the inclusion of zero in the 90% confidence interval for the median difference in tmax between the doses. CONCLUSION: Parameters determining the extent and rate of absorption (AUC and Cmax) increased proportionally with the dose of the new sustained release sodium valproate formulation. This pharmacokinetic behavior offers easier treatment management as dose adjustment is facilitated.

Bioequivalence of a novel minitablet formulation of levetiracetam.

To investigate whether rapidly dissolving levetiracetam minitablets are bioequivalent to a single tablet of the same strength. 2 bioequivalence studies were carried out investigating the 1 000 mg and 1 500 mg strength of such novel medicinal products relative to single-unit film-coated originator tablets for reference. In each study, 16 young healthy subjects (8 males, 8 females) were investigated according to a 2,2,2-cross-over design with 1 week between periods for washout purposes. Each time, the plasma pharmacokinetics were profiled for 36 h after dosing.There were no relevant differences between the formulations with regard to tmax, apparent terminal half-life and the mean residence time. For the 1 000 mg strength, the estimated ratios of the true treatment means for test to reference were 1.008 (90% CI: 0.897-1.133), 1.010 (90% CI: 0.964-1.057), and 1.012 (90% CI: 0.965-1.062) for Cmax, AUC(0-tz), and AUC(0-∞), respectively; for the 1 500 mg strength, the respective ratio estimates were 0.960 (90% CI: 0.892-1.034), 1.005 (90% CI: 0.971-1.040), and 1.006 (90% CI: 0.970-1.042).Rapidly dissolving levetiracetam minitablets are bioequivalent with the originator single-unit reference tablets. Such alternative medicinal products make it easier and more convenient to individualise treatment of patients with epilepsy eligible to treatment with levetiracetam, particularly at higher doses when single-unit tablets, by being very large are difficult to swallow.

Influence of food on the pharmacokinetics of a new multiple unit sustained release sodium valproate formulation.

The influence of concomitant food intake on the pharmacokinetics of sodium valproate (CAS 1039-66-5) was studied in 16 healthy male volunteers. A single dose of a new sustained release formulation containing 300 mg sodium valproate (Orfiril long) was administered on two occasions either after a 12-h over-night fast or immediately after a standardised high energy high fat breakfast. A wash-out period of at least 1 week elapsed between the administrations. Valproate serum concentrations were measured by gas chromatography at intervals suitable for obtaining concentration-time curves for both regimens up to 72 h. The mean maximum serum concentration after fasting (17.0 micrograms/ml) was virtually the same as after a meal (16.8 micrograms/ml). Maximum concentrations were reached after 8 h for both nutritional states. The rate of elimination was not affected (terminal half-life approximately 15 h). The mean AUC0-infinity values were 468 micrograms/ml x h in fasting subjects and 458 micrograms/ml x h in postprandial subjects. The 90% confidence intervals for all pharmacokinetic target parameters were entirely confined in the bioequivalence range of 80 to 125%. The confidence intervals were even tighter, thus demonstrating homogeneity of drug release from the newly developed sodium valproate sustained release preparation. Bioequivalence with respect to extent and rate of absorption is therefore concluded for the comparison of fasting and non-fasting administration. The bioavailability of the sustained release sodium valproate preparation is not altered by the concomitant ingestion of food.

Bioavailability study of two carbamazepine containing sustained release formulations after multiple oral dose administration.

Carbamazepine (CAS 298-46-4), an iminostilbene derivative and a structural congener of the tricyclic antidepressant drugs, has been used in the treatment of epileptic seizures since 1963. The bioavailability/bioequivalence of a carbamazepine sustained release formulation (Timonil retard) was compared with a reference formulation in an open 2-period crossover study in 21 healthy male volunteers (including 1 drop-out) after multiple dose administration. During a run-in phase of 6 days the daily dose was gradually increased from 100 to 400 mg. On days 9 to 15, either the test or the reference formulation was administered twice daily, followed by a switch of preparation for a further 7 days of treatment (days 16 to 22). On the pharmacokinetic profiling days 15 and 22 blood samples were drawn over a 24-h period. In addition, blood samples were withdrawn before morning administrations for determination of carbamazepine and carbamazepine-10,11-epoxide trough values. Plasma concentrations of carbamazepine and its metabolite carbamazepine-10,11-epoxide were determined using a specific and sensitive HPLC method with UV detection. The results showed that autoinduction of carbamazepine metabolism under the chosen dosage regimen was complete within 14 days after start of treatment and that the criteria for bioequivalence were met. The 90% confidence intervals of all ratios were included by a range of 80-125% (AUC0-12: 103-120; AUC12-24: 105-119; Cmax0-12: 104-118; Cmax12-24: 104-118). During the study, 12 subjects experienced a total of 24 adverse events with mild to moderate intensity. Due to a significant increase of liver enzyme activity in serum during the course of the study, one subject was excluded from further study participation. There were no serious adverse events. It was concluded that the test formulation is bioequivalent to the reference formulation with respect to rate and extent of absorption.