Physicians' attitudes toward generic substitutions of antiseizure drugs in epilepsy.

OBJECTIVES: The safety of generic substitution of antiseizure drugs (ASDs) has been questioned for many years. This study aimed to identify physicians' attitudes to the generic substitution of ASDs in epilepsy and which factors were of significance when deciding on compound substitutions. MATERIAL AND METHODS: A cross-sectional web-based survey was sent to neurologists and neurology residents in public health care and at private practices in two Swedish regions between February and March 2020. The 30-item survey covered drug- and patient-related factors, as well as considerations relating to practical, cost-related, and pharmacokinetic issues. RESULTS: The total response rate was 55.8%. Respondents were generally positive to cutting costs through generic ASD utilization (74%) and prescribing generic compounds when starting a new ASD treatment (84.9%). The most substantial concern was a deterioration in seizure control (17.1%). Physicians refrained from switching if the patient wished to remain on the original compound (76.1%), had a cognitive impairment (52.5%), was on a drug with a narrow therapeutic index (47%), or had shown prior susceptibility to adverse effects (45.6%). Opinions on substitution decisions differed significantly between the Stockholm and Skåne regions. Less than one-third of the respondents were aware of supporting guidelines. CONCLUSIONS: Neurologists generally accept the use of generic antiseizure compounds. Patient preference to remain on brand-name drug treatment was the most important factor that led to avoiding a switch. Our results may constitute material for consensus discussions to decide on quality indicators of interest for future research on substitution outcomes.

Unbound valproate fraction in plasma and subcutaneous microdialysate in steady state and after a single dose in humans.

The aim of the current study was to characterize the observed discrepancy between unbound plasma valproate (VPA) in single dose and steady state in humans. Unbound and total plasma VPA and subcutaneous microdialysate VPA concentrations were estimated in single dose (6 subjects, n = 33) and steady state (11 subjects, n = 110). Trough plasma samples from 14 patients with total VPA concentrations of 300 micromol/L and 14 patients with VPA concentrations ranging from 600 to 700 micromol/L were analyzed for the unbound VPA fraction and compared with the unbound VPA fraction in spiked plasma samples from healthy subjects containing similar total VPA concentrations. The unbound plasma VPA fraction was significantly higher (P < 0.001) in the steady-state group compared with the single-dose group. The unbound VPA fraction was significantly higher in steady state compared with spiked plasma samples at high and low total VPA concentrations (P < 0.001). The difference between microdialysate and unbound plasma VPA concentrations was significant in the steady-state group (P < 0.001), while no difference was observed in the single-dose group. The mean (+/- SD) subcutaneous microdialysate-to-unbound plasma ratio in the single-dose and steady-state groups was 1.08 (+/- 0.401) and 0.74 (+/- 0.123), respectively. The ratio difference between the groups was significant (P < 0.001). The results of the current study show that unbound plasma fractions of VPA are consistently higher in steady state compared with single dose. Together with the finding of higher unbound VPA fraction in steady state compared with spiked plasma samples, these results provide indirect evidence of displacement of VPA from plasma proteins by product(s) of VPA biotransformation. In addition, subcutaneous microdialysate VPA levels were consistently lower than unbound plasma levels in steady state but not after single dose. The mechanisms underlying this observation need to be studied further.

Microdialysis sampling of carbamazepine, phenytoin and phenobarbital in subcutaneous extracellular fluid and subdural cerebrospinal fluid in humans: an in vitro and in vivo study of adsorption to the sampling device.

The purpose of the study was to determine if binding of the drugs to the sampling equipment during microdialysis would influence the results for carbamazepine, phenytoin and phenobarbital. In vitro experiments with microdialysis catheters and separate parts of catheters were performed to estimate the degree of drug binding to the dialysis equipment. A mathematical model to calculate drug binding and recovery is proposed. In vivo protein unbound carbamazepine concentrations in subcutaneous extracellular fluid at different flow rates (6 patients), unbound carbamazepine (1 patient) and unbound phenobarbital (I patient) in subdural cerebrospinal fluid and subcutaneous extracellular fluid were estimated and the in vivo data were compared to the in vitro results and data generated by the mathematical model. Binding to the soft outlet polyurethane tubing was extensive and variable for phenytoin, which precluded in vivo testing, but limited and more predictable for carbamazepine and phenobarbital. None of the three compounds bound to the hard internaltubing. Phenytoin and phenobarbital did not bind to the dialysis membrane, while a small degree of binding may be present for carbamazepine. In vivo estimates of carbamazepine protein unbound subcutaneous extracellular concentrations by microdialysis, adjusted for binding to the plastic tubing, were 81% of protein unbound plasma concentrations. In single case studies, subdural cerebrospinal fluid and subcutaneous extracellular levels of carbamazepine and phenobarbital were similar and when corrected for binding to the plastic tubings they were also close to protein unbound plasma concentrations. Microdialysis can be used for reliable estimations of protein unbound carbamazepine and possibly phenobarbital concentrations when drug binding to the plastic tubing is considered. Reliable estimation of unbound phenytoin is not possible at present.

Serum concentrations and effects of gabapentin and vigabatrin: observations from a dose titration study.

To explore possible concentration-effect relationships, gabapentin (GBP) and vigabatrin (VGB) serum concentrations were obtained from patients participating in an add-on dose-titration trial comparing GBP and VGB in partial epilepsy. Patients randomized to GBP started on 1800 mg/d and could have their dosage increased stepwise to 2400 and 3600 mg/d if seizures persisted. Those randomised to VGB started on 1000 mg/d, and the dose could be increased to 2000 and 4000 mg/d. Blood samples were obtained at steady state, at a nonstandardized time, from 27 patients randomized to GBP and from 36 randomized to VGB. Serum samples were analyzed using high-performance liquid chromatography. The treatment effect was expressed as percentage reduction in number of seizures from baseline. In addition, patients were classified as responders (>50% reduction in number of seizures from baseline) or nonresponders. There was no significant correlation between serum concentrations of GBP and seizure reduction at the lowest dosage, 1800 mg/d (r = -0.02, P = 0.94, Spearman-rank), nor between VGB serum levels and seizure reduction at 1000 mg/d of VGB (r = -0.14, P = 0.44). The serum GBP concentrations among responders to GBP 1800 mg/d were 26 +/- 12 micro mol/L (mean +/- SD), which was not different from serum concentrations in nonresponders, 28+/-13 micro mol/L. Nor was there a difference between serum concentrations of responders and nonresponders to VGB 1000 mg/d (32 +/- 23 and 44 +/- 36 micro mol/L, respectively). Hence, with the present study design we were unable to identify specific target ranges of GBP and VGB serum concentrations.