Bioequivalence and switchability of generic antiseizure medications (ASMs): A re-appraisal based on analysis of generic ASM products approved in Europe.

The safety of switching between generic products of antiseizure medications (ASMs) continues to be a hot topic in epilepsy management. The main reason for concern relates to the uncertainty on whether, and when, two generics found to be bioequivalent to the same brand (reference) product are bioequivalent to each other, and the risk of a switch between generics resulting in clinically significant changes in plasma ASM concentrations. This article addresses these concerns by discussing the distinction between bioequivalence and statistical testing for significant difference, the importance of intra-subject variability in interpreting bioequivalence studies, the stricter regulatory bioequivalence requirements applicable to narrow-therapeutic-index (NTI) drugs, and the extent by which currently available generic products of ASMs comply with such criteria. Data for 117 oral generic products of second-generation ASMs approved in Europe by the centralized, mutual recognition or decentralized procedure were analyzed based on a review of publicly accessible regulatory assessment reports. The analysis showed that for 99% of generic products assessed (after exclusion of gabapentin products), the 90% confidence intervals (90% CIs) of geometric mean ratios (test/reference) for AUC (area under the drug concentration vs time curve) were narrow and wholly contained within the acceptance interval (90%-111%) applied to NTI drugs. Intra-subject variability for AUC was <10% for 53 (88%) of the 60 products for which this measure was reported. Many gabapentin generics showed broader, 90% CIs for bioequivalence estimates, and greater intra-subject variability, compared with generics of other ASMs. When interpreted within the context of other available data, these results suggest that any risk of non-bioequivalence between these individual generic products is small, and that switches across these products are not likely to result in clinically relevant changes in plasma drug exposure. The potential for variability in exposure when switching across generics is likely to be greatest for gabapentin.

Pre-Clinical Assessment of the Nose-to-Brain Delivery of Zonisamide After Intranasal Administration.

PURPOSE: Zonisamide clinical indications are expanding beyond the classic treatment of epileptic seizures to Parkinson's disease and other neurodegenerative diseases. However, the systemic safety profile of zonisamide may compromise its use as a first-line drug in any clinical condition. Since zonisamide is marketed as oral formulations, the present study aimed at exploring the potential of the intranasal route to centrally administer zonisamide, evaluating the systemic bioavailability of zonisamide and comparing its brain, lung and kidney pharmacokinetics after intranasal, oral and intravenous administrations. METHODS: In vitro cell studies demonstrated that zonisamide and proposed thermoreversible gels did not affect the viability of RPMI 2650 or Calu-3 cells. Thereafter, male CD-1 mice were randomly administered with zonisamide by oral (80 mg/kg), intranasal or intravenous (16.7 mg/kg) route. At predefined time points, animals were sacrificed and plasma and tissues were collected to quantify zonisamide and describe its pharmacokinetics. RESULTS: Intranasal route revealed a low absolute bioavailability (54.95%) but the highest value of the ratio between the area under the curve (AUC) between brain and plasma, suggesting lower systemic adverse events and non-inferior effects in central nervous system comparatively to intravenous and oral routes. Furthermore, drug targeting efficiency and direct transport percentage into the brain were 149.54% and 33.13%, respectively, corroborating that a significant fraction of zonisamide suffers direct nose-to-brain transport. Lung and kidney exposures obtained after intranasal administration were lower than those observed after intravenous injection. CONCLUSIONS: This pre-clinical investigation demonstrates a direct nose-to-brain delivery of zonisamide, which may be a promising strategy for the treatment of central diseases.

Pharmacometabolomics applied to zonisamide pharmacokinetic parameter prediction.

INTRODUCTION: Zonisamide is a new-generation anticonvulsant antiepileptic drug metabolized primarily in the liver, with subsequent elimination via the renal route. OBJECTIVES: Our objective was to evaluate the utility of pharmacometabolomics in the detection of zonisamide metabolites that could be related to its disposition and therefore, to its efficacy and toxicity. METHODS: This study was nested to a bioequivalence clinical trial with 28 healthy volunteers. Each participant received a single dose of zonisamide on two separate occasions (period 1 and period 2), with a washout period between them. Blood samples of zonisamide were obtained from all patients at baseline for each period, before volunteers were administered any medication, for metabolomics analysis. RESULTS: After a Lasso regression was applied, age, height, branched-chain amino acids, steroids, triacylglycerols, diacyl glycerophosphoethanolamine, glycerophospholipids susceptible to methylation, phosphatidylcholines with 20:4 FA (arachidonic acid) and cholesterol ester and lysophosphatidylcholine were obtained in both periods. CONCLUSION: To our knowledge, this is the only research study to date that has attempted to link basal metabolomic status with pharmacokinetic parameters of zonisamide.

Pharmacokinetics of zonisamide after oral single dosing and multiple-dose escalation administration in domestic chickens (Gallus gallus).

BACKGROUND: There are few effective drugs for treatment of seizures in avian species. OBJECTIVES: To investigate the pharmacokinetics and safety of zonisamide in chickens. METHODS: Phase 1: chickens (n = 4) received a single oral dose of zonisamide at 20 mg/kg. Blood samples were collected intermittently for 36 hr after dosing. Phase 2: chickens (n = 8) received zonisamide in a dose escalation protocol (20, 30, 60 and 80 mg/kg orally every 12 hr). The dose was increased weekly, and peak and trough blood samples were collected on Days 1, 3, and 7 each week. Two birds were randomly euthanized at the end of each week. Plasma zonisamide concentrations were analysed using a commercial immunoassay. Drug concentration vs. time data were subjected to non-compartmental pharmacokinetic analysis. RESULTS: For Phase 1, peak plasma zonisamide (Cmax ) was 15 ± 3 µg/ml at 2 ± 1 hr (Tmax ). The disappearance half-life was 6.5 ± 1 hr. Mean plasma concentrations remained within the (human) therapeutic range (10-40 µg/ml) for 6 hr. For Phase 2 of the study, plasma concentrations of zonisamide remained within or close to the recommended mammalian therapeutic range for birds in the 20 and 30 mg/kg dose. Area under the curve (AUC) and Cmax were dose dependent. Two birds developed immune-mediated haemolytic anaemia. CONCLUSIONS: Zonisamide appears to be a viable drug for use in chickens at a dose of 20 mg/kg orally every 12 hr.

Pharmacokinetics and safety of zonisamide after oral administration of single and multiple doses to Hispaniolan Amazon parrots (Amazona ventralis).

OBJECTIVE To determine pharmacokinetics after oral administration of single and multiple doses and to assess the safety of zonisamide in Hispaniolan Amazon parrots (Amazona ventralis). ANIMALS 12 adult Hispaniolan Amazon parrots. PROCEDURES Zonisamide (30 mg/kg, PO) was administered once to 6 parrots in a single-dose trial. Six months later, a multiple-dose trial was performed in which 8 parrots received zonisamide (20 mg/kg, PO, q 12 h for 10 days) and 4 parrots served as control birds. Safety was assessed through monitoring of body weight, attitude, and urofeces and comparison of those variables and results of CBC and biochemical analyses between control and treatment groups. RESULTS Mean ± SD maximum plasma concentration of zonisamide for the single- and multiple-dose trials was 21.19 ± 3.42 µg/mL at 4.75 hours and 25.11 ± 1.81 µg/mL at 2.25 hours after administration, respectively. Mean plasma elimination half-life for the single- and multiple-dose trials was 13.34 ± 2.10 hours and 9.76 ± 0.93 hours, respectively. Pharmacokinetic values supported accumulation in the multiple-dose trial. There were no significant differences in body weight, appearance of urofeces, or appetite between treated and control birds. Although treated birds had several significant differences in hematologic and biochemical variables, all variables remained within reference values for this species. CONCLUSIONS AND CLINICAL RELEVANCE Twice-daily oral administration of zonisamide to Hispaniolan Amazon parrots resulted in plasma concentrations known to be therapeutic in dogs without evidence of adverse effects on body weight, attitude, and urofeces or clinically relevant changes to hematologic and biochemical variables.

Population pharmacokinetics of extended-release levetiracetam in epileptic dogs when administered alone, with phenobarbital or zonisamide.

BACKGROUND: Extended-release levetiracetam (LEV-XR) has gained acceptance as an antiepileptic drug in dogs. No studies have evaluated its disposition in dogs with epilepsy. HYPOTHESIS/OBJECTIVES: To evaluate the pharmacokinetics of LEV-XR in epileptic dogs when administered alone or with phenobarbital or zonisamide. ANIMALS: Eighteen client-owned dogs on steady-state maintenance treatment with LEV-XR (Group L, n = 6), LEV-XR and phenobarbital (Group LP, n = 6), or LEV-XR and zonisamide (Group LZ, n = 6). METHODS: Pharmacokinetic study. Blood samples were collected at 0, 2, 4, 8, and 12 hours after LEV-XR was administered with food. Plasma LEV concentrations were determined by high-pressure liquid chromatography. A population pharmacokinetic approach and nonlinear mixed effects modeling were used to analyze the data. RESULTS: Treatment group accounted for most of the interindividual variation. The LP group had lower CMAX (13.38 µg/mL) compared to the L group (33.01 µg/mL) and LZ group (34.13 µg/mL), lower AUC (134.86 versus 352.95 and 452.76 hours·µg/mL, respectively), and higher CL/F (0.17 versus 0.08 and 0.07 L/kg/hr, respectively). The half-life that defined the terminal slope of the plasma concentration versus time curve (~5 hours) was similar to values previously reported for healthy dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Considerable variation exists in the pharmacokinetics of LEV-XR in dogs with epilepsy being treated with a common dose regimen. Concurrent administration of phenobarbital contributed significantly to the variation. Other factors evaluated, including co-administration of zonisamide, were not shown to contribute to the variability. Drug monitoring may be beneficial to determine the most appropriate dose of LEV-XR in individual dogs.