Assessing bioequivalence of generic modified-release antiepileptic drugs.
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ABSTRACT: Objectives
The purpose of this study was to determine how closely generic modified-release antiepileptic drugs (MR-AEDs) resemble reference (brand) formulations by comparing peak concentrations (Cmax), total absorption (area under the curve [AUC]), time to Cmax (Tmax), intersubject variability, and food effects between generic and reference products.Methods
We tabulated Cmax and AUC data from the bioequivalence (BE) studies used to support the approvals of generic Food and Drug Administration-approved MR-AEDs. We compared differences in 90% confidence intervals of the generic/reference AUC and Cmax geometric mean ratios, and intersubject variability, Tmax and delivery profiles and food effects.Results
Forty-two MR-AED formulations were studied in 3,175 healthy participants without epilepsy in 97 BE studies. BE ratios for AUC and Cmax were similar between most generic and reference products: AUC ratios varied by >15% in 11.4% of BE studies; Cmax varied by >15% in 25.8% of studies. Tmax was more variable, with >30% difference in 13 studies (usually delayed in the fed compared to fasting BE studies). Generic and reference MR products had similar intersubject variability. Immediate-release AEDs showed less intersubject variability in AUC than did MR-AEDs.Conclusions
Most generic and reference MR-AEDs have similar AUC and Cmax values. Ratios for some products, however, are near acceptance limits and Tmax values may vary. Food effects are common with MR-AED products. High variability in pharmacokinetic values for once-a-day MR-AEDs suggests their major advantage compared to immediate-release AED formulations may be the convenience of less frequent dosing to improve adherence.
SUBMITTER: Johnson EL
PROVIDER: S-EPMC4844239 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The extents of generic-reference and generic-generic average bioequivalence and intra-subject variation of on-market drug products have not been prospectively studied on a large scale.We assessed bioequivalence of 42 generic products of 14 immediate-release oral drugs with the highest number of generic products on the Saudi market. We conducted 14 four-sequence, randomized, crossover studies on the reference and three randomly-selected generic products of amlodipine, amoxicillin, atenolol, cephalexin, ciprofloxacin, clarithromycin, diclofenac, ibuprofen, fluconazole, metformin, metronidazole, paracetamol, omeprazole, and ranitidine. Geometric mean ratios of maximum concentration (Cmax) and area-under-the-concentration-time-curve, to last measured concentration (AUCT), extrapolated to infinity (AUCI), or truncated to Cmax time of reference product (AUCReftmax) were calculated using non-compartmental method and their 90% confidence intervals (CI) were compared to the 80.00%-125.00% bioequivalence range. Percentages of individual ratios falling outside the ±25% range were also determined.Mean (SD) age and body-mass-index of 700 healthy volunteers (28-80/study) were 32.2 (6.2) years and 24.4 (3.2) kg/m2, respectively. In 42 generic-reference comparisons, 100% of AUCT and AUCI CIs showed bioequivalence, 9.5% of Cmax CIs barely failed to show bioequivalence, and 66.7% of AUCReftmax CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUCT and AUCI CIs and 21.4% of Cmax CIs failed to show bioequivalence. In 42 generic-generic comparisons, 2.4% of AUCT, AUCI, and Cmax CIs failed to show bioequivalence, and 66.7% of AUCReftmax CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUCT and AUCI CIs and 14.3% of Cmax CIs failed to show bioequivalence. Average geometric mean ratio deviation from 100% was ?3.2 and ?5.4 percentage points for AUCI and Cmax, respectively, in both generic-reference and generic-generic comparisons. Individual generic/reference and generic/generic ratios, respectively, were within the ±25% range in >75% of individuals in 79% and 71% of the 14 drugs for AUCT and 36% and 29% for Cmax.On-market generic drug products continue to be reference-bioequivalent and are bioequivalent to each other based on AUCT, AUCI, and Cmax but not AUCReftmax. Average deviation of geometric mean ratios and intra-subject variations are similar between reference-generic and generic-generic comparisons.ClinicalTrials.gov identifier: NCT01344070 (registered April 3, 2011).
| S-EPMC5721559 | biostudies-literature
Project description:BackgroundGeneric drugs are used by millions of patients for economic reasons, so their evaluation must be highly transparent.ObjectiveTo assess the quality of reporting of bioequivalence trials comparing generic to brand-name drugs.Methodology/principal findingsPubMed was searched for reports of bioequivalence trials comparing generic to brand-name drugs between January 2005 and December 2008. Articles were included if the aim of the study was to assess the bioequivalency of generic and brand-name drugs. We excluded case studies, pharmaco-economic evaluations, and validation dosage assays of drugs. We evaluated whether important information about funding, methodology, location of trials, and participants were reported. We also assessed whether the criteria required by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) to conclude bioequivalence were reported and that the conclusions were in agreement with the results. We identified 134 potentially relevant articles but eliminated 55 because the brand-name or generic drug status of the reference drug was unknown. Thus, we evaluated 79 articles. The funding source and location of the trial were reported in 41% and 56% of articles, respectively. The type of statistical analysis was reported in 94% of articles, but the methods to generate the randomization sequence and to conceal allocation were reported in only 15% and 5%, respectively. In total, 65 articles of single-dose trials (89%) concluded bioequivalence. Of these, 20 (31%) did not report the 3 criteria within the limits required by the FDA and 11 (17%) did not report the 2 criteria within the limits required by the EMA.Conclusions/significanceImportant information to judge the validity and relevance of results are frequently missing in published reports of trials assessing generic drugs. The quality of reporting of such trials is in need of improvement.
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Project description:Alfuzosin, a selective alpha-1a antagonistis is the most recently approved AARAS, with limited cardiac toxicity and exclusively used for lower urinary tract syndromes (LUTS). In order to reduce pill burden and better patient compliance modified release (MR) formulations have been developed. Alfuzosin MR tablet was developed by the use of hot-melt granulation techniques using mono- and diglycerides as rate controlling membranes to minimize health care cost and uses of costly excipients. The other purpose of the study was to evaluate in vitro-in vivo performance of the scale up batch in healthy human subjects for commercialization. The blend uniformity (mean ± RSD%), assay, cumulative percent dissolution at 24?h, hardness, and friability of the biobatch were 100.2 ± 0.05%, 100.43 ± 0.023%, 93.98%, 4.5?kg, 5?min, and 0.08%, respectively. The in vivo pharmacokinetic parameters under fasting conditions between test and reference formulations (Uroxatral 10?mg extended release tablets) were comparable. The 90% CI, geometric mean ratio (%) and power of C max, AUCT, and AUCI of the fasting study for the test and reference formulation were 99.03% to 122.78%, 109%, 0.998; 92.94% to 116.71%, 104%, 1; 98.17% to 124.01%, 110% 1, respectively. The scale up biobatch showed negligible difference in in vitro properties with respect to the pilot batch. The formulation developed with these agents was safe to use as there were no serious adverse events developed during the conduction of the clinical trial on the healthy subjects. Furthermore, the developed formulation was bioequivalent with respect to rate and extends of absorption to the reference formulation.
| S-EPMC3671720 | biostudies-literature
Project description:There are now 24 antiepileptic drugs (AEDs) approved for use in epilepsy in the United States by the Food and Drug Administration. A literature search was conducted using PubMed, MEDLINE, and Google for all English-language articles that discuss newly approved AEDs and the use of AEDs in epilepsy in the United States from January 1, 2008, through December 31, 2011. Five new agents were identified that have come onto the market within the past 2 years. Moreover, 3 trends involving AEDs have become clinically important and must be considered by all who treat patients with epilepsy. These trends include issues of generic substitution of AEDs, pharmacogenomics predicting serious adverse events in certain ethnic populations, and the issue of the suicide risk involving the entire class of AEDs. This article discusses the most recent AEDs approved for use in the United States and the 3 important trends shaping the modern medical management of epilepsy.
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Project description:The goal of pharmacogenetic research is to assist clinicians in predicting patient response to medications when genetic variations are identified. The pharmacogenetic variation of antiepileptic drug response and side effects has yielded findings that have been included in drug labeling and guidelines. The goal of this review is to provide a brief overview of the pharmacogenetic research on antiepileptic drugs. It will focus on findings that have been included in drug labeling, guidelines, and candidate pharmacogenetic variation. Overall, several genes have been included in guidelines by national and international organizations; however, much work is needed to implement and evaluate their use in clinical settings.
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Project description:BackgroundItraconazole is commonly used to treat systemic fungal infections in dogs, but problems exist with absorption and cost.ObjectiveTo determine oral bioequivalence of generic and compounded itraconazole compared to original innovator (brand name) itraconazole in healthy dogs.AnimalsNine healthy, adult research Beagle dogs.MethodsA randomized, 3-way, 3-period, crossover design with an 8-day washout period. After a 12-hour fast, each dog received 100 mg (average: 10.5 mg/kg) of either innovator itraconazole, an approved human generic capsule, or compounded itraconazole (compounded using a commercially available compounding vehicle) with a small meal. Plasma was collected at predetermined intervals for high pressure liquid chromatography analysis. Concentration data were analyzed using noncompartmental pharmacokinetics to determine area under the curve (AUC), peak concentration (C(MAX)), and terminal half-life. Bioequivalence tests compared generic and compounded itraconazole to the reference formulation.ResultsAverage ratios of compounded and generic formulations to the reference formulation of itraconazole for AUC were 5.52% and 104.2%, respectively, and for C(MAX) were 4.14% and 86.34%, respectively. A test of bioequivalence using 2 one-sided tests and 90% confidence intervals did not meet bioequivalence criteria for either formulation.Conclusion and clinical importanceNeither generic nor compounded itraconazole is bioequivalent to the reference formulation in dogs. However, pharmacokinetic data for generic formulation were similar enough that therapeutic concentrations could be achieved. Compounded itraconazole produced such low plasma concentrations, it is unlikely to be effective; therefore, compounded itraconazole should not be used in dogs.
| S-EPMC4895533 | biostudies-literature
Project description:Epilepsy is the most common neurological disorder which significantly affects the quality of life and poses a health as well as economic burden on society. Epilepsy affects approximately 70 million people in the world. The present article reviews the scientific rationale, brief pathophysiology of epilepsy and newer antiepileptic drugs which are presently under clinical development. We have searched the investigational drugs using the key words 'antiepileptic drugs,' 'epilepsy,' 'Phase I,' 'Phase II' and 'Phase III' in American clinical trial registers (clinicaltrials.gov), the relevant published articles using National Library of Medicine's PubMed database, company websites and supplemented results with a manual search of cross-references and conference abstracts. This review provides a brief description about the antiepileptic drugs which are targeting different mechanisms and the clinical development status of these drugs. Besides the presence of old as well as new AEDs, still there is a need of new drugs or the modified version of old drugs in order to make affected people free of seizures. An optimistic approach should be used to translate the success of preclinical testing to clinical practice. There is an urgent need to improve animal models and to explore new targets with better understanding in order to develop the novel drugs with more efficacy and safety.
| S-EPMC5803110 | biostudies-other
Project description:Although prenatal exposure to antiepileptic drugs (AEDs) is known to impart relatively higher risks of major congenital malformations, prospective studies have provided refined data that allow us to differentiate the risks of different types and doses of AEDs. As the number of AED prescriptions has dramatically increased in reproductive-aged women with a variety of neuropsychiatric indications, the evolving concepts learned from studies in women with epilepsy can be applied to a much larger group of pregnant women to improve child outcomes while maintaining maternal disease control. In addition to careful selection of the type of medication, the amount of fetal exposure at conception and in the first trimester probably matters across all AEDs. Some AED polytherapy regimens are not associated with a higher risk of malformations, although other outcomes have not yet been formally studied. The individual woman's drug target concentration should be established preconception and maintained during pregnancy, to prevent seizure worsening. Substantial pharmacokinetic changes occur with many of the medications during pregnancy and postpartum, and interindividual variability supports the use of therapeutic drug monitoring for most AEDs. During pregnancy, vigilance and close monitoring should also include intrauterine fetal growth, obstetric complications, and neonatal complications. Breastfeeding can provide additional neurodevelopmental benefit and should be an option for women on AEDs. Knowledge of these key principles enhances our ability to make treatment recommendations with resultant improved maternal and child outcomes. Additional prospective studies are needed to further define the risk-benefit ratio across a variety of medications, dosing strategies, and neuropsychiatric disorders.
| S-EPMC5081129 | biostudies-literature
Project description:ObjectiveWith more antiepileptic drugs (AED) becoming available in generic form, we estimated the risk of seizure-related events associated with refilling generic AEDs and the effect of switching between different manufacturers of the same generic drug.MethodsWe designed a population-based case-crossover study using the Medicaid Analytic eXtract and a US commercial health insurance database. We identified 83,001 generic AED users who experienced a seizure-related hospital admission or emergency room visit between 2000 and 2013 and assessed whether they received a refill of the same AED from the same manufacturer or a different manufacturer. Patients served as their own controls and conditional logistic regression was used to compare exposure to a refill during the hazard period, defined as days 2-36 preceding the seizure-related event, to exposure during the control period, defined as days 51-85 preceding the seizure-related event.ResultsGeneric AED refilling was associated with an 8% increase in the odds of seizure-related events (odds ratio [OR] 1.08; 95% confidence interval [CI] 1.06-1.11). The OR following a switch to a different manufacturer of the same AED was 1.09 (95% CI 1.03-1.15); however, after adjusting for the process of refilling, there was no association between switching and seizure-related hospital visits (OR 1.00; 95% CI 0.94-1.07).ConclusionsAmong patients on a generic AED, refilling the same AED was associated with an elevated risk of seizure-related event; however, there was no additional risk from switching during that refill to a different manufacturer. Generic AEDs available to US patients, with Food and Drug Administration-validated bioequivalence, appear to be safe clinical choices.
| S-EPMC5089522 | biostudies-literature
Project description:Drug exposure during critical periods of brain development may adversely affect nervous system function, posing a challenge for treating infants. This is of particular concern for treating neonatal seizures, as early life exposure to drugs such as phenobarbital is associated with adverse neurological outcomes in patients and induction of neuronal apoptosis in animal models. The functional significance of the preclinical neurotoxicity has been questioned due to the absence of evidence for functional impairment associated with drug-induced developmental apoptosis.We used patch-clamp recordings to examine functional synaptic maturation in striatal medium spiny neurons from neonatal rats exposed to antiepileptic drugs with proapoptotic action (phenobarbital, phenytoin, lamotrigine) and without proapoptotic action (levetiracetam). Phenobarbital-exposed rats were also assessed for reversal learning at weaning.Recordings from control animals revealed increased inhibitory and excitatory synaptic connectivity between postnatal day (P)10 and P18. This maturation was absent in rats exposed at P7 to a single dose of phenobarbital, phenytoin, or lamotrigine. Additionally, phenobarbital exposure impaired striatal-mediated behavior on P25. Neuroprotective pretreatment with melatonin, which prevents drug-induced neurodevelopmental apoptosis, prevented the drug-induced disruption in maturation. Levetiracetam was found not to disrupt synaptic development.Our results provide the first evidence that exposure to antiepileptic drugs during a sensitive postnatal period impairs physiological maturation of synapses in neurons that survive the initial drug insult. These findings suggest a mechanism by which early life exposure to antiepileptic drugs can impact cognitive and behavioral outcomes, underscoring the need to identify therapies that control seizures without compromising synaptic maturation.
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