儿童抗癫痫药物治疗药物监测

抗癫痫药物（AEDs）是治疗癫痫的主要药物,现有27种抗癫痫药物,这使得治疗药物监测（TDM）的应用越来越广泛,同时,抗癫痫药物也是进行TDM最常见的药物。第一代抗癫痫药物卡马西平、苯巴比妥、苯妥英钠、乙琥胺、扑米酮、丙戊酸在TDM方面积累了很多经验,现在TDM将更多地应用于新的抗癫痫药物如醋酸艾司利卡西平、非氨酯、加巴喷丁、拉科酰胺、拉莫三嗪、左乙拉西坦、奥卡西平、吡仑帕奈、哌拉西坦、普瑞巴林、瑞替加滨、卢非酰胺、司替戊醇、噻加宾、托吡酯、氨己烯酸和唑尼沙胺。本文通过对样本类型、样本的采集和处理、参考范围的概念进行综述,旨在为儿童抗癫痫用药的药物监测提供依据。     

Pharmacokinetic variability of newer antiepileptic drugs: when is monitoring needed?

A new generation of antiepileptic drugs (AEDs) has reached the market in recent years with ten new compounds: felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin and zonisamide. The newer AEDs in general have more predictable pharmacokinetics than older AEDs such as phenytoin, carbamazepine and valproic acid (valproate sodium), which have a pronounced inter-individual variability in their pharmacokinetics and a narrow therapeutic range. For these older drugs it has been common practice to adjust the dosage to achieve a serum drug concentration within a predefined 'therapeutic range', representing an interval where most patients are expected to show an optimal response. However, such ranges must be interpreted with caution, since many patients are optimally treated when they have serum concentrations below or above the suggested range. It is often said that there is less need for therapeutic drug monitoring (TDM) with the newer AEDs, although this is partially based on the lack of documented correlation between serum concentration and drug effects. Nevertheless, TDM may be useful despite the shortcomings of existing therapeutic ranges, by utilisation of the concept of 'individual reference concentrations' based on intra-individual comparisons of drug serum concentrations. With this concept, TDM may be indicated regardless of the existence or lack of a well-defined therapeutic range.The ten newer AEDs all have different pharmacological properties, and therefore, the usefulness of TDM for these drugs has to be assessed individually. For vigabatrin, a clear relationship between drug concentration and clinical effect cannot be expected because of its unique mode of action. Therefore, TDM of vigabatrin is mainly to check compliance. The mode of action of the other new AEDs would not preclude the applicability of TDM. For the prodrug oxcarbazepine, TDM is also useful, since the active metabolite licarbazepine is measured.For drugs that are eliminated renally completely unchanged (gabapentin, pregabalin and vigabatrin) or mainly unchanged (levetiracetam and topiramate), the pharmacokinetic variability is less pronounced and more predictable. However, the dose-dependent absorption of gabapentin increases its pharmacokinetic variability. Drug interactions can affect topiramate concentrations markedly, and individual factors such as age, pregnancy and renal function will contribute to the pharmacokinetic variability of all renally eliminated AEDs. For those of the newer AEDs that are metabolised (felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide), pharmacokinetic variability is just as relevant as for many of the older AEDs. Therefore, TDM is likely to be useful in many clinical settings for the newer AEDs. The purpose of the present review is to discuss individually the potential value of TDM of these newer AEDs, with emphasis on pharmacokinetic variability.     

口服"纯中药"患儿的抗痫西药血浓度监测

目的：用治疗药物监测(TDM)方法监测口服“纯中药”患儿的抗痫西药血浓度,及时发现和调整患儿的不合理用药。方法：凡是临床上出现药物中毒、无法解释的药理现象或者怀疑服有中药掺杂西药的癫痫患者,用HPLC法和PLIA法监测其血药浓度．并动态地现察疗效。结果：45例服用“纯中药”的癫痫患儿,血清中检测出1．5种常用抗痫西药,其中苯巴比妥最多(42例)。其次为卡马西平、丙戊酸钠、苯妥英纳和氯硝西泮,有些已达中毒浓度。这种现象给病人造成极大的诊疗困难、中毒危险、心理创伤及经济     

The role of pharmacogenetics in the metabolism of antiepileptic drugs: pharmacokinetic and therapeutic implications

Several different factors, including pharmacogenetics, contribute to interindividual variability in drug response. Like most other agents, many antiepileptic drugs (AEDs) are metabolised by a variety of enzymatic reactions, and the cytochrome P450 (CYP) superfamily has attracted considerable attention. Some of those CYPs exist in the form of genetic (allelic) variants, which may also affect the plasma concentrations or drug exposure (area under the plasma concentration-time curve [AUC]) of AEDs. With regard to the metabolism of AEDs, the polymorphic CYP2C9 and CYP2C19 are of interest. This review summarises the evidence as to whether such polymorphisms affect the clinical action of AEDs. In the case of mephenytoin, defects in its metabolism may be attributable to >10 mutated alleles (designated as *2, *3 and others) of the gene expressing CYP2C19. Consequently, poor metabolisers (PMs) and extensive metabolisers (EMs) could be differentiated, whose frequencies vary among ethnic populations. CYP2C19 contributes to the metabolism of diazepam and phenytoin, the latter drug also representing a substrate of CYP2C9, with its predominant variants being defined as *2 and *3. For both AEDs, there is maximally a 2-fold difference in the hepatic elimination rate (e.g. clearance) or the AUC between the extremes of EMs and PMs which, in the case of phenytoin (an AED with a narrow 'therapeutic window'), would suggest a dosage reduction only for patients who are carriers of mutated alleles of both CYP2C19 and CYP2C9, a subgroup that is very rare among Caucasians (about 1% of the population) but more frequent in Asians (about 10%). The minor contribution of CYP2C19 to the metabolism of phenobarbital (phenobarbitone) can be overlooked. In rare cases, valproic acid can be metabolised to the reactive (hepatotoxic) metabolite, 4-ene-valproic acid. It is not yet clear whether genetic variants of the involved enzyme (CYP2C9) are responsible for this problem. Likewise, the active metabolite of carbamazepine, carbamazepine-10,11-epoxide, is transformed by the microsomal epoxide hydrolase, an enzyme that is also highly polymorphic, but the pharmacokinetic and clinical consequences still need to be evaluated.Pharmacogenetic investigations have increased our general knowledge of drug disposition and action. As for old and especially new AEDs the pharmacogenetic influence on their metabolism is not very striking, it is not surprising that there are no treatment guidelines taking pharmacogenetic data into account. Therefore, the traditional and validated therapeutic drug monitoring approach, representing a direct 'phenotype' assessment, still remains the method of choice when an individualised dosing regimen is anticipated. Nevertheless, pharmacogenetics and pharmacogenomics can offer some novel contributions when attempts are made to maximise drug efficacy and enhance drug safety.     

药物代谢酶CYP2C9多态位点CYP2C9*13的发现及底物药用药安全启示

在非甾体抗炎药氯诺昔康的生物等效性试验中发现1名药物慢代谢者携带药物代谢基因CYP2C9＊3突变位点,并携带一个新CYP2C9多态性位点—CYP2C9＊13。CYP2C9酶的基因多态性通过影响酶的活力,改变底物药在体内的清除率。因此,CYP2C9突变体的携带者将面临着底物药的用药安全问题,特别是有效剂量和毒性剂量距离近的药物,如华法林、甲苯磺丁脲和苯妥英钠等。筛查CYP2C9基因型,有助于提高CYP2C9酶底物药的用药安全,减少不良反应的发生。     

Development and clinical applications of the dried blood spot method for therapeutic drug monitoring of anti‐epileptic drugs

Anti‐epileptic drugs (AEDs) have various pharmacokinetic profiles, inter‐individual variabilities, high possibilities of drug‐drug interactions and narrow therapeutic indices. To provide optimal treatment for patients, therapeutic drug monitoring (TDM) is necessary. However, TDM requires sufficient quantities of blood samples to measure drug concentrations. Therefore, TDM could be a burden, particularly in paediatric cases. A good alternative that overcomes these disadvantages is the dried blood spot (DBS) method, which is simple, convenient to use and less invasive, requiring a lower quantity of blood than traditional blood sampling methods. However, the DBS method is affected by haematocrit (Hct) levels to varying extents depending on the drug properties. In addition, different papers with varying characteristics are available for use when applying the DBS method. Therefore, it has not yet been applied to TDM in clinical practice. To achieve this, several steps are required, including method development, method validation and clinical validation. Currently, the development status of the DBS method is different for each AED and unclear. Therefore, we assessed the development status of the following 19 AEDs in 26 studies: lamotrigine, valproic acid, levetiracetam, phenytoin, topiramate, carbamazepine, carbamazepine epoxide, gabapentin, phenobarbital, pregabalin, clobazam, clonazepam, ethosuximide, felbamate, monohydroxycarbamazepine, nitrazepam, rufinamide, vigabatrin and zonisamide. Among them, carbamazepine, lamotrigine, topiramate and valproic acid have been developed such that they are nearly available for TDM. In addition, Whatman 903 Protein Saver Cards and concentration analysis by liquid chromatography with triple quadrupole mass spectrometer were used most often.     

Various pharmacogenetic aspects of antiepileptic drug therapy: a review

Pharmacogenetics concerns the influence of an individual's genetic background on the pharmacokinetics and pharmacodynamics of xenobiotics. Much of the pharmacogenetic data in the field of epilepsy deals with the pharmacokinetics of antiepileptic drugs (AEDs). In particular, two polymorphisms of cytochrome P450 2C9 are known to slow down the metabolism of phenytoin to a degree that increases the risk of the neurotoxic adverse effects of this drug among carriers of these polymorphisms. A significant number of patients with epilepsy do not respond to AEDs and such pharmacoresistance is a major, largely unsolved, problem that is likely to be multifactorial in nature. In this regard, genetic factors may influence transmembrane drug transporter proteins, thereby modifying the intracerebral penetration of AEDs. Monogenic idiopathic epilepsies are rare and frequently associated with ion channel mutations; however, to date, a consistent relationship between changes in channel properties and clinical phenotype has not been established nor has any association between genotype and response to specific treatment options. Polymorphisms of drug targets may represent another genetic facet in epilepsy: a recent study demonstrated for the first time a polymorphism of a drug target (the alpha-subunit of a voltage-gated sodium channel) associated in clinical practice with differing response to two classic AEDs. Adverse drug reactions and teratogenicity of AEDs remain a major concern. Whole-genome single nucleotide polymorphism profiling might in the future help to determine genetic predisposing factors for adverse drug reactions. Recently, in Han Chinese treated with carbamazepine and presenting with Stevens-Johnson syndrome, a strong association was found with HLA B*1502. If genetically targeted drug development becomes more affordable/cost efficient in the near future, the development of new drugs for relatively rare diseases could become economically viable for the pharmaceutical industry. The synergy of lower trial costs and efficacy-based prescribing may reduce the cost of medical treatment for a particular disease. This hypothetical advantage of the practical use of pharmacogenetics is, however, counterbalanced by several possible dangers, including illicit data mining and the development of a human 'genetic underclass' with the risk of exclusion from, for example employment or health insurance, because of an 'unfavourable' genetic profile.     

Pharmacokinetics, toxicology and safety of lamotrigine in epilepsy

Optimisation of pharmacotherapy for epilepsy requires consideration of the impact of drug metabolism and toxicology on the therapeutic profiles and clinical use of antiepileptic drugs (AEDs). This review discusses the pharmacokinetics and toxicology of the AED lamotrigine, and considers the implications of these data for optimising its use in the management of epilepsy. Lamotrigine has good absorption, minimal plasma protein binding and linear pharmacokinetics. Partly because of these properties, frequent dosing adjustments are generally unnecessary, and therapeutic monitoring is not required under most circumstances. Lamotrigine is not associated with clinically significant neurological, cognitive, metabolic, hepatic or reproductive endocrine toxicity. Like other AEDs, including carbamazepine and phenytoin, lamotrigine has been associated with serious rash. With some exceptions, lamotrigine has relatively few clinically relevant drug interactions, a characteristic important in reducing safety risks, especially among patients who require polytherapy. The clinical impact of pharmacokinetic interactions between lamotrigine and enzyme-inducing AEDs or valproate can be minimised by adhering to recommended dose-escalation schedules with demonstrated reliability in clinical trials and clinical practice. Likewise, adhering to recommended dosing guidelines can minimise the risk of lamotrigine-associated rash. The pharmacokinetic, toxicology and safety profiles of lamotrigine make the drug suitable for use across a spectrum of patients with epilepsy.     

New antiepileptic drugs: review on drug interactions.

During the Past decade, nine new antiepileptic drugs (AEDs) namely, Felbamate, Gabapentin, Levetiracetam, Lamotrigine, Oxcarbazepine, Tiagabine, Topiramate, Vigabatrin and Zonisamide have been marketed worldwide. The introduction of these drugs increased appreciably the number of therapeutic combinations used in the treatment of epilepsy and with it, the risk of drug interactions. In general, these newer antiepileptic drugs exhibit a lower potential for drug interactions than the classic AEDs, like phenytoin, carbamazepine and valproic acid, mostly because of their pharmacokinetic characteristics. For example, vigabatrin, levetiracetam and gabapentin, exhibit few or no interactions with other AEDs. Felbamate, tiagabine, topiramate and zonisamide are sensitive to induction by known anticonvulsants with inducing effects but are less vulnerable to inhibition by common drug inhibitors. Felbamate, topiramate and oxcarbazepine are mild inducers and may affect the disposition of oral contraceptives with a risk of failure of contraception. These drugs also inhibit CYP2C19 and may affect the disposition of phenytoin. Lamotrigine is eliminated mostly by glucuronidation and is susceptible to inhibition by valproic acid and induction by classic AEDs such as phenytoin, carbamazepine, phenobarbital and primidone.     

Can pharmacokinetic variability be controlled for the patient's benefit? The place of TDM for new AEDs

The aim of this brief communication is to update our recent review on therapeutic drug monitoring (TDM) of the newer antiepileptic drugs (AEDs). The potential value of TDM is discussed in relation to their mode of action and their pharmacokinetic proper-ties. Data on the relationships between serum concentrations and clinical efficacy are limited, and few studies have been designed primarily to study these relationships. As yet there are no generally accepted target ranges for any of the new AEDs. For most drugs a wide range in serum concentration is associated with clinical efficacy,and there is a considerable overlap in serum concentrations related to toxicity and lack of clinical efficacy. Although the available documentation is clearly insufficient, the pharmacological properties of some of the drugs suggest that they may be suitable candidates for TDM. The primary role of TDM for both the newer and established AEDs is to identify an individual's optimum concentration and thus establish a reference value in that patient.     

Generic medicines: perceptions of consumers in Melbourne,Australia

Objective The objective of this study was to explore consumers' perceptions and opinions of generic medicines and to identify barriers to their use of generic medicines. Method A qualitative approach was used. A purposive sample of consumers, aged 22–80 years, living in the Melbourne, Australia, metropolitan area were interviewed using a semi‐structured interview guide. Key findings Sixteen consumers were interviewed. Thematic content analysis of the interviews identified four major themes: knowledge about generic medicines, acceptance of generics, non‐acceptance of generics, and education needs pertaining to generic medicine use. In terms of knowledge, some consumers were not familiar with the term ‘generic medicines’, but were more familiar with the term ‘cheaper brand of medicine’. The major reason for acceptance of generic medicines among the consumers interviewed was cost. Positive encouragement from the healthcare providers was seen to influence generic medicine uptake by consumers. The major barriers to acceptance included influence from medical practitioners, side‐effects from generic brands, and confusion that may arise from using different brands. To encourage future uptake of generics by consumers, some of the respondents recommended that education strategies be implemented by healthcare practitioners and governmental agencies to educate people on the safety and efficacy of generic medicines. Conclusions This study indicated that consumers interviewed generally had positive attitudes towards the use of generic medicines. The findings also suggest that direct patient education by the healthcare providers on issues relating to safety and efficacy of generic medicines could further enhance their uptake.     

抗癫痫药物在肝肾功能不全患者中使用的研究进展

临床常用抗癫痫药物根据其药动学特点可分为主要经肝代谢、主要经肾排泄和肝肾双通道清除。肝功能不全患者尽量选择主要经肾排泄的抗癫痫药物,如加巴喷丁、普瑞巴林,或评估肝功能不全的程度,适当的减少剂量。肾功能不全的患者尽量选择主要经肝代谢的抗癫痫药物,如丙戊酸钠、卡马西平、拉莫三嗪,或评估患者的肌酐清除率（CLcr）,根据CLcr进行剂量调整。对于透析的患者,结合血药浓度监测透析后补充剂量有助于个体化治疗。肝肾功能不全患者抗癫痫药物的选择、剂量调整应综合考虑患者肝肾功能情况、药物代谢特点、合并疾病、个体耐受性等因素,在抗癫痫药物使用过程中,加强对药物相互作用、药物不良反应等的监护,结合血药浓度监测,以提高临床用药的有效性与安全性。     

Generic Drug Regulation in the US Under the Hatch-Waxman Act

Generic drugs are bioequivalent copies of original drugs patented by brand-name companies. The regulation of generic drugs in the US has paralleled that of brand-name drugs. They were first allowed under US regulations in 1938 upon the initiation of the ‘modern era’ of drug regulation with the enactment of the Federal Food, Drug and Cosmetic Act (FDCA). As with brand-name drugs, regulation of generics underwent significant change in the wake of the 1962 amendments to the FDCA, particularly with the passage of the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Act. This act required the US FDA to establish an abbreviated new drug approval procedure for generic drugs, including a means of evaluating the bioequivalence of generic drugs to that of pioneer drugs, as well as a mechanism for identifying approved pioneer drugs and challenging their patents. The administrative tool developed to assist this process was a listing of approved drugs, patents, and equivalence ratings, commonly called the ‘Orange Book.’ In the aftermath of the Hatch-Waxman Act, the generic drug industry experienced considerable ‘growing pains’: a bribery scandal, disenfranchisement by FDA regulatory reform, persistence of barriers to generic entry, continuing problems with establishing equivalence to pioneer drugs, and lack of congressional support. Recently, as a result of increasing public pressure to address the rising costs of healthcare, the problems of generic drug makers, such as patent listing abuses and the lack of a regulatory review process for biogenerics, have received attention from both the legislative and executive branches of the US government. The FDA issued a proposed rule to close some of the loopholes in the Hatch-Waxman Act in late 2002, while the congressional tussle over various legislative proposals to promote generics has begun anew with the initiation of the 108th Congress. While these activities will determine some near-term outcomes for the generic drug industry, the industries’ long-term prospects will depend on whether it continues to benefit the healthcare system by providing low-cost competition to brand-name products without decimating the brand-name industry’s economic incentive to provide innovative new medicines.     

The economic implications of generic substitution of antiepileptic drugs: a review of recent evidence

Background: The US Food and Drug Administration (FDA) considers generic and branded drugs to be therapeutically equivalent if they are pharmaceutically equivalent and bioequivalent. The American Academy of Neurology (AAN) disagrees and opposes generic substitution of branded antiepileptic drugs (AEDs) without physician and patient approval due to the risk of loss of seizure control. Objective: To review the evidence to date surrounding the economic impact of brand-to-generic substitutions of AEDs. Methods: A systematic search of PubMed and MEDLINE was conducted; the bibliographies of key articles obtained from the search were used to identify additional sources. Results/conclusion: Current literature suggests statistically higher overall healthcare costs during periods of generic AED use than during periods when branded AED are used, consistently demonstrated across different countries (Canada and the USA) and in both stable and unstable epilepsy patients, with more pronounced cost increases in patients receiving multiple generic versions. Brand-to-generic substitutions of AEDs do not necessarily reduce overall healthcare costs and may even increase them.     

Statistical approaches to indirectly compare bioequivalence between generics: a comparison of methodologies employing artemether/lumefantrine 20/120?mg tablets as prequalified by WHO

Purpose

The objective of this study was to compare different methods of adjusted indirect comparisons that can be used to investigate the relative bioavailability of different generic products. To achieve this goal, generic artemether/lumefantrine 20/120?mg tablets that have been prequalified by the World Health Organization (WHO) were selected as model products for study.

Methods

Data from three bioequivalence studies conducted independently that compared three generics with the same reference product were used to indirectly determine the relative bioavailability between the generics themselves.

Results

The different methods of indirect comparison examined in this study provide consistent results. Methods based on the assumption of a large sample size give slightly narrower 90?% confidence intervals. Therefore, the use of methods based on the t test is recommended. Given the precision of the area under the time–concentration curve (AUC) data, it is possible to conclude that the extent of exposure of artemether and lumefantrine is bioequivalent between the different generics studied. However, given the precision of the drug peak concentration (C_max) data, it is not possible to demonstrate equivalence within the conventional acceptance range for all comparisons; it is possible to conclude bioequivalence within the widened acceptance range 75–133?%.

Conclusions

From a clinical viewpoint, not only are these prequalified generics bioequivalent and interchangeable with the reference product (Coartem, Novartis), but also the existing indirect evidence makes it possible to conclude that these WHO prequalified products are bioequivalent between themselves with respect to the AUC. The lack of the necessary precision to demonstrate bioequivalence between generics with respect to the C_max within the conventional acceptance range does not preclude considering them as interchangeable, if necessary, since C_max is considered to be of less clinical relevance for the relevant therapy.     

The new antiepileptic drugs lamotrigine and felbamate are effective in phenytoin-resistant kindled rats

We evaluated the anticonvulsant efficacy of the antiepileptic drugs (AEDs) lamotrigine (LTG) and felbamate (FBM) in amygdala kindled rats that had been preselected with respect to their response to phenytoin. Anticonvulsant response was tested by determining the afterdischarge threshold (ADT), i.e., a sensitive measure for drug effects on focal seizure activity. By repeated testing with the phenytoin prodrug fosphenytoin, 3 groups of kindled rats were separated: rats in which consistent anticonvulsant effects were obtained (phenytoin responders), rats which showed no anticonvulsant response (phenytoin nonresponders), and rats with variable responses (variable phenytoin responders). The latter, largest group was used to evaluate at which doses LTG and FBM exerted significant anticonvulsant effects on ADT 1 h after i.p. drug administration. Effective doses were then used for drug testing in phenytoin responders and nonresponders. Both LTG and FBM proved to be effective anticonvulsant drugs in the kindling model by markedly increasing the ADT. Seizure severity and duration recorded at ADT currents were hardly reduced, indicating that both drugs predominantly affect induction of focal seizures and not seizure spread from the focus. In phenytoin nonresponders, LTG and FBM significantly increased ADT, which is in line with their proven efficacy in patients with refractory partial epilepsy in whom phenytoin has failed. However, LTG and, more markedly, FBM were clearly more efficacious in increasing ADT in phenytoin responders than in nonresponders, substantiating that the difference in phenytoin response between these groups of kindled rats extends to other AEDs. The data in this study reveal that phenytoin nonresponders are a unique model for the search for new AEDs with improved efficacy in refractory partial epilepsy.     

Efficacy and safety of innovator versus generic drugs in patients with epilepsy: a systematic review

Generic antiepileptic drugs achieve blood concentrations similar to those of innovator drugs in healthy volunteers, but their comparative effectiveness has not been well evaluated. Thus, we assessed the efficacy, tolerability, and safety of innovator versus generic antiepileptic drugs. We searched the MEDLINE database, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science for studies that evaluated innovator and generic antiepileptic drugs in patients with epilepsy and reported data on prespecified outcomes. We extracted data on study design, interventions, quality criteria, study population, baseline characteristics, and outcomes. Compared with initiation of innovator antiepileptic drugs, initiation of generic antiepileptic drugs did not significantly alter seizure occurrence (relative risk [RR] 0.87, 95% confidence interval [CI] 0.64-1.18; strength of evidence: low) or frequency (standardized mean difference 0.03, 95% CI -0.08-0.14; strength of evidence: low), withdrawals due to lack of efficacy (RR 1.02, 95% CI 0.41-2.54; strength of evidence: low) or adverse events (RR 0.79, 95% CI 0.28-2.20; strength of evidence: low), pharmacokinetic concentrations (maximum, minimum, or area under the curve [strength of evidence: low]), or a myriad of adverse events (strength of evidence: low or insufficient) in clinical trials. In qualitatively evaluated observational studies, switching between forms of antiepileptic drug (innovator to generic, generic to generic) may increase the risk of hospitalization (strength of evidence: low), hospital stay duration (strength of evidence: low), and a composite end point of medical service utilization (strength of evidence: insufficient) but may not increase outpatient service utilization (strength of evidence: low). Data are limited predominantly to carbamazepine, phenytoin, and valproic acid. Clinical trials are limited by small sample size, short-term nature, and lack of specification of A-rated generic products (generics that the United States Food and Drug Administration has deemed bioequivalent to the innovator drug). Observational trials lack full accounting for confounders and have inherent limitations. With a low strength of evidence, it appears that initiating an innovator or generic antiepileptic drug will provide similar efficacy, tolerability, and safety but that switching from one form to the other may be associated with more hospitalizations and longer hospital stays.     

开展仿制药质量一致性评价的探讨

2012年1月20日,国务院下发的《关于印发国家药品安全“十二五”规划的通知》中要求开展仿制药一致性评价工作。本文概述我国仿制药质量存在的问题及其原因,提出开展一致性评价重点在于多条溶出曲线都要与原研药一致,旨在为进一步开展仿制药一致性评价工作提供建议。