Therapeutic Index Estimation of Antiepileptic Drugs: A Systematic Literature Review Approach

Greenberg, Rachel G.; Melloni, Chiara; Wu, Huali; González, Daniel; Ku, Lawrence; Hill, Kevin D.; Hornik, Christoph P.; Cohen‐Wolkowiez, Michael; Guptill, Jeffrey T.

doi:10.1097/wnf.0000000000000172

Cited by 57 publications

(52 citation statements)

References 77 publications

(60 reference statements)

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“…This can have serious consequences for narrow therapeutic index (NTID) drugs, where the difference between therapeutic and toxic doses is minimal (e.g. cardenolides, carbamazepine, phenytoin or warfarin [17,18]) and any changes in the concentration of unbound, active form may be poorly tolerated by the organism. A sudden increase in the unbound fraction of the drug may provide a toxic effect [19].…”

Section: Drug-protein Bindingmentioning

confidence: 99%

Biological barriers, and the influence of protein binding on the passage of drugs across them

Wanat

2020

Mol Biol Rep

104

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Drug-protein binding plays a key role in determining the pharmacokinetics of a drug. The distribution and protein binding ability of a drug changes over a lifetime, and are important considerations during pregnancy and lactation. Although proteins are a significant fraction in plasma composition, they also exist beyond the bloodstream and bind with drugs in the skin, tissues or organs. Protein binding influences the bioavailability and distribution of active compounds, and is a limiting factor in the passage of drugs across biological membranes and barriers: drugs are often unable to cross membranes mainly due to the high molecular mass of the drug-protein complex, thus resulting in the accumulation of the active compounds and a significant reduction of their pharmacological activity. This review describes the consequences of drug-protein binding on drug transport across physiological barriers, whose role is to allow the passage of essential substances-such as nutrients or oxygen, but not of xenobiotics. The placental barrier regulates passage of xenobiotics into a fetus and protects the unborn organism. The blood-brain barrier is the most important barrier in the entire organism and the skin separates the human body from the environment.

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Section: Drug-protein Bindingmentioning

confidence: 99%

Biological barriers, and the influence of protein binding on the passage of drugs across them

Wanat

2020

Mol Biol Rep

104

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“…• Clinical studies show that switching to or among generics has an impact on drug serum levels similar to lots of the same brand • If switching to or among generic AEDs is necessary, physicians should counsel their patients on the need for good adherence to reduce risks on a systematic literature review, only identified phenytoin as an NTI drug; the therapeutic index of phenobarbital and valproate exceeded 2, and available data for carbamazepine and lamotrigine were insufficient for calculations. 6 Regulatory bodies such as the FDA require proof of "bioequivalence" between innovator and generic drugs as the criterion of approving the latter. The FDA criterion for bioequivalence is 90% confidence that the ratios of the test to "reference (innovator)" drug log-transformed mean values for area under the plasma concentration-time curve (AUC) and peak plasma concentration (C max ) lie within an interval of 80%-125% ( Figure 2).…”

Section: Key Pointsmentioning

confidence: 99%

“…Several issues have been raised regarding the use of generic AEDs for patients with epilepsy. Although generally overestimated, a few AEDs may have a narrow therapeutic index (NTI): small fluctuations in drug levels potentially lead to loss of efficacy at the low end or to side effects at the high end of the range . The U.S. Food and Drug Administration (FDA) defines NTI drugs as those having less than a 2‐fold difference between median lethal dose (LD50) and median effective dose (ED50), or less than a 2‐fold difference between minimum blood toxic and effective concentrations, requiring careful titration and monitoring .…”

Section: Introductionmentioning

confidence: 99%

“…Currently, the FDA classifies only carbamazepine and phenytoin as NTI AEDs and demands tighter criteria for approval of these compounds as generics, that is, studies with a 4‐period crossover repeat design . Considering the FDA definition for NTI drugs, a recent study, which estimated the therapeutic index of some AEDs based on a systematic literature review, only identified phenytoin as an NTI drug; the therapeutic index of phenobarbital and valproate exceeded 2, and available data for carbamazepine and lamotrigine were insufficient for calculations …”

Section: Introductionmentioning

confidence: 99%

“…Although generally overestimated, a few AEDs may have a narrow therapeutic index (NTI): small fluctuations in drug levels potentially lead to loss of efficacy at the low end or to side effects at the high end of the range. 6 The U.S. Food and Drug Administration (FDA) defines NTI drugs as those having less than a 2-fold difference between median lethal dose (LD50) and median effective dose (ED50), or less than a 2-fold difference between minimum blood toxic and effective concentrations, requiring careful titration and monitoring. 7 Currently, the FDA classifies only carbamazepine and phenytoin as NTI AEDs and demands tighter criteria for approval of these compounds as generics, that is, studies with a 4-period crossover repeat design.…”

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confidence: 99%

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Generic antiepileptic drugs—Safe or harmful in patients with epilepsy?

Holtkamp

Theodore

2018

Epilepsia

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Summary Generic antiepileptic drugs (AED) are significantly cheaper than brand name drugs, and may reduce overall health care expenditures. Regulatory bodies in Europe and North America require bioequivalence between generic and innovator drugs with regard to area under the plasma concentration–time curve (AUC) and peak plasma concentration (Cmax); strict cutoff values have been defined. The main issue is if bioequivalence ensures therapeutic equivalence. Are switches from brand to generic, or between generic AEDs entirely safe or potentially harmful in patients with epilepsy? We summarized and evaluated the available evidence from bioequivalence, health care utilization, and clinical studies on safety of generic AEDs. In most cases, variations in AUC and Cmax were negligible when comparing innovator and generic AEDs. Due to interindividual pharmacokinetic and pharmacodynamic variability, measured differences between innovator and generic drugs may be the same as differences between different lots of the same brand. Studies from several countries based on insurance data have reported an increase in health care usage after switch from brand to generic AEDs; switchback rates are significantly higher for AEDs compared to other compounds. Patients may be confused, and nonadherence may increase, when AEDs are switched between manufacturers, perhaps due to changes in medication shape and color. But clinical studies do not report changes in seizure frequency and tolerability attributable to generics. Sufficient evidence indicates that most generics are bioequivalent to innovator AEDs; they do not pose a relevant risk for patients with epilepsy. However, some patients are reluctant towards variations in color and shape of their AEDs which may result in nonadherence. We recommend administering generics when a new AED is initiated. Switches from brand to generic AEDs for cost reduction and between generics, which is rarely required, generally seem to be safe, but should be accompanied by thorough counseling of patients on low risks.

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Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA‐B Genotypes and Phenytoin Dosing: 2020 Update

Karnes

Rettie

Somogyi

et al. 2020

Clin Pharma and Therapeutics

118

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Phenytoin is an antiepileptic drug with a narrow therapeutic index and large interpatient pharmacokinetic variability, partly due to genetic variation in CYP2C9. Furthermore, the variant allele HLA-B*15:02 is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotypes (updates on cpicpgx.org). The purpose of this guideline is to provide information for the interpretation of human leukocyte antigen B (HLA-B) and/or cytochrome P450 2C9 (CYP2C9) genotype test results to guide use and/or dosing of phenytoin. Guidelines for phenytoin use and cost-effectiveness of genetic testing are outside the scope of this report. This guideline updates the 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing. 1 CPIC guidelines are periodically updated at www.cpicp gx.org. FOCUSED LITERATURE REVIEW We reviewed literature focused on CYP2C9 and HLA variation and phenytoin use (details in Supplementary Material). Evidence is summarized in Table S1 and Table S2. Genes: HLA-B and CYP2C9 Background. This guideline discusses HLA-B and the risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with phenytoin and CYP2C9 as it relates to phenytoin metabolism and dosing. Updated CYP2C9 allele function assignments are provided using the activity score system.

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Therapeutic Index Estimation of Antiepileptic Drugs: A Systematic Literature Review Approach

Cited by 57 publications

References 77 publications

Biological barriers, and the influence of protein binding on the passage of drugs across them

Biological barriers, and the influence of protein binding on the passage of drugs across them

Generic antiepileptic drugs—Safe or harmful in patients with epilepsy?

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA‐B Genotypes and Phenytoin Dosing: 2020 Update

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