The therapeutic promise of single enantiomers: introduction

Wainer, Irving W.

doi:10.1002/hup.333

Cited by 11 publications

(7 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As a result of strong grass root movements that started and flourished in the whole of 1980s, the thinking towards chirality aspects and their likely impact on therapeutic outcome and redefining the benefit-risk potential of enantiomers vs racemate, via chiral switches, has taken a front seat. Now it is well understood that the therapeutic dilemma posed by the use of racemic drugs is largely due to the differences in interactions between individual enantiomers and the asymmetric environment of the biological systems (Ariens, 1984;Hutt and O'Grady, 1996;Wainer, 2001;Benedetti et al, 2002;Baumann et al, 2002). As a direct consequence, the enantiomers have been observed to demonstrate disparities in the respective pharmacological, pharmacokinetic, pharmacodynamic and toxicological properties (Drayer, 1986;Jamali et al, 1989;Rentsch, 2002;Srinivas, 2001).…”

mentioning

confidence: 99%

Evaluation of experimental strategies for the development of chiral chromatographic methods based on diastereomer formation

Srinivas

2004

Biomedical Chromatography

View full text Add to dashboard Cite

The past two decades has seen explosive growth in the field of chirality as illustrated by the rapid progress in the various facets of this intriguing field. Firstly, it is the basic understanding of the importance of chirality and, secondly, the awareness of the therapeutic pitfalls due to failure to recognize chirality that have paved the way for a rejuvenated interest in the field. Needless to say that the impetus for chiral separation advancement and enhancement has been found to be the highest in the past decade and still continues to be an area of high focus. In this regard, both direct and indirect separation approaches have been instrumental in placing into literature stereoselective pharmacokinetic and pharmacodynamic data of plethora of drug racemates. Also, today, the cloud of uncertainty associated with the development of a chiral molecule is a thing of the past because the field is so evolved and numerous options are available for stereoselective analysis. However, the decision to advance either a single enantiomer or a racemate for development has to be made by a rational approach with adequate justification. Although indirect method of chiral separation has been well established with numerous examples of well-documented cases of stereoselective pharmacokinetic data, there is a growing need for a review that provides a strategic overview of considerations and key issues for developing chromatographic methods based on diastereomer formation. This review provides a general framework for the exploratory planning and a definitive game plan for the establishment of chiral methods based on diastereomer formation. Also, it provides an exhaustive list of applications of numerous chiral derivatization reagents that have been used in the generation of stereoselective pharmacokinetic data.

show abstract

mentioning

confidence: 99%

Evaluation of experimental strategies for the development of chiral chromatographic methods based on diastereomer formation

Srinivas

2004

Biomedical Chromatography

View full text Add to dashboard Cite

show abstract

“…Our study identified RCTs favoring a single-enantiomer drug over its racemic precursor based on any safety end point for only 3 of 15 drugs, and differences were often observed for a single adverse event or vital sign without clear clinical relevance. Benefits claimed with chiral switching often revolve around safety, 5 , 14 and previous reviews relying on preclinical evidence or trials in healthy volunteers have suggested that single-enantiomer drugs are safer than racemic drugs. 12 , 25 , 26 For example, according to animal studies and trials in healthy volunteers, levobupivacaine, which accounted for two-thirds of identified RCTs, was believed to pose less risk of cardiac and central nervous system toxicity than its precursor, bupivacaine.…”

Section: Discussionmentioning

confidence: 99%

“… 3 However, the suggested benefits of single-enantiomer drugs are often based on nonclinical trial evidence, such as in vitro and animal studies. 3 , 5 , 12 , 13 , 14 Moreover, manufacturers of single-enantiomer drugs are not required to conduct randomized clinical trials (RCTs) directly comparing their products with existing racemic drugs before receiving FDA approval. 15 , 16 , 17 Between 2001 and 2011, only one-third of approvals of single-enantiomer drugs with racemic precursors were based on RCTs directly comparing the 2 drugs.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Trials Comparing Single-Enantiomer Drugs to Their Racemic Precursors

et al. 2021

View full text Add to dashboard Cite

Key Points Question How often do randomized clinical trials directly compare new single-enantiomer drugs to their existing racemic precursors, and how often are efficacy or safety differences observed? Findings In this systematic review of 15 single-enantiomer racemic drug pairs, 185 direct-comparison randomized clinical trials (median, 2 trials; interquartile range, 1-8 trials) were identified, 124 (67.0%) of which studied 1 drug pair. For 9 single-enantiomer drugs, no randomized clinical trials were identified providing evidence of improved efficacy, based on primary end point results, or safety as compared with their racemic precursors. Meaning Results of this systematic review suggest that most newly marketed single-enantiomer drugs are infrequently directly compared with their existing racemic precursors, and when compared, they are uncommonly found to provide improved efficacy or safety, despite their greater costs.

show abstract

“…In the case of indacrinone which is used in the treatment of hypertension and congestive heart failure, the free fractions are 0.9% and 0.3% for the (R)-and (S)-enantiomer respectively [130].…”

Section: Ix)mentioning

confidence: 99%

Exploiting the Power of Stereochemistry in Drugs: An Overview of Racemic and Enantiopure Drugs

Sekhon¹

2013

J. Mod. Med. Chem.

View full text Add to dashboard Cite

Stereochemistry is one of the essential dimensions in pharmacology as it dictates how enantiomers interact with biological systems. Chirality is very important in drug design. Enantiomers of the same chiral drug can have different pharmacodynamic and/or pharmacokinetic properties. In this context, replacing some existing racemates with single isomers has resulted in improved safety and/or efficacy profile of various racemates. Single enantiomer drug use can potentially lead to simpler and more selective pharmacologic profiles, improved therapeutic indices, simpler pharmacokinetics due to different rates of metabolism of the different enantiomers, decreased drug interactions, and drug companies are increasingly using chiral switching as a marketing strategy. Additionally, due to different pharmacological activity, enantiomers of chiral drugs can differ in toxicity. However, unpredicted toxicity has been reported in some chiral switching cases which has resulted the withdrawal of the enantiomer from the market or a halt in its development. In view of above, before switching to single enantiomer drugs, prescribers should look for evidence from well-conducted clinical trials to prove that the chiral switch is cost-effective and improves the outcomes for patients rather than patents. The U.S. Food and Drug Administration (FDA) have allowed single enantiomers of generic drugs to be patented and marketed under different name. FDA regulations require that all chiral bioactive drug molecules must be isolated and tested for the efficacy and safety, and have to be as pure as possible containing a single pure enantiomer.

show abstract

The therapeutic promise of single enantiomers: introduction

Cited by 11 publications

References 13 publications

Evaluation of experimental strategies for the development of chiral chromatographic methods based on diastereomer formation

Evaluation of experimental strategies for the development of chiral chromatographic methods based on diastereomer formation

Evaluation of Trials Comparing Single-Enantiomer Drugs to Their Racemic Precursors

Exploiting the Power of Stereochemistry in Drugs: An Overview of Racemic and Enantiopure Drugs

Contact Info

Product

Resources

About