Chiral Switch Drugs for Asthma and Allergies: True Benefit or Marketing Hype

Blake, Kathryn; Raissy, Hengameh H.

doi:10.1089/ped.2013.0285

Cited by 11 publications

(11 citation statements)

References 38 publications

(33 reference statements)

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“…However, regulatory agencies' interest in evaluating each enantiomer in a racemate spurred development of single enantiomers, which now account for 55% of the new molecular entities approved by the US Food and Drug Administration (Agranat et al, 2012). Although the decision to develop a single-enantiomer product should include both scientific and economic rationales (Blake and Raissy, 2013), poor understanding of the kinetics of each individual enantiomer, especially the interplay between enantiomer racemization and difference in enantiomer elimination, can still lead to redundant investment in developing an enantiomer over the racemate. Levalbuterol, the R-enantiomer of albuterol, was introduced in the US market in 1999 based on the fact that the R-enantiomer is stereoselective at the target receptor with a 68-fold greater potency than the S-enantiomer (Brittain et al, 1973).…”

Section: Discussionmentioning

confidence: 99%

“…However, a randomized crossover study in which the racemate and the R-and S-enantiomers were administered demonstrated that the therapeutic ratio of the Renantiomer was comparable with that of the racemate in asthma patients (Lotvall et al, 2001), which might be due to the limited understanding of the interplay between enantiomer racemization and enantiomer elimination in vivo. Similarly, arformoterol, the (R,R)-enantiomer of formoterol, having a 1000-fold greater potency than the (S,S)-enantiomer, was approved by the US Food and Drug Administration in 2006 (Blake and Raissy, 2013). Available data indicate that there is no evidence to suggest an advantage of the (R,R)-enantiomer, which might be due to the different kinetic profiles.…”

Section: Discussionmentioning

confidence: 99%

“…The scientific decision tree to inform the development of an active enantiomer from a racemate begins with confirmation of stereoselectivity in receptor recognition and includes in vivo efficacy (Blake and Raissy, 2013). Importantly, the active enantiomer must not racemize (interconvert between enantiomers) in any clinically meaningful time frame and extent, have no pharmacodynamic or PK interaction with the inactive enantiomer, and have no adverse effects not already known for the racemate.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, the active enantiomer must not racemize (interconvert between enantiomers) in any clinically meaningful time frame and extent, have no pharmacodynamic or PK interaction with the inactive enantiomer, and have no adverse effects not already known for the racemate. Moreover, the enantiomer must represent a therapeutic advantage for the patient by having a more selective pharmacodynamic profile; improved therapeutic index; a less complex PK profile, such as a more direct relationship between concentration and effect; and reduced potential for drug interactions (Blake and Raissy, 2013).…”

Section: Discussionmentioning

confidence: 99%

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Modeling and Simulation to Probe the Pharmacokinetic Disposition of PomalidomideR- andS-Enantiomers

Li¹,

Zhou²,

Hoffmann³

et al. 2014

J Pharmacol Exp Ther

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Pomalidomide, a potent novel immunomodulatory agent, has been developed as a racemic mixture of its R-and S-isomers. Pharmacokinetic (PK) analyses were conducted to determine the PK disposition of the isomers from their PK profiles in humans and monkeys. Modeling and simulation were performed to describe the observed PK profiles and explore potential differences in isomer disposition and exposure. PK profiles of Sand R-isomers were measured in a human absorption, distribution, metabolism, and excretion study after oral administration of racemate. PK profiles of S-and R-isomers were measured in monkeys after intravenous and oral administration of S-or Risomers and pomalidomide racemate. Modeling and simulation were performed using NONMEM 7.2 (Globomax, Ellicott City, MD) to describe the observed PK profiles of S-and R-isomers in humans and monkeys. The results showed that in humans, the in vivo elimination rate of pomalidomide isomers was lower than the R-/S-interconversion rate, resulting in no clinically relevant difference in overall exposure to the two isomers. However, in monkeys, the in vivo elimination rate was higher than the R-/Sinterconversion rate, resulting in 1.72-and 1.55-fold differences in R-versus S-isomer exposures. Monte Carlo simulation indicated that exposure to R-and S-enantiomers in humans should be comparable even if single isomers are administered. Thus, in humans, rapid isomeric interconversion of pomalidomide isomers results in comparable exposure to R-and S-enantiomers regardless of whether pomalidomide is administered as a single enantiomer or as a racemate, therefore justifying the clinical development of pomalidomide as a racemate.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Modeling and Simulation to Probe the Pharmacokinetic Disposition of PomalidomideR- andS-Enantiomers

Li¹,

Zhou²,

Hoffmann³

et al. 2014

J Pharmacol Exp Ther

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show abstract

“…For better clinical performance of the molecule, it has become necessity to study the chirality of the molecule. In most of the cases, it can be studied by optical rotatory dispersion and circular dichroism [8].…”

Section: Chiralitymentioning

confidence: 99%

Preformulation Studies: An Integral Part of Formulation Design

Patel¹

2020

Pharmaceutical Formulation Design - Recent Practices

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When a promising new chemical entity is synthesized, it needs transformation to appropriate formulation in order to show a better and desirable action at appropriate site. Preformulation study is a phase which is initiated once the new molecule is seeded. In a broader way, it deals with studies of physical, chemical, analytical, and pharmaceutical properties related to molecule and provides idea about suitable modification in molecule to show a better performance. Study of these parameters and suitable molecular modification can be linked to generation of effective, safer, stable, and reliable pharmaceutical formulation. Therefore, preformulation study is an approach for generation of pharmaceutical formulation which utilizes knowledge and area application of toxicology, biochemistry, medicinal chemistry, and analytical chemistry. The highlighted chapter is framed with a vision to provide an in-depth knowledge about pharmaceutical formulation development.

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Rationalization of stereoselectivity in enzyme reactions

Chan

Pan

et al. 2018

WIREs Comput Mol Sci

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Enzymes are responsible for more than 5,000 different types of biochemical reactions. Enzymes speed up various chemical reactions in cell that would otherwise take millions of years to occur in milliseconds. The ability to discriminate between optical isomers is vital for living systems. The selective formation of only one product stereoisomer from achiral substrates is one of the most sophisticated tasks for enzymes. Because of the importance of stereoselectivity in biology, the structural and mechanistic basis underlying these phenomena has become the subject of intensive research. Enzymatic reactions provide the basis of cellular biochemistry and typically display high stereoselectivity. With the advances of enzyme engineering, in vitro evolution and, especially, computational rational design, scientists start to provide various methods and tools to manipulate the stereoselective properties of enzymes. To gain an insightful view of stereoselectivity in enzyme reactions, we present an extensive discussion on the latest progresses in this area.

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Chiral Switch Drugs for Asthma and Allergies: True Benefit or Marketing Hype

Cited by 11 publications

References 38 publications

Modeling and Simulation to Probe the Pharmacokinetic Disposition of PomalidomideR- andS-Enantiomers

Modeling and Simulation to Probe the Pharmacokinetic Disposition of PomalidomideR- andS-Enantiomers

Preformulation Studies: An Integral Part of Formulation Design

Rationalization of stereoselectivity in enzyme reactions

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