Bioequivalence of Racemic Drugs

Abstract

Although pharmacokinetic and pharmacodynamic differences between the enantiomers of a chiral drug have been known or suspected for many years, racemate drugs have frequently been developed and approved without clinical pharmacologic consideration of their chiral components. In the late 1970s, the technology to isolate, manufacture, and detect pure enantiomers of racemate drugs became generally available. This availability has created new demands on both pharmaceutical firms and regulatory agencies. To prepare for this new technology, the Center for Drug Evaluation and Research at the Food and Drug Administration is formulating a policy statement to guide evaluation of new chiral drugs. At this time, it appears that whatever new policies are developed will not necessarily be applied retroactively to previously approved racemate drugs. Additional policies to guide the development and approval of generic and OTC chiral drugs may be required. In the Office of Generic Drugs in the Center, abbreviated new drug or antibiotic applications are approved on the basis of adequate chemistry, manufacturing, and control procedures and comparative pharmacokinetics (bioequivalence). The generic drug must be a racemate or single enantiomer if the corresponding innovator drug is a racemate or single enantiomer respectively. Whether a generic firm will be required to provide bioequivalence information on enantiomers of a racemate is determined on a case-by-case basis. Although it might be claimed that a generic drug product should be required only to undergo the same general kind of pharmaceutical evaluation as did the innovator, there may be instances when the approval of a generic drug or antibiotic will require measurement of specific enantiomers of a chiral drug.

Pharmacokinetics and pharmacodynamics of stereoisomeric drugs with particular reference to bioequivalence determination

“…For many years, the availability of racemic mixture drug products, in preference to single enantiomers, was justified by lower production costs and/or lack of availability of chirally specific drug synthesis methods (Nerurkar et al. , 1992).…”

Comparison of the Effects of Pantoprazole and Its Enantiomers on Gastric Acid, Mucus, and Mucosa as Well as Endocrine Cells

“…(-)-PAN·Na shows stronger efficacy than (+)-PAN·Na and (±)-PAN·Na in preventing gastric mucosal lesions induced by water-immersion stress, aspirin, ethanol, reserpine, histamine, and pyloric ligation. 14,15) We have also observed that (-)-PAN·Na is more potent than (+)-PAN·Na and (±)-PAN·Na in inhibiting acid secre- No. 5 521 tion in adult rats with acute fistula.…”

“…: +81-3-3784-8131; Fax: +81-3-3784-3069; E-mail: whzhao@med.showa-u.ac.jp nism. [4][5][6] Esomeprazole was the first proton pump inhibitor developed as an optical isomer of omeprazole and shows an improved pharmacokinetic profile, such as less interindividual variability and stronger activity to suppress gastric acid secretion than racemic omeprazole. [7][8][9][10] There are some reports on pharmacokinetic differences between pantoprazole and its enantiomers, [11][12][13] however, to date little information can be found on the pharmacodynamics of pantoprazole enantiomers.…”

Assessment of bioequivalence of drug racemates: what are the cues from a bioanalytical perspective—stereoselective vs nonstereoselective?

“…While the pipeline of availability of chiral assays continues to increase, the debate on the dependency of bioequivalence assessment of racemic drugs using nonstereoselective assays has persisted for over two decades (Brocks, 2006;Garcia-Arieta et al, 2005;Srinivas, 2004c;Boni et al, 2000;Bui et al, 2000;Deprez et al, 1998;Mehvar and Jamali, 1997;Marzo and Balant, 1995;Nerurkar et al, 1992;Jamali, 1992).…”