Chiral bioequivalence: effect of absorption rate on racemic etodolac.
BACKGROUND
For many racemic drugs, bioequivalence assessment based on isomer-nonspecific assays is appropriate because enantiomeric area under the concentration-time curve (AUC) exposure ratios are close to unity. Use of nonspecific methods in cases in which the ratio is substantially greater or less than 1, however, may obscure real therapeutic differences among formulations, especially if the enantiomers exhibit differing pharmacological potencies.


OBJECTIVE
To examine the influence of absorption rate on etodolac bioequivalence as measured by total [(R,S)-] and (S)-etodolac.


METHODS
Single dose, 3-period, crossover, pharmacokinetic study in 24 healthy volunteers in which the administration rate of etodolac was varied.


METHODS
Participants received etodolac 400mg in solution, given as a single dose over 1 minute or as divided doses over 30 and 90 minutes. Unresolved and enantiomer concentrations of etodolac were measured by a validated HPLC assay. The enantiomer ratio was similarly measured by HPLC.


RESULTS
Bioequivalence parameters derived for both unresolved and (S)etodolac indicate that peak plasma drug concentration (Cmax) was not bioequivalent. By delaying absorption, bioequivalence was lost.


CONCLUSIONS
Collectively, these data demonstrate that bioequivalence between 2 products of etodolac based on enantiomerically nonspecific criteria alone may not generalise to the pharmacologically relevant (S)-enantiomer. This suggests that enantiospecific assays are necessary for bioequivalence assessments.
Boni
J R
JR
Department of Clinical Pharmacokinetics, Wyeth-Ayerst Research, Radnor, Pennsylvania 19101-1245, USA. bonij@war.wyeth.com
Korth-Bradley
J M
JM
Richards
L S
LS
Chiang
S T
ST
Hicks
D R
DR
Benet
L Z
LZ
D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D017308:Etodolac / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D013237:Stereoisomerism; D013810:Therapeutic Equivalency
D000894:Anti-Inflammatory Agents, Non-Steroidal; D017308:Etodolac