BIOEQUIVALENCE STUDY OF ALPHA-DIHYDROERGOCRYPTINE - UTILITY OF METABOLITE EVALUATION

Metabolite assessment is an open question in bioequivalence studies. I n situations of low absorption, high first-pass metabolism, and intras ubject variability, metabolites may reflect absorption more adequately than the parent drug, and their determination may help decision-makin g in bioequivalence issues. Treating alpha-dihydroergocryptine (DHECT) as a model, we used both unchanged DHECT and a pool of DHECT metaboli tes to evaluate the bioequivalence of 2 oral DHECT formulations (refer ence-R and test-T) in 12 subjects. DHECT and its metabolites were immu noassayed. There was no difference between the 2 formulations in terms of the AUC(0-infinity) (area under the curve) values determined from unchanged DHECT or DHECT with metabolites profiles: 572 +/- 490 pg/ml. h (R) and 442 +/- 276 pg/ml.h (T) for unchanged DHECT, and 7,141 +/- 2 ,936 pg/ml.h (R) and 6,941 +/- 1,462 pg/ml.h (R) for DHECT with metabo lites. Confidence intervals were within the ranges 0.8 - 1.25 (AUC(0-i nfinity)) and 0.7 - 1.43 (C-max) for DHECT with metabolites but not fo r unchanged DHECT. This study describes a particular case where only m easurements on the basis of the metabolites can justify the assumption of bioequivalence.