Abstract
In planning comparative bioavailability and bioequivalence trials, the half-life of
the parent compound and metabolites included in the active moiety requires careful
attention. Drugs cleared with long or very long half-lives, mainly in cases of clearance
from a deep compartment, could suffer from an inappropriate prevision of the half-life.
Prevision of a too short half-life would produce shorter blood sampling and wash-out
periods with critical consequences on the extrapolation of AUC to infinity and on
a possible carryover effect of the circulating concentration of analytes in the pre-dose
sample of the second study period. This problem is further complicated by the evidence
that half-lives are influenced by the low limit of quantification of the bioassay
method (inverse correlation) and by the blood sampling period (direct correlation).
Examples of tamoxifen (CAS 10540-29-1) and its active metabolite desmethyl-tamoxifen
and ramipril (CAS 87333-19-5) and its active metabolite ramiprilat are described on
the basis of experimental data, focusing on the clearance from a deep compartment
occurring with ramiprilat.
Key words
Bioassay - Bioequivalence - Clearance - Guidelines - Terminal half-life
