Evaluation of truncated areas in the assessment of bioequivalence of immediate release formulations of drugs with long half-lives and of Cmax with different dissolution rates.
OBJECTIVE
To Evaluate truncated AUC in place of AUCt or extrapolated AUCinf, for drugs with long half-lives and to study the relationship between Cmax and in vitro dissolution rates.


METHODS
Monte-Carlo simulations were conducted using actual mean plasma concentrations of five long half-life drug products. The simulations were based on a catenary pharmacokinetic system in which the drug disposition in the body was represented by a one-or two-compartment model, characterizing the observed mean profiles. The influence of dramatic changes in the in vitro dissolution rate constant 'kd', was simulated in scenarios consisting of 20 crossover trials with 24 subjects per trial, comparing a fast dissolving reference and a hypothetical, slow dissolving test formulation.


RESULTS
The AUC's truncated after the completion of distribution phase were found surrogate to the AUCt or AUCinf measures. Except for Phenylbutazone, the Cmax measure was insensitive to the changes in the in vitro dissolution rate. The Cmax measure was found to be useful in the bioequivalence assessment since it reflected both the rate and extent of absorption. (Cmax/AUCt) measure was specific to absorption rate.


CONCLUSIONS
For the bioequivalence determination of long half-life drug products, (1) the use of truncated AUC's after completion of the distribution phase instead of AUCinf, appears feasible. (2) Cmax measure may be insensitive to input rate changes, if the absorption rate is not constrained by the input rate in relation to the distribution or elimination rate. (3) (Cmax/AUCt) may be more specific to 'ka' differences, but Cmax reflects differences in both rate and extent of absorption.
Office of Pharmaceutical Science, CDER, USFDA, Rockville, Maryland 20852, USA.
P
P
Sathe
J
J
Venitz
L
L
Lesko
D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D005069:Evaluation Studies as Topic; D006207:Half-Life; D009010:Monte Carlo Method; D010599:Pharmacokinetics; D012995:Solubility; D013810:Therapeutic Equivalency