A limited sampling approach in bioequivalence studies: application to long half-life drugs and replicate design studies.
OBJECTIVE
The objectives of this study was to develop a limited sampling model (LSM) to predict the area under the curve (AUC) and the maximum plasma concentration (Cmax) for the assessment of bioequivalence studies.


METHODS
Two drugs (A and B) were selected for this purpose. Drug A was chosen to test bioequivalence of two formulations with a long half-life (> 35 hours), whereas drug B was chosen to test the bioequivalence of two formulations (half-life = 12 hrs) with a replicate design study. The LSM for both drugs was developed using 5 blood samples each from 15 healthy subjects. The relationship between plasma concentration (independent variable) at selected time points with the AUC or Cmax (dependent variable) was evaluated by multiple linear regression analysis. The multiple linear regression which gave the best correlation coefficient (r) for 5 sampling time vs AUC or Cmax was chosen as the LSM. The predicted AUC and Cmax from the LSM were then used to assess bioequivalence of two different formulations of each drug following a single oral dose.


RESULTS
The model provided good estimates of both AUC and Cmax for both drugs. The 90% confidence intervals on log-transformed observed and predicted AUC and Cmax were comparable for both drugs.


CONCLUSIONS
The method described here may be used to estimate AUC and Cmax for bioequivalence studies for drugs with long half-lives or for highly variable drugs which may require replicate design studies without detailed blood sampling.
Office of Clinical Pharmacology and Biopharmaceutics, Division of Pharmaceutical Evaluation I, and III, Food and Drug Administration, Rockville, MD, USA.
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Mahmood
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Mahayni
D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D005260:Female; D006207:Half-Life; D006801:Humans; D016014:Linear Models; D008297:Male; D008962:Models, Theoretical; D012016:Reference Values; D013810:Therapeutic Equivalency