A limited sampling approach in bioequivalence studies.
A limited sampling model (LSM) has been developed for an antidepressant immediate-release product (Drug A) and an antiepileptic controlled release product (Drug B) to predict the area under the curve (AUC) and the maximum plasma concentration (Cmax) and to compare the bioequivalence of two formulations of each drug using predicted versus observed AUC and Cmax after a single oral dose. The LSM for drug A was developed using data from 10 healthy people. The correlation between plasma concentration (independent variable) at selected time points with the AUC or Cmax (dependent variable) was evaluated by simple regression analysis. The linear regression that gave the best correlation coefficient (r) for a single sampling time versus AUC or Cmax was chosen as the LSM. The model provided good estimates of AUC and Cmax for drug A. The 90% confidence interval on log transformed observed and predicted AUC and Cmax were as follows: AUC observed = 100% to 118%, AUC predicted = 101% to 117%, Cmax observed = 99% to 125%, and Cmax predicted = 100% to 131%. The LSM for drug B was developed using a similar approach to drug A. The 90% confidence interval on log transformed observed and predicted AUC and Cmax were: AUC observed = 99% to 110%, AUC predicted = 99% to 118%, Cmax observed = 107% to 120%, and Cmax predicted = 99% to 111%. Although the predicted Cmax did not meet the 90% confidence interval for drug A, the method described here may be used to estimate AUC and Cmax for a drug in bioequivalence studies without detailed blood sampling. More research is needed in this direction.
Mahmood
I
I
Division of Pharmaceutical Evaluation I, Office of Clinical Pharmacology and Biopharmaceutics, Food & Drug Administration, Rockville, MD 20852, USA.
Chamberlin
N
N
Tammara
V
V
D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics*; D000928:Antidepressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D006801:Humans; D008297:Male; D008954:Models, Biological; D011237:Predictive Value of Tests; D013810:Therapeutic Equivalency
D000927:Anticonvulsants; D000928:Antidepressive Agents; D003692:Delayed-Action Preparations