title: Evaluation of a limited sampling method used to determine the bioequivalence of highly variable drugs with long half-lives.
abstract: The usefulness of a limited sampling method (LSM) to determine the bioequivalence of highly variable drugs with long half-lives was investigated. The LSM uses multiple linear regression of observed drug plasma concentrations versus area under the curve (AUC) or C(max) (peak plasma concentration) to obtain a best set of coefficients, concentration times and intercept based upon the regression coefficient, R(2), to predict the selected pharmacokinetic parameter (i.e. AUC or C(max)). The LSM, used successfully in clinical settings, has also been suggested for data analysis of in vivo bioequivalence studies. Because the method has not yet been thoroughly tested under many conditions likely to be encountered in bioequivalence studies, a further investigation of the method's applicability to bioequivalence determination was undertaken. In the present study, training and test data sets incorporating various levels of intrasubject variability in clearance (CL) with different ratios for fraction absorbed (Fa) of test and reference drug formulations were used to further evaluate the applicability of the limited sampling method (LSM) to the evaluation of bioequivalence for drugs with long half-lives of elimination. Both simulated (a one-compartment pharmacokinetic (PK) model with first-order elimination) and experimental data were used in the study. The results indicated that the determination of bioequivalence using the LSM was significantly influenced by the ratio of Fa(test)/Fa(reference) and by the level of intrasubject error (variability) in CL. Therefore, use of the LSM to determine bioequivalence of drugs with long half-lives and highly variable in CL seems suitable only for formulations that have point estimates of Fa(test)/Fa(reference) within the range of 0.9-1.10. Because the Fa ratio range would have to be verified through use of observed data obtained from a pilot study, the practical utility of the LSM in the determination of bioequivalence would be severely limited.
authors.affiliation: Division of Bioequivalence, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD 20857, USA. jacksonan@cder.fda.gov
authors.forename: A J
authors.initials: AJ
authors.lastname: Jackson
mesh_terms: D019540:Area Under Curve; D006207:Half-Life; D006801:Humans; D015983:Selection Bias; D013810:Therapeutic Equivalency