Untangling Absorption Mechanisms and Variability in Bioequivalence Studies Using Population Analysis

Both inter-individual (IIV) and inter-occasion (IOV) variabilities are observed in bioequivalence studies. High IOV may be a cause of problems on the demonstration of bioequivalence, despite strict measures are taken to control it. The objective of this study is to investigate further means of controlling IIV by optimizing study design of crossover studies.

Data from 18 bioequivalence studies were used to develop population pharmacokinetics (popPK) models to characterize the absorption and disposition processes of 14 drugs, to estimate IOV for each drug substance and to evaluate possible correlations with biopharmaceutical properties of drug substances, classified in accordance to the Biopharmaceutics Drug Disposition Classification System (BDDCS).

Plasma-pharmacokinetics profiles for the 14 drugs analyzed were successfully described using popPK. The pharmacokinetic parameters that showed greater variability were first-order rate constant of absorption, duration of the zero-order absorption process, relative bioavailability and time of latency. ISCV% estimated for C_max seems to correlate with the log-Dose-Number for Class 1, 2 and 3, despite no direct correlation was observed between popPK model residual variability (RUV) and ISCV%. Nevertheless, higher RUV estimates were observed for Class 2 drugs in comparison to Class 1 and 3.

Pharmacokinetic parameters related to drug absorption showed greater variability. Ingestion of the IMP along with 240 mL of water showed to standardize gastric emptying. Given the dependency between C_max variability and dose-solubility ratio, for classes 2 and 4, ad libitum water intake may increase C_max and AUC ISCV%. A water ingestion standardization until the expected T_max of the drug is suggested.