Limitations of fexofenadine limited sampling strategy using plasma concentrations and partial area under the concentration-time curve to estimate transporter activity in healthy adults

Objective: Fexofenadine is a probe drug used to phenotype P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/3 activities. This study evaluated a limited sampling strategy using plasma concentrations and/or partial area under the concentration versus time curves (AUCs) to estimate systemic exposure and, potentially, P-gp and OATP1B1/3 activities. Materials and methods: Plasma concentration versus time data were obtained from 53 healthy adult participants (22 females) from four published studies. Participants were administered a single oral dose (120 mg) of fexofenadine during constitutive P-gp and OATP1B1/3 conditions. Concentration-time data were divided into a training (n = 18) and validation (n = 35) set. Backwards stepwise linear regression generated single-, 2-timepoint, and partial AUC limited sampling models (LSMs). Noncompartmental analysis methods were used to determine total AUC (AUC(0–lNF)) from intensive sampling. Coefficient of determination (r(2)) and bias and precision were assessed via relative percent mean prediction error (%MPE), relative percent mean absolute error (%MAE), and relative percent root mean square error (%RMSE). Results: The geometric mean observed AUC(0–INF) was 1,680 ng×h/mL. The 2-, 5-, and 2- plus 5-hour LSMs met backwards stepwise linear regression significance (p < 0.15) to remain in the model but had unacceptable %RMSE (17 – 29%). The majority of partial AUC LSMs had unacceptable r(2) (0.21 – 0.83), with all models having unacceptable %MAE (12 – 35%). Conclusion: Fexofenadine limited sampling strategy using single-timepoint, 2-timepoint, and partial AUCs were unable to accurately estimate AUC(0–lNF) and thus constitutive P-gp and OATB1B1/3 activities in healthy adults. Timepoints that were not measured or selected may have improved LSM performance.