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

Marlon Liyanage, Chelsea L. Blaquera, Joseph Piscitelli, Scott R. Penzak, Thomas D. Nolin, Mary F. Paine, and Joseph D. Ma

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42.00 $

Volume 61 (2023) p. 262 - 269

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 61 – No. 6/2023 (262-269)

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

Marlon Liyanage¹, Chelsea L. Blaquera¹, Joseph Piscitelli¹, Scott R. Penzak², Thomas D. Nolin³, Mary F. Paine⁴, Joseph D. Ma¹ 

¹Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, ²Harrison School of Pharmacy, Auburn University, Auburn, AL, ³University of Pittsburgh School of Pharmacy, Pittsburgh, PA, and ⁴College of Pharmacy & Pharmaceutical Sciences, Washington State University, Spokane, WA, USA
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 (r²) 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 r² (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.Correspondence to:
Joseph D. Ma, PharmD
University of California, San Diego
Skaggs School of Pharmacy and Pharmaceutical Sciences
9500 Gilman Drive, MC 0657
La Jolla, CA 92093-0657, USA
Email: [email protected]

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