Physiologically Based Pharmacokinetic Models of Probenecid and Furosemide to Predict Transporter Mediated Drug-Drug Inte
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RESEARCH PAPER
Physiologically Based Pharmacokinetic Models of Probenecid and Furosemide to Predict Transporter Mediated Drug-Drug Interactions Hannah Britz 1 & Nina Hanke 1 & Mitchell E. Taub 2 & Ting Wang 2 & Bhagwat Prasad 3 & Éric Fernandez 4 & Peter Stopfer 4 & Valerie Nock 4 & Thorsten Lehr 1 Received: 24 August 2020 / Accepted: 26 October 2020 # The Author(s) 2020
ABSTRACT Purpose To provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical OAT victim drug furosemide for their application in transporter-based drug-drug interaction (DDI) modeling. Methods PBPK models of probenecid and furosemide were developed in PK-Sim®. Drug-dependent parameters and plasma concentration-time profiles following intravenous and oral probenecid and furosemide administration were gathered from literature and used for model development. For model evaluation, plasma concentration-time profiles, areas under the plasma concentration–time curve (AUC) and peak plasma concentrations (Cmax) were predicted and compared to observed data. In addition, the models were applied to predict the outcome of clinical DDI studies. Results The developed models accurately describe the reported plasma concentrations of 27 clinical probenecid studies and of 42 studies using furosemide. Furthermore, application of these models to predict the probenecidfurosemide and probenecid-rifampicin DDIs demonstrates their good performance, with 6/7 of the predicted DDI AUC ratios and 4/5 of the predicted DDI Cmax ratios within
* Thorsten Lehr [email protected] 1
Clinical Pharmacy, Saarland University, Campus C2 2, 66123 Saarbrücken, Germany
2
Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA
3
Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington, USA
4
Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
1.25-fold of the observed values, and all predicted DDI AUC and Cmax ratios within 2.0-fold. Conclusions Whole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.
KEY WORDS drug-drug interaction (DDI) . furosemide . organic anion transporter (OAT) . physiologically based pharmacokinetic modeling (PBPK) . probenecid
ABBREVIATIONS AADAC ADME AUClast
Cmax DDI EMA FDA GFR GMFE MRD MRP OAT OATP PBPK Pgp SLC Tmax UGT
Arylacetamide deacetylase Absorption, distribution, metabolism and excretion Area under the plasma concentration-time curve (AUC) from the time of drug administration to the time of the last concentration measurement Peak plasma concentration Drug-drug interaction European Medicines Agency U.S. Food and Drug Administration Glomerular filtration rate Geometric mean fold error Mean relative deviation Multidrug resistance-associated protein Organic anion transporter Organic a
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