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Clinical Trial
. 2021 Sep;60(9):1187-1199.
doi: 10.1007/s40262-021-01004-2. Epub 2021 Apr 10.

Clinical Investigation on Endogenous Biomarkers to Predict Strong OAT-Mediated Drug-Drug Interactions

Marie-Emilie Willemin  1 , Thomas K Van Der Made  2 , Ils Pijpers  3 , Lieve Dillen  3 , Annett Kunze  3 , Sophie Jonkers  3 , Kathleen Steemans  3 , An Tuytelaars  3 , Frank Jacobs  3 , Mario Monshouwer  3 , Daniel Scotcher  2 , Amin Rostami-Hodjegan  2 , Aleksandra Galetin  2 , Jan Snoeys  3
Affiliations
Clinical Trial

Clinical Investigation on Endogenous Biomarkers to Predict Strong OAT-Mediated Drug-Drug Interactions

Marie-Emilie Willemin et al. Clin Pharmacokinet. 2021 Sep.

Erratum in

Abstract

Background: Endogenous biomarkers are promising tools to assess transporter-mediated drug-drug interactions early in humans.

Methods: We evaluated on a common and validated in vitro system the selectivity of 4-pyridoxic acid (PDA), homovanillic acid (HVA), glycochenodeoxycholate-3-sulphate (GCDCA-S) and taurine towards different renal transporters, including multidrug resistance-associated protein, and assessed the in vivo biomarker sensitivity towards the strong organic anion transporter (OAT) inhibitor probenecid at 500 mg every 6 h to reach close to complete OAT inhibition.

Results: PDA and HVA were substrates of the OAT1/2/3, OAT4 (PDA only) and multidrug resistance-associated protein 4; GCDCA-S was more selective, having affinity only towards OAT3 and multidrug resistance-associated protein 2. Taurine was not a substrate of any of the investigated transporters under the in vitro conditions tested. Plasma exposure of PDA and HVA significantly increased and the renal clearance of GCDCA-S, PDA and HVA decreased; the magnitude of these changes was comparable to those of known clinical OAT probe substrates. PDA and GCDCA-S were the most promising endogenous biomarkers of the OAT pathway activity: PDA plasma exposure was the most sensitive to probenecid inhibition, and, in contrast, GCDCA-S was the most sensitive OAT biomarker based on renal clearance, with higher selectivity towards the OAT3 transporter.

Conclusions: The current findings illustrate a clear benefit of measuring PDA plasma exposure during phase I studies when a clinical drug candidate is suspected to be an OAT inhibitor based on in vitro data. Subsequently, combined monitoring of PDA and GCDCA-S in both urine and plasma is recommended to tease out the involvement of OAT1/3 in the inhibition interaction.

Clinical trial registration: EudraCT number: 2016-003923-49.

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