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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Change history
17 February 2022
A Correction to this paper has been published: https://doi.org/10.1007/s40262-022-01109-2
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Acknowledgements
The authors thank Syneos Health who provided the bioanalytical method of probenecid and Emmanuel Njumbe Ediage for bioanalysis assistance.
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Funding
This study was funded by Janssen Pharmaceutical Companies of Johnson & Johnson. Thomas K. Van Der Made is supported by a PhD studentship funded by Janssen Pharmaceutical Companies of Johnson & Johnson.
Conflict of interest
Marie-Emilie Willemin, Ils Pijpers, Lieve Dillen, Sophie Jonkers, Kathleen Steemans, An Tuytelaars, Frank Jacobs, Mario Monshouwer and Jan Snoeys are full-time employees of Janssen Pharmaceutical Companies of Johnson & Johnson.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
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Informed consent was obtained from all individual participants included in the study.
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All research participants provided informed consent for publication.
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The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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MEW, TVDM, IP, FJ and AG wrote the manuscript. MEW, TVDM, AK, FJ, MM, DS, AR, AG and JS designed the research. TVDM, IP, SJ, KS and AT performed the research. MEW, TVDM, IP, LD, AK, SJ, KS, AT, FJ and JS analysed the data.
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The original Online version of this article was revised: The online supplementary file has been incorrectly published.
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40262_2021_1004_MOESM1_ESM.pdf
Material and Methods of the manuscript “Clinical investigation on endogenous biomarkers to predict strong OAT-mediated drug–drug interactions” (PDF 241 kb)
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Willemin, ME., Van Der Made, T.K., Pijpers, I. et al. Clinical Investigation on Endogenous Biomarkers to Predict Strong OAT-Mediated Drug–Drug Interactions. Clin Pharmacokinet 60, 1187–1199 (2021). https://doi.org/10.1007/s40262-021-01004-2
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DOI: https://doi.org/10.1007/s40262-021-01004-2