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

Autor: Thomas K van der Made, Jan Snoeys, Lieve Dillen, Ils Pijpers, Daniel Scotcher, Aleksandra Galetin, Sophie Jonkers, Mario Monshouwer, Amin Rostami-Hodjegan, Frank Jacobs, Annett Kunze, Kathleen Steemans, An Tuytelaars, Marie-Emilie Willemin
Rok vydání: 2021
Předmět:
Zdroj: Willemin, M, Van Der Made, T K, Pijpers, I, Dillen, L, Kunze, A, Jonkers, S, Steemans, K, Tuytelaars, A, Jacobs, F, Monshouwer, M, Scotcher, D, Rostami-hodjegan, A, Galetin, A & Snoeys, J 2021, ' Clinical Investigation on Endogenous Biomarkers to Predict Strong OAT-Mediated Drug–Drug Interactions ', Clinical Pharmacokinetics . https://doi.org/10.1007/s40262-021-01004-2
ISSN: 1179-1926
0312-5963
DOI: 10.1007/s40262-021-01004-2
Popis: BackgroundEndogenous biomarkers are promising tools to assess transporter-mediated drug–drug interactions early in humans.MethodsWe 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.ResultsPDA 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.ConclusionsThe 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.
Databáze: OpenAIRE
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