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

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

doi:10.1007/s40262-021-01004-2

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

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

^*Corresponding author for this work

Drug Metabolism and Pharmacokinetics
Manchester University
University of Manchester

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1187-1199
Number of pages	13
Journal	Clinical Pharmacokinetics
Volume	60
Issue number	9
DOIs	https://doi.org/10.1007/s40262-021-01004-2
Publication status	Published - Sept 2021
Externally published	Yes

Bibliographical note

Keywords

Biomarkers
Drug Interactions
HEK293 Cells
Humans
Kidney
Organic Anion Transport Protein 1
Organic Anion Transporters, Sodium-Independent
Pharmaceutical Preparations

Access to Document

10.1007/s40262-021-01004-2

Cite this

Willemin, M.-E., 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, 60(9), 1187-1199. https://doi.org/10.1007/s40262-021-01004-2

@article{fb5536d77a6f4793922bb6db5b1c914d,

title = "Clinical Investigation on Endogenous Biomarkers to Predict Strong OAT-Mediated Drug-Drug Interactions",

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.",

keywords = "Biomarkers, Drug Interactions, HEK293 Cells, Humans, Kidney, Organic Anion Transport Protein 1, Organic Anion Transporters, Sodium-Independent, Pharmaceutical Preparations",

author = "Marie-Emilie Willemin and \{Van Der Made\}, \{Thomas K\} and Ils Pijpers and Lieve Dillen and Annett Kunze and Sophie Jonkers and Kathleen Steemans and An Tuytelaars and Frank Jacobs and Mario Monshouwer and Daniel Scotcher and Amin Rostami-Hodjegan and Aleksandra Galetin and Jan Snoeys",

note = "{\textcopyright} 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature.",

year = "2021",

month = sep,

doi = "10.1007/s40262-021-01004-2",

language = "English",

volume = "60",

pages = "1187--1199",

journal = "Clinical Pharmacokinetics",

issn = "0312-5963",

publisher = "Adis",

number = "9",

}

Willemin, M-E, Van Der Made, TK, 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, vol. 60, no. 9, pp. 1187-1199. https://doi.org/10.1007/s40262-021-01004-2

TY - JOUR

T1 - Clinical Investigation on Endogenous Biomarkers to Predict Strong OAT-Mediated Drug-Drug Interactions

AU - Willemin, Marie-Emilie

AU - Van Der Made, Thomas K

AU - Pijpers, Ils

AU - Dillen, Lieve

AU - Kunze, Annett

AU - Jonkers, Sophie

AU - Steemans, Kathleen

AU - Tuytelaars, An

AU - Jacobs, Frank

AU - Monshouwer, Mario

AU - Scotcher, Daniel

AU - Rostami-Hodjegan, Amin

AU - Galetin, Aleksandra

AU - Snoeys, Jan

PY - 2021/9

Y1 - 2021/9

N2 - 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.

AB - 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.

KW - Biomarkers

KW - Drug Interactions

KW - HEK293 Cells

KW - Humans

KW - Kidney

KW - Organic Anion Transport Protein 1

KW - Organic Anion Transporters, Sodium-Independent

KW - Pharmaceutical Preparations

U2 - 10.1007/s40262-021-01004-2

DO - 10.1007/s40262-021-01004-2

M3 - Article

C2 - 33840062

SN - 0312-5963

VL - 60

SP - 1187

EP - 1199

JO - Clinical Pharmacokinetics

JF - Clinical Pharmacokinetics

IS - 9

ER -

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

Abstract

Bibliographical note

Keywords

Access to Document

Fingerprint

Cite this