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Prediction of the Renal Organic Anion Transporter 1 (OAT1)- Mediated Drug Interactions for LY404039, the Active Metabolite of Pomaglumetad Methionil

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Abstract

Purpose

The objective of this work was to demonstrate that clinical OAT1-mediated DDIs can be predicted using physiologically based pharmacokinetic (PBPK) modeling.

Methods

LY404039 is a metabotropic glutamate receptor 2/3 agonist and the active moiety of the prodrug pomaglumetad methionil (LY2140023). After oral administration, pomaglumetad methionil is rapidly taken up by enterocytes via PEPT1 and once absorbed, converted to LY404039 via membrane dehydropeptidase 1 (DPEP1). LY404039 is renally excreted by both glomerular filtration and active secretion and in vitro studies showed that the active secretion of LY404039 was mediated by the organic anion transporter 1 (OAT1). Both clinical and in vitro data were used to build a PBPK model to predict OAT1-mediated DDIs.

Results

In vitro inhibitory potencies (IC50) of the known OAT inhibitors, probenecid and ibuprofen, were determined to be 4.00 and 2.63 µM, respectively. Subsequently, clinical drug-drug interaction (DDI) study showed probenecid reduced the renal clearance of LY404039 by 30 to 40%. The PBPK bottom-up model, predicted a renal clearance that was approximately 20% lower than the observed one. The middle-out model, using an OAT1 relative activity factor (RAF) of 3, accurately reproduced the renal clearance of LY404039 and pharmacokinetic (PK) changes of LY404039 in the presence of probenecid.

Conclusions

OAT1- mediated DDIs can be predicted using in vitro measured IC50 and PBPK modeling. The effect of ibuprofen was predicted to be minimal (AUC ratio of 1.15) and not clinically relevant.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AE:

Adverse event

AUC:

Area under the concentration time curve

AUC0-∞ :

AUC from time 0 extrapolated to infinity

CLr :

Renal clearance

Cmax :

Maximum observed plasma concentration

DDI:

Drug-drug interaction

fmet :

Fraction of the metabolite formed

GFR:

Glomerular filtration rate

HEK:

Human embryonic kidney

HEK-VC:

HEK vector control

ITC:

International Transporter Consortium

kfmet :

The first order metabolite formation rate constant

KHB:

Krebs Henseleit buffer

OAT:

Organic anion transporter

PEPT1:

Peptide transporter 1

PKPD:

Pharmacokinetics and pharmacodynamics

PBPK:

Physiologically based pharmacokinetic

RAF:

Relative activity factor

t1/2 :

Elimination half-life

tlag :

The lag time

tmax , :

Time of maximum observed plasma concentration

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Authors and Affiliations

  1. Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA

    Y. Anne Pak, Maria M. Posada, James Bacon, William Annes, Jennifer Witcher, Malcolm Mitchell, Stephen D. Hall & Kathleen M. Hillgren

  2. Division of Clinical Pharmacology, Department of Medicine, The University of Western Ontario, London, ON, Canada

    Rommel G. Tirona

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  1. Y. Anne Pak
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  2. Maria M. Posada
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Contributions

Data acquisition, analysis, or interpretation: Pak, Posada, Bacon, Long, Annes, Witcher, Mitchell, Tirona, Hall, and Hillgren.

Manuscript drafting: Pak and Posada.

Manuscript review: Pak, Posada, Bacon, Long, Annes, Witcher, Mitchell, Tirona, Hall, and Hillgren.

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Correspondence to Maria M. Posada.

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Y. Anne Pak, Maria M. Posada, James Bacon, Amanda Long, William Annes, Jennifer Witcher, Malcolm Mitchell, Stephen D. Hall, and Kathleen M. Hillgren are current or previous employees of Eli Lilly and Company. 

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Pak, Y.A., Posada, M.M., Bacon, J. et al. Prediction of the Renal Organic Anion Transporter 1 (OAT1)- Mediated Drug Interactions for LY404039, the Active Metabolite of Pomaglumetad Methionil. Pharm Res 40, 2499–2511 (2023). https://doi.org/10.1007/s11095-022-03464-y

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