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

January 2023
Pharmaceutical Research 40(2):1-13

Authors:

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.

The in vitro studies. Substrate potential for (A) LY404039 (46 µM) and (B) LY2140023 (18 µM) in panel of uptake transporters using a recombinant vaccinia system in HeLa cells. The uptake of LY404039 or LY2140023 was incubated for 10 min. Relative uptake was compared to HeLa cells transfected with a vector lacking transporter cDNA (vector control). Data (n = 3–9) are presented as mean ± S.D. (C) The concentration-dependent uptake of LY404039 in OAT1 (●) and VC (■) cells. The experiment was conducted for 3 min at 37°C. (D) Time-course accumulation of LY404039 (25 µM) in OAT1 (●) and VC (■) cells. Each symbol represents mean ± S.D. (E) The concentration-dependent uptake of LY404039 in OAT4 (●) and VC (■) cells. The experiment was conducted for 3 min at 37°C. (F) Time-course accumulation of LY404039 (25 µM) in OAT4 (●) and VC (■) cells. Each symbol represents mean ± S.D. (G) The uptake of LY2140023 (25 µM) for 3 min at 37°C in OAT1 ( ), OAT4 ( ), and VC ( or ) cells. Each column represents mean ± S.D. (H) Bidirectional transport of vinblastine, LY2140023, and LY404039 in MDCK-MDR1 cells. The permeability of each compound was measured in B to A, A to B, B to A in the presence of 5 µM LSN335984, and A to B in the presence of 5 µM LSN335984.

…

Pharmacokinetic profiles of prodrug (LY2140023) and active moiety (LY404039) measured in the clinical study. The circles represent the mean values, and the error bars the standard deviations. (A) LY2140023 plasma concentrations after oral administration of 40 mg of LY2140023 with (open red circles) and without probenecid (solid black circles). (B) LY404039 plasma concentrations after oral administration of 40 mg of LY2140023 with (open red circles) and without probenecid (solid black circles). (C) LY2140023 plasma concentrations after oral administration of 40 mg of LY2140023 with (open red circles) and without probenecid (solid black circles). (D) LY404039 plasma concentrations after oral administration of 40 mg of LY2140023 with (open red circles) and without probenecid (solid black circles).

…

Predicted and observed plasma concentration–time profiles of LY404039 in healthy subjects. The solid circles represent the observed mean data, and the error bars the standard deviation. The solid lines represent the mean predicted concentration, and the dashed lines represent the predicted 5th and 95th percentiles. (A) LY404039 plasma concentrations after intravenous administration of 100 ug of LY404039 using the bottom-up model. (B) LY404039 plasma concentrations after intravenous administration of 100 ug of LY404039 using the middle-out model with an OAT1 RAF value of 3. (C) LY404039 plasma concentrations after oral administration of 40 mg LY2140023 (prodrug). (E) LY404039 plasma concentrations after co-administration of 40 mg LY2140023 (prodrug) with 1000 mg probenecid. (D) LY404039 plasma concentrations after oral administration of 80 mg LY2140023 (prodrug). (F) LY404039 plasma concentrations after oral co-administration of 80 mg LY2140023 with 1000 mg probenecid.

…

Sensitivity analyses. (A) sensitivity analysis of the effect of changes in passive permeability in the kidney (CLPD) on the renal clearance and the AUC ratio of LY404039 with probenecid. The measured basolateral passive permeability clearance value of 0.039 µL/min/10^6 cells was decreased and increased tenfold. (B) Sensitivity analysis of the effect of changes in the Vmax of OAT4 (apical efflux mechanism) on the renal clearance and the AUC ratio of LY404039 with probenecid. The measured Vmax value of 624 pmol/min/10^6 cells was decreased and increased tenfold. (C) Sensitivity analysis of the effect of including an apical influx transporter in the model and how changes in the Vmax influx will impact the renal clearance and the AUC ratio of LY404039 with probenecid. The influx Vmax was assumed to be the same as for OAT4 efflux and the value was decreased and increased tenfold. (D) Sensitivity analysis on the effect of fmet on plasma concentration time curve.

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Vol.:(0123456789)

1 3

Pharmaceutical Research (2023) 40:2499–2511

https://doi.org/10.1007/s11095-022-03464-y

ORIGINAL RESEARCH ARTICLE

Prediction oftheRenal Organic Anion Transporter

1 (OAT1)‑ Mediated Drug Interactions forLY404039, theActive

Metabolite ofPomaglumetad Methionil

Y.AnnePak1· MariaM.Posada1· JamesBacon1· AmandaLong· WilliamAnnes1· JenniferWitcher1·

MalcolmMitchell1· RommelG.Tirona2· StephenD.Hall1· KathleenM.Hillgren1

Received: 24 May 2022 / Accepted: 16 December 2022 / Published online: 12 January 2023

Abstract

Purpose The objective of this work was to demonstrate that clinical OAT1-mediated DDIs can be predicted using physi-

ologically 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 ibu-

profen was predicted to be minimal (AUC ratio of 1.15) and not clinically relevant.

Keywords active transport· drug interaction· organic anion transporters· PBPK model· renal transporters

Abbreviations

AE Adverse event

AUC Area under the concentration time curve

AUC

0-∞ 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

Introduction

Pomaglumetad methionil (LY2140023 monohydrate) is a

potent and selective prodrug of the metabotropic glutamate

receptor 2/3 agonist, LY404039, and was developed for

* Maria M. Posada

mmposada@lilly.com

1 Eli Lilly andCompany, Lilly Corporate Center, Indianapolis,

IN46285, USA

2 Division ofClinical Pharmacology, Department ofMedicine,

The University ofWestern Ontario, London, ON, Canada

Content courtesy of Springer Nature, terms of use apply. Rights reserved.

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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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