new developments in renal drug transport · mate2-k 34 0.0026 lepist e.i. et al. kidney...
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New Developments in Renal Drug Transport
Adrian S. Ray, Ph.D.Senior Director, Clinical Research
Gilead Sciences, Inc. Foster City, CA, USA
International Transporter Consortium Workshop 3 (ITCW3) - Transporters in Drug Development Pre-conferenceMarch 13-14, 2017, Washington DC
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Renal EliminationContribution of Secretion and Filtration
Adapted from Morrissey, K.M. et al. Annu Rev Pharmacol Toxicol 2013,53:503-29
PassiveFiltration
ActiveSecretion
Glomerulus
Proximal Tubule
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Proximal TubuleTransporter Expression
Adapted from Lepist E.I. and Ray A.S. Expert Opin Drug Metab Toxicol 2012,8:433-48
Blood (Basolateral) Urine (Apical)
Na+NaDC3
MATE1,MATE2-KH+
OC+
OCTN1,2carnitine or ergothioneine
H+ or OC+
MRP2,4,BCRPOA-
OATP4C1 OA-
OA- OAT4,10
OCT2 OC+
H+
peptides PEPT1,2
ATP
K+Na+
Na,K-ATPase
OAT1,3 -ketoglutarateOA-
ENT1,2 nucleosidesnucleosides
nucleosides/monoamines
OA-
-ketoglutarate
URAT1OA-/Cl-
H+
Na+ NHE3
H+ H+-ATPase
CNT1,2,3nucleosides Na+ or H+
ENT1,PMAT
urate
ATP
P-gpOC+
OAT2 OA-
OC+ THTR1,2
ATP
ATP
SGLT2glucose Na+
GLUT9burateglucose
GLUT9a urateglucose
nucleosides/monoamines
LAT1,2 amino acidNPT2aphosphate
Na+
Proximal Tubule
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Creatinine Renal Transport is ComplexUptake, Secretion and Reabsorption
UrineProximal Tubule
OAT2
Blood
MATE2-K
MATE1
Over a half dozen transporters have been implicated
*evidence in rodents
Oat2*
THTR1/2
OCT2
Oat3*
OCT3
Imamura Y. et al. Clin Pharm Ther 2011, 89:8108; Vallon V. Am J Physiol Renal Physiol 2012, 302:F1293-9; Lepist E.I. et al. Kidney International 2014, 57(10):4982-9; Shen H. et al. Drug Metab Dispos 2015, 45(2), 228-36
OAT4
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Clinical RelevanceDrugs Reported to Affect Serum Creatinine
Class Drug
Antacid Cimetidine
Famotidine
Antibiotic DX-619
PA-824
Trimethoprim
Antiparasitic Pyrimethamine
Antiviral Dolutegravir
Rilpivirine
Pharmacoenhancer Cobicistat
Ritonavir
Cardiovascular Amiodarone
Dronedarone
Ranolazine
Thrombin inhibitor AZD0837
Oncology Imatinib
Lepist EI. et al. Kidney International 2014, 57(10):4982-9; Chu X., et al. Drug Metab Dispos 2016, 44(9):1498-509
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Clinical Relevance of Renal InteractionsAdverse Drug-Drug Interactions
Cimetidine (400 mg) reduced dofetilide renal clearance by 33% Increased ∆QTc corresponding with exposure
Dofetilide Pharmacokinetics
Placebo150 mg rantidine BID100 mg cimetidine BID400 mg cimetidine BID
[Dof
etili
de] (
ng/m
L)
Time (h)
Abel S. et al. Br J Clin Pharmacol 2000,49:64-71
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Relative Contribution of Tubular SecretionEffect of Renal Impairment
16%36% 48%
Contribution to Creatinine elimination:
Glomerular Filtration Tubular Secretion
Shemesh O. et al. Kidney Int. 1985,28:830-8
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In mice, cisplatin induced nephrotoxicity is increased by MATE1-/- and the inhibitor ondansetron
Clinical Relevance of Renal InteractionsOndansetron and Cisplatin
Cisplatin induced nephrotoxicity in wild type and MATE1 KO mice
Adapted from Li Q. et al. Toxicology Applied Pharmacol. 2013
WT MATE1-/-
P < 0.05
P < 0.001
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Regulatory GuidanceRenal Transporters
Blood (Basolateral) Urine (Apical)
MATE1,MATE2-K
H+OC+
BCRPOA-
OCT2 OC+
OAT1,3 OA-
ATP P-gpOC+
ATP
Proximal Tubule
FDAEMA
PMDA
PMDA
FDA Draft Guidance on Drug Interactions Studies. Issued: Feb 2012; EMA Guidelines on Investigation of Drug Interaction Studies. Issued: July 2012; PMDA Drug Interaction Guideline for Drug Development and Labeling Recommendations (Draft for Public Comment). Issued: Jan 2014
FDA EMA PMDACut-Off >1.10 (10x) >1.02 (50x) >1.25 (4x)
1 + [I1]/IC50[I1] = Fraction unbound (Fu) plasma Cmax where Fu < 1% use 1%
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Efficient transport by OAT2 >> OCT2
Creatinine Renal Transport is ComplexBasolateral Uptake – Role of OAT2?
Lepist E.I. et al. Kidney International 2014, 57(10):4982-9
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Shen H. et al. Drug Metab Dispos 2015, 45(2), 228-36
Rat
e (p
mol
/min
/mg/
prot
ein)
[Creatinine](µM)
2,000 4,000 6,000 8,000
10,000
20,000
10,000
Vmaxpmol/min/mg
KmµM
EfficiencyµL/min/mg
OAT2 24,987 795 31.4
OCT2 17,546 18,771 0.93
OAT2 is ~30-fold more efficient creatinine transporter than OCT2
OAT2
OCT2
Creatinine TransportKinetics
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Kidney TransportersQuantitative Proteomics
Prasad B. et al. Drug Metab Dispos. 2016, 44:1920-4
8-fold
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Perpetrator Most Affected Transporter
Creatinine (mg/dl)
Metformin(∆AUC) Ref
Pyrimethamine MATE1/2-K ↑0.24 ↑35% Kusuhara et al. Clin Pharmacol Ther 2011
Trimethoprim MATE1/2-K ↑0.28 ↑37% Grun et al. Br J Clin Pharmacol 2013
Cimetidine MATE1 ↑0.37 ↑50% Somogyi et al. 1987
Famotidine MATE1 ↑0.11 ↔ Hibma et al. Clin Pharmacokinet 2016
Rilpivirine MATE2-K ↑0.10 ↔http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002264/WC500118874.pdf
Dolutegravir OCT2 ↑0.11 ↑79% (QD)↑145% (BID)
Song et al. J Int AIDS Soc 2014
Ranolazine OCT2 ↑0.10 ↑37% (500 mg)↑79% (1000 mg)
Zack J. et al. ClinPharmacol Drug Dev 2015
Clinical Evidence for a Role of OAT2Creatinine versus Metformin
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Clinical Drug-Drug InteractionFamotidine Effect on Creatinine and Metformin
Hidma J.E. et al. Clin Pharmacokinet 2016,55:711-21
Transporter IC50 (µM) [I1]/IC50
OCT1 19 0.015OCT2 66 0.053
MATE1 0.25 4.0MATE2 2.5 0.40
[I1] = unbound Cmax 1.0 µM
S
NN
S
N
NH2
S NH2
O
O
H2N
H2N
Serum Creatinine (mg/dL)
Metformin (∆AUC)
↑0.11** ↔
Effect of 800 mg Famotidine in Healthy Volunteers (n = 12)
Bioavailability Renal Secretion
↑1.24-fold** ↑1.36-fold**P<0.05,**P<0.01
Significant increase in Metformin pharmacodynamic effect also observed
~
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Transporter IC50 (µM) [I1]/IC50
OAT1 2.12 0.04OAT3 1.97 0.04OCT2 1.93 0.04
MATE1 6.34 0.01[I1] = Unbound Cmax = 80 nM
Little or no potential for clinically relevant inhibition– Lack of OAT1/3 interaction confirmed by lack of effect on PAH
and TFV in clinical studies
Reese M.J. et al. Drug Metab Dispos 2013,41:353-61
Renal Transporter InhibitionDecision Tree Analysis
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Transporter InhibitionDolutegravir Inhibition of OCT2
Lepist E.I. et al. Kidney International 2014,86:350-7
OCT2 Inhibition
DolutegravirIC50 = 66 nM
TEA
upta
ke (%
con
trol
)
More than 20-fold more potent than published value– Similar MATE1 IC50 (4.67 µM) to that previously reported
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Transporter InhibitionEffect of Serum Protein
Dolutegravir Inhibition of OCT2-Dependent Metformin Transport
Human Serum
IC50(µM)
0% (Buffer) 0.085
5% 0.10
10% 0.20
25% 0.71
100% 1.4
Estimated IC50 = 11 µM (Fu 0.8%)
Cimetidine has same IC50 in buffer and 100% serums (~ 80 µM)
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Based on metformin total clearance (0.4 L/h/kg) and GFR (0.11 L/h/kg), inhibition of tubular secretion of 60% for 1.79-fold increase in metformin
Inhibition of OCT2 by DolutegravirPrediction Based on IC50 in Human Serum
Multidose pharmacokinetics from Greener B.N. J Acquir Immune Defic Syndr 2013,64:39-44
Time (h)
Dol
uteg
ravi
r (μM
)
Dolutegravir Pharmacokinetics
HS IC50
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Little or no potential for clinically relevant inhibition– Weak inhibition of cationic transporters
Renal Transporter InhibitionDecision Tree Analysis
Transporter IC50 (µM) [I1]/IC50
OAT1 >100 <0.001OAT2 >100 <0.001OAT3 6.6 0.014MRP2 71 0.0012MRP4 24 0.0037[I1] = unbound Cmax 90 nM
Transporter IC50 (µM) [I1]/IC50
OCT2 14 0.0064OCT3 12 0.0075
OCTN1 2.5 0.036MATE1 1.9 0.047
MATE2-K 34 0.0026
Lepist E.I. et al. Kidney International 2014,86:350-7
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Reversible decrease in creatinine secretion in the absence of an effect on renal function
Inhibition of Creatinine SecretionCobicistat
German P. et al. J Acquir Immune Defic Syndr 2012, 61(1):32-40
n = 12*p<0.05
-9.9 mL/min*
Actual versus EstimatedGlomerular Filtration Rate
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Lepist E.I. et al. Kidney International 2014,86:350-7
Facilitated Inhibitor AccumulationCobicistat Transport by OCT2
Mean ± SD; N = 3 independent experiment**, P < 0.005; ****, P < 0.0001; Students t-test
OCT2 Transport
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Assay SystemsMultiple Transfection Model
Creatinine Secretion
OAT2OCT2OCT3MATE1MATE2-K
Tran
scel
lula
r Tra
nspo
rt(p
mol
/min
/cm
2 )
Zhang, X.et al. AAPS Workshop, Bethesda, MD, March 17-20, 2013
% C
ontro
l
CimetidineVehicle
OCT2 potentiates cimetidine inhibition of MATE1
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Proximal Tubule Model SystemsPrimary Proximal Tubule Cells
Billington S. et al. AAPS, San Diego, California, November 2-6, 2014
Secretory transport of Tenofovir
MRP4
OAT1
Proximal Tubule
Blood (Basolateral)
Urine (Apical)
ATP
OAT3
OATP4C1???
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Proximal Tubule Model Systems3D Bioprinting
King SM. Front Physiol 2017, in press
Basal interstitium– Renal fibroblasts and Endothelial cells (HUVEC)
Epithelium– Monolayer of primary polarized proximal epithelium cells
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Conclusions
Clinically significant renal DDIs are rare but are difficult to predict, underappreciated and may be more severe in sensitive populations
Renal transport pathways are complex– Fractional transport (ft) often spread across multiple
transporters– Involvement of transporters not often studied
Need for more holistic models to study potential for renal drug-drug interactions– Actual victim/perpatrator– Addition of plasma proteins– Multiple transfection and PPT systems
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Thank you for your attention !
Kathy GiacominiXiaomin Liang
Leslie Benet
Yong HuangJason Baik
Alan KosakaJane Huang
Xuexiang Zhang
Eve-Irene LepistMarilyn Giacomini
Jia HaoKelly MacLennan
Jolyn Twelves
Thomas Murphy
Colin BrownSarah Billington