Strategy on Drug Transporter Investigation Why, How, Which & When. Jasminder Sahi
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1 Strategy on Drug Transporter Investigation Why, How, Which & When Jasminder Sahi
2 Intestine Drug Absorption PEPT1 OATPs MCTs AE2 Epithelial Cell MCTs MRP3 Liver Excretion via Liver Kidney MRPs OATPs N PT1 PEPTs OCTN MATE OATs OCTs Blood MRP1,3,6 OATPs NTCP OATs NPT1 Vascular site MRP2 BSEP Hepatocyte Biliary tract site Excretion via Kidney MRP1,4,5 Blood-Brain Barrier OATs OCTNs Capillary vessel endothelial cell Brain Cancer Cells MRP2
3 Tissue distribution studies (rat QWBA A) Drugs are differentially distributed Vd = 3 L/kg Good general distribution Vd = 6 L/kg Good general distribution Very poor CNS penetration Pgp Substrate Vd = 1.2 L/kg Low general distribution Very high liver concentrations OATP1B1 Substrate
4 CNS efflux/uptake Pgp, OAT3, MRP1, Drug Cardiac efflux/uptake Pgp,, MRP2-5, OCTN1, OATP2B1 CNS Influx CNS Efflux Lung efflux/up Pgp, OCTN, oth Hepatic Efflux Hepatic Uptake Biliary Secretion Renal Secretion Renal up OAT1, OA OCT2, O Renal secretio Pgp, MR OAT4, OC MATE1/ Pgp, MDR3, MRP2, BSEP Intestinal Absorption Intestinal uptake OATP1A2, OATP2B1, PEPT-1, MRP3 Intestinal Secretion Renal reabsorption Intestinal efflux Pgp, MRP2, Renal re-upta OATP2B PEPT-2 URAT1
5 -Transporter Involvement in Disposition of a Drug Effects of SLCO1B1, ABCG2 & ABCB genotypes on systemic exposure of various statins. N.B. There are additional roles pl by drug metabolism enzymes for each statin. (2010) CPT 87:130
6 % (21/88) submitted with Transport er data % (53/95) submitted with Transport er data % (20/24) submitted with Transporter data 30%Labels with Transporter info 4/24 large molecu 100% of small molecule NDAs transporter data 2013
7 -Drug Interactions Because Transporter mediated DDI can cause problems Polypharmacy is common
8 3 DDI/NDA No Transporter studies 12 DDI/NDA P-gp Transporter Studies based on PK changes DDI studies/nda 7 Transporters In vitro DDI Follow-up clinical PK studies PBPK NMEs approve between
9 Object Precipitant % Change in AUC cyclosporine cyclosporine cyclosporine gemfibrozil cyclosporine cyclosporine rifampin lopinavir & ritonavir cyclosporine rifampin erythromycin rifampin cyclosporine rifampin & Transporter Drug Interaction Database-Univ of Washington OATPs NOT the only transporters involved Drug metabolizing enzymes involved as well Transporter DDI can extend Transporters and Enzymes OATP1B1, MRP2, OAT3, OATP1B1, OATP1B3, P-gp, CYP3A4 OATP1B1, P-gp,, CYP3A4, UGT1A1/3 OATP1B1, CYP3A4, CYP2C8 OATP1B1, CYP3A4 OATP1B1, OATP1B3,, CYP2C9, UGT1A1, UGT OATP1B1, UGT OATP1B1, OATP1B3, CYP3A4, CYP2C9 OATP1B1, P-gp, CYP2C8, CYP3A4, UGT1A1/3 OATP1B1, OAT1, CYP3A4 OATP1B1, CYP3A4 OATP1B1/3, P-gp, CYP3A4 OATP1B1, CYP3A4, CYP3A5, CYP2C9, CYP2C8, CY OATP1B1/3, P-gp, CYP3A4 to endogenous substrates
10 CI-1034 Endothelin A receptor antagonist No significant preclinical hepatotoxicity in rat or dog Linear PK in clinic Pharmacologically very active for pulmonary hypertension O O Et CO 2 H O S F F N O F
11 -1034 on Plasma Bile Acids in Phase I Clinical Trials Day 42: ALT 1.2 ULN AST 1.7 ULN Bil 1.8 mg/dl Placebo ALT 1.2 AST 1.4 Bil 3.3 No day Day 42: ALT 7ULN AST 5ULN Bil h 12 hr Day 1 Day 4 0 h 1 h 12 h Day 14
12 Taurocholate Uptake by CI-1034 in Primary % Taurochol late Uptake Cyclosporin A CI-1034 Glyburide Salicylic acid
13 Taurocholate Canalicular Efflux in Primary Hepatocytes 120 % Taurocho olate Efflux % Inhibition Cyclosporin A CI-1034 Glyburide (mm) Rose, Pfizer
14 -1034 on OATP Transporters OATP2B1 OATP1B1 OATP1B /BSP Uptake K i : 3.3 mm 2..0 mm 1.8 mm 1/BSP Uptake CI-1034 (µm) CI-1034 (µm) CI-1034 (µm) /BSP Uptake 0.1( ), 0.2( ) and 0.8( )µm DeMorais
15 -1034 Transporter Mediated O O Et CO 2 H 20% O N S F O F F O O Et CO 2 H O O Et BSEP S N CO 2 H O F O F F 80% O N S F O F F Inhibition of BSEP can contribute to cholestasis Inhibition of NTCP & OATP1B1 can contribute to increased bile salts in circulation
16 Intestine Drug Absorption PEPT1 OATPs MCTs AE2 Epithelial Cell MCTs MRP3 Liver Excretion via Liver Kidney MRPs OATPs N PT1 PEPTs OCTN MATE OATs OCTs Blood MRP1,3,6 OATPs NTCP OATs NPT1 Vascular site MRP2 BSEP Hepatocyte Biliary tract site Excretion via Kidney MRP1,4,5 Blood-Brain Barrier OATs OCTNs Capillary vessel endothelial cell Brain Cancer Cells MRP2
17 A -MDCKII Cells Pgp is expressed on apical (A) surface A B Assay B B-to-A/A-to-B = Efflux Ratio lines (Caco-2, MDCK, LLCPK1) expressed on apical membrane ABC Transporters: Inside out Vesicles (su assay-atp) In Vivo Models Knock Out Animal Model Chemical Inhibitors Primary Cells (hepatocytes etc)
18 Efflux Uptake ATPase assay ABC Transporter Cell SLC Transporter Inside-out Vesicle ABC Transporter ATP ADP+PO 4 2- Membrane
19 Single Transfection Double Transfection
20 for Transporter Studies Bile canaliculus
21 ols for Uptake Transporters tably / transiently transfected cell lines (HEK-293, MDCK, LLCPK) Do not have to be polarized Vesicles Primary Cells (hepatocytes etc) Single/ Double transfectant Wild-type vs transfected or +/- inhibitor(s) more transporter-specific data In Vivo Models Knock Out Animal M Chemical Inhibitors
22 uptake in vitro Tools Transfected cell lines Cryopreserved Hepatocytes with Pitavasta Hepatocytes Parallel studies at 37 C and 4 C Specific inhibitors Single Cocktail
23 Uptake Mechanism Is it Active or Passive? Evaluate in human hepatocytes Plated or suspension Active Likely to see impact (~3.3 fold change) when active > 70% > 50% Passive No additional work > 50-70% Overexpressed cell lines Evaluate OATP1B1&1B3
24 Induction Study Design for P-gp 0.25 mg oral dose Digoxin Single 0.25 mg oral dose Day 10 Day 2 to Day 10: Avasimibe 50 mg dose (8 subjects) 750 mg dose (8 subjects) - 16 healthy volunteers, cross-over design - Second dose of dogoxin administered at steady state of Avasimibe - PK for digoxin for 16 hours after each dose (Day 1 and Day 10)
25 HICH?? is more clearly defined Intestine Drug Absorption PEPT1 OATPs MCTs AE2 Epithelial Cell MCTs MRP3 Excretion via Liver Liver MRPs OATPs Vascular site OATs MRP1,3,6 OATPs N PT1 Kidney MRP2 NTCP PEPTs OCTN MATE OCTs Blood Biliary tract site Hepatocyte MRP1,4,5 Blood-Brain Barrier BSEP NPT1 Excretion via Kidney OATs MRP2 Brain OATs OCTNs Capillary vessel endothelial cell Cancer Cells
26 outes of Clearance
27 Uptake Efflux A and EMA Guidance on Transporters Inhibition studies Transporter Substrate studies EMA FDA EMA* FDA P-gp () BSEP MRPs OATP1B1 yes yes prefer no yes yes yes yes yes yes OATP1B3 yes yes 25% of elimination hepatic OCT1 no OAT1 yes yes OAT3 yes yes 25% of total clearance is hepa or biliary no 25% of total clearance is acti renal 25% of total clearance is acti renal OCT2 yes yes MATE1 MATE2
28 idance on Renal Transporters TEs gaining importance MA renal (...) secretion separately is estimated to account for more than 25% of drug elimination, empts should be made to identify the transporters involved in active secretion A. investigational drugs should be evaluated in vitro to determine whether they are a substrate of T1/3 and OCT2 when their renal active secretion is important (active secretion >25% of total arance) C.incorporate MATEs into existing OCT2 decision trees MDA r investigational drugs of which renal secretion is major (total clearance of the renal elimination is re than 25% of whole body clearance), the possibility that the drug may be a substrate of OAT1, T3, OCT2, MATE1 and MATE2-K should be studied. studied
29 off values that Trigger Clinical linical DDI Studies DA EMA Pgp/ Pgp/ Total Cmax/IC50 > 0.1 I2/IC50 > 10 Ki < 0.1x dose/250 ml ( = I2) OATPs, OATs, OCTs, MATEs OATPs Total Cmax/IC50 > 0.1 OATs and OCT2/MATEs Unbound Cmax/IC50 > 0.1 Ki < 25x [I]u, inlet,max or Ki < 50x unbound Cmax
30 HEN?? pends on so many factors Intestine Drug Absorption PEPT1 OATPs MCTs AE2 Epithelial Cell MCTs MRP3 Excretion via Liver Liver MRPs OATPs Vascular site OATs MRP1,3,6 OATPs N PT1 Kidney MRP2 NTCP PEPTs OCTN MATE OCTs Blood Biliary tract site Hepatocyte MRP1,4,5 Blood-Brain Barrier BSEP NPT1 Excretion via Kidney OATs MRP2 Brain OATs OCTNs Capillary vessel endothelial cell Cancer Cells
31 ug Transporter Assessment Strategy Discovery to First Time In Human (FTIH) CLINICAL STRATEGY herapeutically aligned co-meds target delivery roduct Profile evelopment Plan hysicochemical properties FTIH to Proof of Concept (POC) POC to New Drug Application (NDA)/Marketing TRANSLATION UNDERSTANDING Pharmacokinetics Drug labeling Non-clinical mechanistic and/or investigative studies Clinical Studies Safety PMC Non-clinical clinical studies (in ( vitro and in vivo) Clinical Studies are no agreed timings for transporter studies, they should be driven by the clinical plan, which therapeutic area, co-medications medications and the patient population
32 mmary of Role of Drug Transporters in ADME rug transporters play a significant role in ADME as effective barriers to drug exposure the rate determining step in uptake and/or excretion of a compound or metabolite mediators of drug interactions via inhibition or induction In drug discovery (development) it is important to identify key drug transporters (and their genetic variants) elucidate their role in disposition of a compound establish robust transport assays ultiple transporters from theabc & SLC families likely influence the disposition of a drug eviews Drug Discovery 9, , (2010)
33 o Keep in Mind ift in study conduct paradigm ITC White Papers and 2013 DDI guidance documents Group assays based on tissue based approach Area still evolving. Focus on your patient population Transporter data can be generated in Phase III to help draft drug label. tend interactions around clinical safety Biomarkers (e.g. bile salts), clinical chemistry to address these in the moment (e.g. BSEP, OCT..) chanistic Modeling integral for understanding and extrapolation ransporter and enzyme in vitro data. Expected by all agencies along with details of the extrapolation nsporter Assay Validation Questions uestions by agencies around the details of in vitro assays and controls
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