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Risk Assessment of Reactive Metabolites in Drug Discovery: a Focus on Acyl Glucuronides and Acyl-Coa Thioesters

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Risk Assessment of Reactive Metabolites in Drug Discovery: a Focus on Acyl Glucuronides and Acyl-Coa Thioesters Risk Assessment of Reactive Metabolites in Drug Discovery: A Focus on Acyl Glucuronides and Acyl-CoA Thioesters The Delaware Valley Drug Metabolism Discussion Group 2017 Rozman Symposium HUMAN BIOTRANSFORMATION: THROUGH THE MIST Langhorne, PA, June 13, 2017 Mark Grillo, PhD Drug Metabolism & Pharmacokinetics MyoKardia South San Francisco, CA [email protected] CommercializationDrug Process Discovery Overview & Development Therapeutic Area/Disease Lead Selection & Product Strategy Market Readiness & Launch / Post-Launch Opportunity Assessment Pre-clinical Testing Development Regulatory Approval Lifecycle Management Hit-to- Lead Post- Discovery Screen Pre-clinical Phase 1 Phase 2 Phase 3 Filing Launch Lead Optimization Launch Preclinical Pharmacokinetics & Drug Metabolism Assays Target Selection & Validation Lead compound Selection Discovery Screen Hit-to-Lead Lead Optimization Optimize Pharmacokinetics Characterize Preclinical Candidate Liver microsomal stability Intrinsic clearance Membrane permeability Excretion balance Efflux/transport assays Definitive metabolite ID Plasma stability Higher species PK Rat PK Human PK prediction Protein binding Assess DDI Potential Blood to plasma ratio Competitive CYP IC50 Early DDI Assessment Time-dependent CYP inhibition Enzyme induction PXR activation Hepatocyte induction CYP inhibition CYP reaction phenotyping Detection and Assessment of Chemically-Reactive Metabolites 2 Circumstantial Evidence Links Reactive Metabolites to Adverse Drug Reactions • Toxicity is a frequent cause of drug withdrawal from the market. • Reactive drug metabolites may mediate liver injury via covalent modification of biological macromolecules. • Reactive metabolites of carboxylic acid- containing drugs, acyl glucuronides and acyl-CoA thioesters, might contribute to idiosyncratic drug toxicity. Liver • Underlying mechanisms not clear. Injury 3 • Believed to be immune-mediated. Drugs Withdrawn and Associated with Idiosyncratic Drug Toxicity Alcofenac (anti-inflammatory) Metiamide (antiulcer) Hepatitis, rash Bone marrow toxicity Alpidem (anxiolytic) Nomifensine (antidepressant) Hepatitis (fatal) Hepatitis (fatal), anemia Amodiaquine (antimalarial) Practolol (antiarrhythmic) Hepatitis, agranulocytosis Severe cutaneous ADRs Amineptine (antidepressant) Remoxipride (antipsychotic) Hepatitis, cutaneous ADRs Aplastic anaemia Benoxaprofen (anti-inflammatory) Sudoxicam (anti-inflammatory) Hepatitis, cutaneous ADRs Hepatitis (fatal) Bromfenac (anti-inflammatory) Tienilic Acid (diuretic) Hepatitis (fatal) Hepatitis (fatal) Carbutamide (antidiabetic) Tolrestat (antidiabetic) Bone marrow toxicity Hepatitis (fatal) Ibufenac (anti-inflammatory) Troglitazone (antidiabetic) Hepatitis (fatal) Hepatitis (fatal) Iproniazid (antidepressant) Zomepirac (anti-inflammatory) Hepatitis (fatal) Hepatitis, cutaneous ADRs In many cases, metabolic activation reactive metabolites leading to covalent binding to protein demonstrated in vitro and/or in vivo. 4 Carboxylic acid drugs Kalgutkar and Soglia (2005) Exp. Opin. Drug Metab. Toxicol. 1, 91-141. Danger Hypothesis Illustration for Immune-mediated Idiosyncratic Hepatotoxicity 5 Kaplowitz (2005) Idiosyncratic drug hepatotoxicity. Nature Reviews 4, 489-499. Assessing Formation of / Exposure to Reactive Drug Metabolites • Formation of adducts with nucleophiles • In vitro “trapping” studies with glutathione (GSH) or CN-, and others • In vivo metabolic profiling studies (e.g., GSH-adducts in bile, NAC- adducts in urine) • Covalent binding studies with radiolabeled drug • Definitive • Measures “total” burden of protein bound-drug residue • Helpful compliment to trapping studies • Trapping studies with glutathione and covalent binding studies with radiolabel carboxylic acid-containing drugs to examine the importance of acyl glucuronides vs. acyl-CoA thioesters as reactive intermediates in vitro and in vivo. 6 Park et al. (2011) Nature Rev. Drug Discov., 10:292-306. Evans et al. (2004) Chem. Res. Toxicol., 17:3-16. Relationship between daily-dose of oral medications and idiosyncratic drug-induced liver injury (DILI) Drugs dosed at <10 mg/day extremely rare to lead to idiosyncratic drug toxicity (whether or not these drugs are prone to metabolic activation). 7 Kalgutkar (2009) Chem. Biodiver. 6, 2115-36; Lammert et al., Hepatology 47, (2008) Assessing the Potential for Risk of Idiosyncratic Drug Toxicity Caused by Candidate Drugs (AstraZeneca, 2012) Drugs that demonstrated high covalent binding (CVB) burden (>1 mg/day, Zones 3 and 4) correlated with many of the toxic compounds. CVB Burden f cvb= (CVB•0.26 mg)/(turnover•4000 pmol) (#9) Ibufenac 24 CVB burden = fcvb•dose (#32) Ibuprofen 5.2 (#20) Diclofenac 1.8 Recommendation: <1 mg/day exposure (#29) Caffeine <0.23 (CVB burden) to reactive metabolites 8 Thompson et al. (2012) Chem. Res. Toxicol. 25: 1616-1632. Cross-species Liver Microsomes Metabolite Profile: LC/UV detection Identification of GSH-adduct as Major Metabolite in HLM fortified with NADPH and GSH RT: 6.88 - 22.09 SM: 11G Drug NL: 2000 UV 280 nm GSH-adduct 5.38E4 1000 nm=280.0- Rat 280.0 PDA 0 hydroxylated 3509rlm+n+g -1000 metabolite uAU metabolite -2000 ndr -3000 -4000 NL: 2000 UV 280 nm 5.94E4 nm=280.0- 1000 280.0 PDA 0 Dog 3509dlm+n+ g -1000 uAU -2000 -3000 -4000 NL: 2000 5.16E4 1000 nm=280.0- UV 280 nm 280.0 PDA 0 3509clm+n+ Cyno monkey g -1000 uAU -2000 -3000 -4000 NL: 2000 5.92E4 UV 280 nm nm=280.0- 1000 280.0 PDA 0 3509hlm+n+ Human g -1000 uAU -2000 -3000 -4000 ndr, not drug related 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Time (min) • GSH-adduct major metabolite formed in HLM (1.5 % relative peak area to parent, ~50% of total metabolite peak area) • Decision to perform reactive metabolite/toxicity risk assessment prior to advancement. 9 Unpublished observations Covalent Binding (CVB) of Radiolabeled Test Drug and [14C]Diclofenac to Protein in Human Hepatocytes in Suspension: Prediction of “CVB Burden” in Human Covalent Binding Metabolic Stability 1 7 5 1 1 0 R a d io la b e le d T e st C o m p o u n d 1 4 1 0 0 n n i [ C ]D ic lo fe n a c 1 5 0 i (0 % tu rn o v e r) e e ) t 1 4 ) 9 0 t n [ C ]D ic lo fe n a c (lite ra tu re ) o n o i r i r e e P t 1 2 5 8 0 P t o o o r o r t t 7 0 p p / / g g g 1 0 0 g n n i i 6 0 m d m d / / . n . n i i q 5 0 7 5 q B B e e t l t l 4 0 n o n o e R a d io la b e le d e l l m 5 0 m a 3 0 a p T e st C o m p o u n d p v ( v ( o o 2 0 1 4 C 2 5 C [ C ]D ic lo fe n a c 1 0 (8 7 .5 % tu rn o v e r) 1 4 0 0 [ C ]D ic lo fe n a c (lite ra tu re ) 0 1 2 3 4 0 1 2 3 4 In c u b a tio n T im e (h ) In c u b a tio n T im e (h ) CVB (pmol/mg Incubation Turnover Daily CVB Burden Compound f protein) time (h) (%) cvb Dose (mg) (mg) 24.0 ± 2.6 1 0 ± 3.0 0.174* 13.9 Test Compound 34.8 ± 4.8 2 0 ± 2.9 0.252* 80† 20.2 49.8 ± 8.3 4 0 ± 4.3 0.361* 28.8 78.9 ± 2.6 1 68.6 ± 2.8 0.008 1.67 Diclofenac 109. ± 8.3 2 78.9 ± 1.1 0.010 200 2.01 151.6 ± 7.5 4 87.6 ± 0.5 0.013 2.51 Diclofenac 140.8 2 100 0.0092 200 1.84 (Thompson, et al.) Substrate concentration (10 µM), incubation volume (2.5 mL); *no loss of drug detected (assume 1% turnover); †Preliminary prediction of drug dose in human based on rat PK/PD and simple allometric scaling (4-species) for human PK. 10 Metabolites in Safety Testing (MIST) (FDA, 2008) Acyl Glucuronides Ref. 5 Faed, EM, 1984, Properties of Acyl Glucuronides. Implications for Studies of the Pharmacokinetics and Metabolism of Acidic Drugs, Drug Metab Rev, 15: 1213–1249. 11 https://www.fda.gov/downloads/Drugs/.../Guidances/ucm079266.pdf Partial list of carboxylic-acid containing drugs withdrawn from clinical use and/or also associated with allergic reactions Withdrawn Allergic reactions O C l C l O O C l O OH O OH OH OH C l O O C H3 O H C H3 S H3C Ibuprofen Clofibric Acid Alclofenac Tienilic Acid O OH O C l Br NH2O C l O O OH OH C l NH O N N S H OH O C H3 O Bromfenac Benoxaprofen Probenecid Diclofenac O O F HO OH O O OH OH O N OH H F O C H3 H Ibufenac H C Flunoxaprofen 3 O Fenoprofen Diflunisal C H O O O 3 F O N OH OH O C H3 O OH C l N H N OH H3C C H3 H 3C Indoprofen Zomepirac Tolmetin Valproic Acid Fung et al. (2001) Drug Information Journal, 35, 293-317. 12 Stepan et al. (2011) Chem Res Toxicol, 24, 1345-1410. Drug Acyl Glucuronide: Instability (Primarily by Acyl Migration) 100 •Incubation of 1-O-β- 90 1 0 0 drug-acyl glucuronide 80 o 8 0 g in buffer (pH 7.4, 37 C) Time = 0 min n 70 i b n 1-O- - i t ~ 1 0 m in 6 0 1 /2 60 o a to determine pH 7.4, 37 C m isomer e R 4 0 50 degradation rate/ % 40 2 0 degradation half-life. 30 0 20 0 5 1 0 1 5 2 0 2 5 3 0 In c u b a tio n T im e (m in ) •LC-MS/MS analysis: 10 0 Xue et al. 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 “Optimization to 90 1-O-b- * eliminate interference 80 isomer Relative Intensity (%) (%) Intensity Relative 70 Time = 20 min of migration isomers 60 o for measuring 1-O-β- pH 7.4, 37 C ** 50 acyl glucuronide with 40 out extensive 30 *Acyl migration isomers 20 chromatographic ** 10 separation”.
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