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Review

Predicting the pharmacokinetics and pharmacodynamics of antisense oligonucleotides: an overview of various approaches and opportunities for PBPK/PD modelling

, , , &
Pages 979-990 | Received 24 Jul 2023, Accepted 08 Nov 2023, Published online: 18 Nov 2023

References

  • Crooke ST, Liang X-H, Baker BF, et al. Antisense technology: a review. Journal Of Biological Chemistry Internet. 2021 cited Feb 21;296:39. doi: 10.1016/j/jbc.2021.100416
  • Crooke ST. Antisense therapeutics. Biotechnol Genet Eng Rev Internet. 1998;15(1):121–158. doi: 10.1080/02648725.1998.10647954
  • Crooke ST, Witztum JL, Bennett F, et al. RNA-Targeted therapeutics. Cell Metab. 2018;27(4):714–739. doi: 10.1016/j.cmet.2018.03.004
  • Sugo T, Terada M, Oikawa T, et al. Development of antibody-siRNA conjugate targeted to cardiac and skeletal muscles. J Control Release Internet. 2016;237:1–13. doi: 10.1016/j.jconrel.2016.06.036
  • Nair JK, Attarwala H, Sehgal A, et al. Impact of enhanced metabolic stability on pharmacokinetics and pharmacodynamics of GalNAc–siRNA conjugates. Nucleic Acids Res. 2017;45(19):10969–10977. doi: 10.1093/nar/gkx818
  • Prakash TP, Graham MJ, Yu J, et al. Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res. 2014;42(13):8796–8807. doi: 10.1093/nar/gku531
  • Perry C, Davis G, Conner TM, et al. Utilization of physiologically based pharmacokinetic modeling in clinical pharmacology and therapeutics: an overview. Curr Pharmacol Reports. 2020;6(3):71–84. doi: 10.1007/s40495-020-00212-x
  • Arya V, Venkatakrishnan K. Role of physiologically based pharmacokinetic modeling and simulation in enabling model‐informed development of drugs and biotherapeutics. J Clin Pharmacol. 2020;60(S1):S7–S11. doi: 10.1002/jcph.1770
  • Rose RH, Sepp A, Stader F, et al. Application of physiologically based pharmacokinetic models for therapeutic proteins and other novel modalities. Xenobiotica. 2022;52(8):840–854. doi: 10.1080/00498254.2022.2133649
  • Monine M, Norris D, Wang Y, et al. A physiologically-based pharmacokinetic model to describe antisense oligonucleotide distribution after intrathecal administration. J Pharmacokinet Pharmacodyn Internet. 2021;48(5):639–654. doi: 10.1007/s10928-021-09761-0
  • Peng B, Andrews J, Nestorov I, et al. Tissue distribution and physiologically based pharmacokinetics of antisense phosphorothioate oligonucleotide ISIS 1082 in rat. Antisense Nucleic Acid Drug Dev. 2001;11(1):15–27. doi: 10.1089/108729001750072092
  • Bai H, Cheng Y, Che J. Pharmacokinetics and disposition of heparin-binding growth factor midkine antisense oligonucleotide nanoliposomes in experimental animal species and prediction of human pharmacokinetics using a physiologically based pharmacokinetic model. Front Pharmacol. 2021 cited Nov 3;12.10. doi: 10.3389/fphar.2021.769538
  • Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-α phosphorothioate 2′- O -(2-Methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos Internet. 2003;31(11):1419–1428. doi: 10.1124/dmd.31.11.1419
  • Geary RS. Antisense oligonucleotide pharmacokinetics and metabolism. Expert Opin Drug Met. 2009;5(4):381–391. doi: 10.1517/17425250902877680
  • Geary RS, Baker BF, Crooke ST. Clinical and Preclinical Pharmacokinetics and Pharmacodynamics of Mipomersen (Kynamro®): A Second-Generation Antisense Oligonucleotide Inhibitor of Apolipoprotein B. Clin Pharmacokinet Internet. 2015;54(2):133–146. doi: 10.1007/s40262-014-0224-4
  • Wang Y, Yu RZ, Henry S, et al. Pharmacokinetics and clinical pharmacology considerations of GalNAc3-conjugated antisense oligonucleotides. Expert Opin Drug Metab Toxicol Internet. 2019;15(6):475–485. doi: 10.1080/17425255.2019.1621838
  • Mahmood I. Pharmacokinetic allometric scaling of oligonucleotides. Nucleic Acid Ther. 2011;21(5):315–321. doi: 10.1089/nat.2011.0299
  • Yu RZ, Lemonidis KM, Graham MJ, et al. Cross-species comparison of in vivo PK/PD relationships for second-generation antisense oligonucleotides targeting apolipoprotein B-100. Biochem Pharmacol Internet. 2009;77(5):910–919. doi: 10.1016/j.bcp.2008.11.005
  • Geary RS, Yu RZ, Siwkowski A, et al. Pharmacokinetic/Pharmacodynamic properties of phosphorothioate 2’ - O-(2-methoxyethyl)-modified antisense oligonucleotides in animals and man. Antisense Drug Technol, Princ, Strategies And Appl. 2007;2:305–326.
  • Benichou SA, Jauvin D, Serres-Bérard TD, et al. Enhanced delivery of ligand-conjugated antisense oligonucleotides (C16-HA-ASO) targeting dystrophia myotonica protein kinase transcripts for the treatment of myotonic dystrophy type 1. Hum Gene Ther. 2022;33(15–16):810–820. doi: 10.1089/hum.2022.069
  • Roberts TC, Langer R, Wood MJA. Advances in oligonucleotide drug delivery. Nat Rev Drug Discov. 2020;19(10):673–694. doi: 10.1038/s41573-020-0075-7
  • Akinc A, Querbes W, De S, et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol Ther. 2010;18(7):1357–1364. doi: 10.1038/mt.2010.85
  • Kanasty R, Dorkin JR, Vegas A, et al. Delivery materials for siRNA therapeutics. Nat Mater. 2013;12(11):967–977. doi: 10.1038/nmat3765
  • Kazmi F, Yerino P, McCoy C, et al. An assessment of the in vitro inhibition of cytochrome P450 enzymes, UDP-Glucuronosyltransferases, and transporters by phosphodiester- or phosphorothioate-linked oligonucleotides. Drug Metab Dispos Internet. 2018;46(8):1066–1074. doi: 10.1124/dmd.118.081729
  • Rogers H, Adeniyi O, Ramamoorthy A, et al. Clinical pharmacology studies supporting oligonucleotide therapy development: an assessment of therapies approved and in development between 2012 and 2018. Clin Transl Sci Internet. 2021;14(2):468–475. doi: 10.1111/cts.12945
  • Yu RZ, Geary RS, Flaim JD, et al. Lack of pharmacokinetic interaction of mipomersen sodium (ISIS 301012), a 2′-O-Methoxyethyl modified antisense oligonucleotide targeting apolipoprotein B-100 messenger RNA, with simvastatin and ezetimibe. Clin Pharmacokinet Internet. 2009;48(1):39–50. doi: 10.2165/0003088-200948010-00003
  • Shemesh CS, Yu RZ, Warren MS, et al. Assessment of the drug interaction potential of unconjugated and GalNAc3-conjugated 2’-MOE-ASOs. Mol Ther Nucleic Acids Internet. 2017;9:34–47. doi: 10.1016/j.omtn.2017.08.012
  • Yu RZ, Warren MS, Watanabe T, et al. Lack of interactions between an antisense oligonucleotide with 2′- O -(2-methoxyethyl) modifications and major drug transporters. Nucleic Acid Ther Internet. 2016;26(2):111–117. doi: 10.1089/nat.2015.0588
  • Geary RS, Bradley JD, Watanabe T, et al. Lack of pharmacokinetic interaction for ISIS 113715, a 2’-0-methoxyethyl modified antisense oligonucleotide targeting protein tyrosine phosphatase 1B messenger RNA, with oral antidiabetic compounds metformin, glipizide or rosiglitazone. Clin Pharmacokinet Internet. 2006;45(8):789–801. doi: 10.2165/00003088-200645080-00003
  • Adjei AA, Dy GK, Erlichman C, et al. A phase I trial of ISIS 2503, an antisense inhibitor of H-ras, in combination with gemcitabine in patients with advanced cancer. Clin Cancer Res Official J Am Assoc Cancer Res. 2003;9:115–123.
  • Geary RS, Norris D, Yu R, et al. Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. Adv Drug Deliv Rev Internet. 2015;87:46–51. doi: 10.1016/j.addr.2015.01.008
  • Yu RZ, Grundy JS, Henry SP, et al. Predictive dose-based estimation of systemic exposure multiples in mouse and monkey relative to human for antisense oligonucleotides with 2′-O-(2-methoxyethyl) modifications. Mol Ther Nucleic Acids Internet. 2015 cited Jan 20;4:18. doi: 10.1038/mtna.2014.69
  • Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, et al. Targeting huntingtin expression in patients with Huntington’s disease. N Engl J Med Internet. 2019;380(24):2307–2316. doi: 10.1056/NEJMoa1900907
  • Rigo F, Chun SJ, Norris DA, et al. Pharmacology of a central nervous System delivered 2′- O -methoxyethyl–Modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates. J Pharmacol Exp Ther Internet. 2014;350(1):46–55. doi: 10.1124/jpet.113.212407
  • Jafar-Nejad P, Powers B, Soriano A, et al. The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration. Nucleic Acids Res Internet. 2021;49(2):657–673. doi: 10.1093/nar/gkaa1235
  • Cole TA, Zhao H, Collier TJ, et al. α-synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease. JCI Insight Internet. 2021 cited Mar 8;6(5):17. doi: 10.1172/jci,insight.135633
  • US Food and Drug Administration Guidance for Industry: estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. 2005. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/estimating-maximum-safe-starting-dose-initial-clinical-trials-therapeutics-adult-healthy-volunteers
  • Geary RS, Leeds JM, Henry SP, et al. Antisense oligonucleotide inhibitors for the treatment of cancer: 1. Pharmacokinetic properties of phosphorothioate oligodeoxynucleotides. Anticancer Drug Des Internet. 1997;12(5):383–393.
  • Nanavati C, McMullen G, Yu R, et al. Interspecies scaling of human clearance and plasma trough exposure for antisense oligonucleotides: a retrospective analysis of GalNAc3-conjugated and unconjugated-antisense oligonucleotides. Nucleic Acid Ther Internet. 2021;31(4):298–308. doi: 10.1089/nat.2020.0911
  • Frazier KS, Sobry C, Derr V, et al. Species-specific inflammatory responses as a primary component for the development of glomerular lesions in mice and monkeys following chronic administration of a second-generation antisense oligonucleotide. Toxicol Pathol Internet. 2014;42(5):923–935. doi: 10.1177/0192623313505781
  • Yu RZ, Gunawan R, Post N, et al. Disposition and pharmacokinetics of a GalNAc3-conjugated antisense oligonucleotide targeting human lipoprotein (a) in monkeys. Nucleic Acid Ther Internet. 2016;26(6):372–380. doi: 10.1089/nat.2016.0623
  • Yu RZ, Wang Y, Norris DA, et al. Immunogenicity assessment of inotersen, a 2′-O-(2-methoxyethyl) antisense oligonucleotide in animals and humans: effect on pharmacokinetics, pharmacodynamics, and safety. Nucleic Acid Ther Internet. 2020;30(5):265–275. doi: 10.1089/nat.2020.0867
  • Boxenbaum H, DiLea C. First-time-in-human dose selection: allometric thoughts and perspectives. J Clin Pharmacol Internet. 1995;35(10):957–966. doi: 10.1002/j.1552-4604.1995.tb04011.x
  • Martino MTD, Arbitrio M, Fonsi M, et al. Allometric scaling approaches for predicting human pharmacokinetic of a locked Nucleic Acid oligonucleotide targeting Cancer-associated miR-221. Cancers. 2019 cited Dec 19;15. doi: 10.3390/cancers12010027
  • Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet Internet. 2016;388(10063):3017–3026. doi: 10.1016/S0140-6736(16)31408-8
  • Miller TM, Pestronk A, David W, et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol Internet. 2013;12(5):435–442. doi: 10.1016/S1474-4422(13)70061-9
  • DiChiro G, Knop RH, Girton ME, et al. MR cisternography and myelography with gd-DTPA in monkeys. Radiology Internet. 1985;157(2):373–377. doi: 10.1148/radiology.157.2.4048444
  • Pardridge WM. CSF, blood-brain barrier, and brain drug delivery. Expert Opin Drug Deliv Internet. 2016;13(7):963–975. doi: 10.1517/17425247.2016.1171315
  • Poplack DG, Bleyer WA, Wood JH, et al. A primate model for study of methotrexate pharmacokinetics in the central nervous system. Cancer Res [Internet]. 1977;37(7 Pt 1):1982–1985.
  • Hodel J, Lebret A, Petit E, et al. Imaging of the entire cerebrospinal fluid volume with a multistation 3D SPACE MR sequence: feasibility study in patients with hydrocephalus. Eur Radiol Internet. 2013;23(6):1450–1458. doi: 10.1007/s00330-012-2732-7
  • Matsuzawa J, Matsui M, Konishi T, et al. Age-related volumetric changes of brain gray and white matter in healthy infants and children. Cereb Cortex Internet. 2001;11(4):335–342. doi: 10.1093/cercor/11.4.335
  • Shimizu R, Kitade M, Kobayashi T, et al. Pharmacokinetic–pharmacodynamic modeling for reduction of hepatic apolipoprotein B mRNA and plasma total cholesterol after administration of antisense oligonucleotide in mice. J Pharmacokinet Phar. 2015;42(1):67–77. doi: 10.1007/s10928-014-9398-5
  • Diep JK, Yu RZ, Viney NJ, et al. Population pharmacokinetic/pharmacodynamic modeling of eplontersen, an antisense oligonucleotide in development for transthyretin amyloidosis. Br J Clin Pharmacol Internet. 2022;88(12):5389–5398. doi: 10.1111/bcp.15468
  • Yu RZ, Collins JW, Hall S, et al. Population pharmacokinetic–pharmacodynamic modeling of inotersen, an antisense oligonucleotide for treatment of patients with hereditary transthyretin amyloidosis. Nucleic Acid Ther Internet. 2020;30(3):153–163. doi: 10.1089/nat.2019.0822
  • Ayyar VS, Song D, Zheng S, et al. Minimal physiologically based pharmacokinetic-pharmacodynamic (mPBPK-PD) model of N -Acetylgalactosamine–Conjugated small interfering RNA disposition and gene silencing in preclinical species and humans. J Pharmacol Exp Ther Internet. 2021;379(2):134–146. doi: 10.1124/jpet.121.000805
  • Cao Y, Jusko WJ. Applications of minimal physiologically-based pharmacokinetic models. J Pharmacokinet Phar. 2012;39(6):711–723. doi: 10.1007/s10928-012-9280-2
  • Hsu Y, Hettiarachchi HDM, Zhu DC, et al. The frequency and magnitude of cerebrospinal fluid pulsations influence intrathecal drug distribution. Anesthesia & Analgesia. 2012;115(2):386–394. doi: 10.1213/ANE.0b013e3182536211
  • Goto A, Yamamoto S, Iwasaki S. Biodistribution and delivery of oligonucleotide therapeutics to the central nervous system: advances, challenges, and future perspectives. Biopharm Drug Dispos. 2022;44(1):26–47. doi: 10.1002/bdd.2338
  • Luu KT, Norris DA, Gunawan R, et al. Population pharmacokinetics of nusinersen in the cerebral spinal fluid and plasma of pediatric patients with spinal muscular atrophy following intrathecal administrations. J Clin Pharmacol Internet. 2017;57(8):1031–1041. doi: 10.1002/jcph.884
  • Willmann S, Marostica E, Snelder N, et al. PK/PD modeling of FXI antisense oligonucleotides to bridge the dose‐FXI activity relation from healthy volunteers to end‐stage renal disease patients. CPT Pharmacometrics Syst Pharmacol. 2021;10(8):890–901. doi: 10.1002/psp4.12663
  • Bennett CF, Swayze EE. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol. 2010;50(1):259–293. doi: 10.1146/annurev.pharmtox.010909.105654
  • Bennett CF, Baker BF, Pham N, et al. Pharmacology of antisense drugs. Annu Rev Pharmacol Toxicol. 2016;57(1):81–105. doi: 10.1146/annurev-pharmtox-010716-104846
  • Bon C, Hofer T, Bousquet-Mélou A, et al. Capacity limits of asialoglycoprotein receptor-mediated liver targeting. MAbs. 2017;9(8):1360–1369. doi: 10.1080/19420862.2017.1373924
  • Shadid M, Badawi M, Abulrob A. Antisense oligonucleotides: absorption, distribution, metabolism, and excretion. Expert Opin Drug Met. 2021;17(11):1281–1292. doi: 10.1080/17425255.2021.1992382
  • Koller E, Vincent TM, Chappell A, et al. Mechanisms of single-stranded phosphorothioate modified antisense oligonucleotide accumulation in hepatocytes. Nucleic Acids Res Internet. 2011;39(11):4795–4807. doi: 10.1093/nar/gkr089
  • Liang XH, Sun H, Hsu CW, et al. Golgi-endosome transport mediated by M6PR facilitates release of antisense oligonucleotides from endosomes. Nucleic Acids Res Internet. 2020;48(3):1372–1391. doi: 10.1093/nar/gkz1171
  • Juliano RL. Intracellular trafficking and endosomal release of oligonucleotides: what we know and what we don’t. Nucleic Acid Ther Internet. 2018;28(3):166–177. doi: 10.1089/nat.2018.0727
  • Dewey M, Bosserdt M, Dodd JD, et al. Clinical imaging research: higher evidence, global collaboration, improved reporting, and data sharing are the grand challenges. Radiology. 2019;291(3):547–552. doi: 10.1148/radiol.2019181796
  • Izmailova ES, Maguire RP, McCarthy TJ, et al. Empowering drug development: leveraging insights from imaging technologies to enable the advancement of digital health technologies. Clin Transl Sci. 2023;16(3):383–397. doi: 10.1111/cts.13461
  • Kim Y, Jo M, Schmidt J, et al. Enhanced potency of GalNAc-conjugated antisense oligonucleotides in hepatocellular Cancer models. Mol Ther Internet. 2019;27(9):1547–1557. doi: 10.1016/j.ymthe.2019.06.009
  • Kinberger GA, Prakash TP, Yu J, et al. Conjugation of mono and di-GalNAc sugars enhances the potency of antisense oligonucleotides via ASGR mediated delivery to hepatocytes. Bioorg Med Chem Lett Internet. 2016;26(15):3690–3693. doi: 10.1016/j.bmcl.2016.05.084
  • Prakash TP, Yu J, Kinberger GA, et al. Evaluation of the effect of 2′-O-methyl, fluoro hexitol, bicyclo and morpholino nucleic acid modifications on potency of GalNAc conjugated antisense oligonucleotides in mice. Bioorg Med Chem Lett Internet. 2018;28(23–24):3774–3779. doi: 10.1016/j.bmcl.2018.10.011
  • Viney NJ, Guo S, Tai LJ, et al. Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data. ESC Heart Fail Internet. 2021;8(1):652–661. doi: 10.1002/ehf2.13154

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