Skip to main content
SpringerLink
Log in

Randomised, Double-Blind, Placebo-Controlled, Dose-Escalating Phase I Study of QGC001, a Centrally Acting Aminopeptidase A Inhibitor Prodrug

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

Inhibition of brain aminopeptidase A (APA), which converts angiotensin II into angiotensin III, has emerged as a novel antihypertensive treatment, as demonstrated in several experimental animal models. QGC001 (originally named RB150) is a prodrug of the specific and selective APA inhibitor EC33, and as such it is the prototype of a new class of centrally acting antihypertensive agents. Given by the oral route in hypertensive rats, it enters the brain and generates EC33, which blocks the brain renin–angiotensin system activity and normalises blood pressure. The aim of the present study was to evaluate the safety, pharmacokinetics and pharmacodynamic effects of QGC001 in humans.

Design and Methods

Fifty-six healthy male volunteers were randomly assigned to receive in double-blind and fasted conditions single oral doses of 10, 50, 125, 250, 500, 750, 1,000 and 1,250 mg of QGC001 (n = 6/dose) or placebo (n = 2/dose). We measured plasma and urine concentrations of both QGC001 and EC33 by liquid chromatography–tandem mass spectrometry, plasma renin concentrations (PRC), plasma and free urine aldosterone (PAldo and UAldo), plasma copeptine (PCop), and plasma and urine cortisol (PCort and UCort) concentrations, and supine systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) at various time points.

Results

All doses of QGC001 were clinically and biologically well-tolerated. Peak plasma concentrations (C max) of QGC001 and EC33 increased linearly with the dose, with a median time to reach C max (t max) of 1.5 h for QGC001 and 3.0 h for EC33. The median plasma elimination half-life of QGC001 was 1.6 h consistently throughout doses. Urinary excretion of QGC001 and EC33 was below 2 % of the administered dose. When compared with placebo, QGC001 did not significantly change PRC, PAldo, UAldo, PCop, PCort or UCort. No significant change was observed for supine HR, SBP and DBP in any treatment group.

Conclusion

Single oral administration of QGC001 up to 1,250 mg in healthy volunteers was well-tolerated. Following oral administration, QGC001 is absorbed via the gastrointestinal tract and converted partially into its active metabolite EC33 in plasma. As in animal experiments, in normotensive subjects QGC001 had no effect on the systemic renin–angiotensin–aldosterone parameters and on PCop concentrations, a marker of vasopressin release. In normotensive subjects, a single dose of QCG001 had no effect on SBP, DBP or HR. These data support further evaluation of multiple oral doses of QGC001 in human volunteers and its clinical efficacy in hypertensive patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al., American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2013 update: a report from the American Heart Association. Circulation. 2013 Jan 1;127(1):e6–e245.

  2. Wright JW, Harding JW. Regulatory role of brain angiotensins in the control of physiological and behavioral responses. Brain Res Brain Res Rev. 1992;17(3):227–62.

    Article  PubMed  CAS  Google Scholar 

  3. Basso N, Ruiz P, Kurnjek ML, Cannata MA, Taquini AC. The brain renin-angiotensin system and the development of DOCA-salt hypertension. Clin Exp Hypertens. 1985;7(9):1259–68.

    Article  CAS  Google Scholar 

  4. Ganten D, Hermann K, Bayer C, Unger T, Lang RE. Angiotensin synthesis in the brain and increased turnover in hypertensive rats. Science. 1983;221(4613):869–71.

    Article  PubMed  CAS  Google Scholar 

  5. Zini S, Fournie-Zaluski MC, Chauvel E, Roques BP, Corvol P, Llorens-Cortes C. Identification of metabolic pathways of brain angiotensin II and III using specific aminopeptidase inhibitors: predominant role of angiotensin III in the control of vasopressin release. Proc Natl Acad Sci USA. 1996;93(21):11968–73.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  6. Chauvel EN, Coric P, Llorens-Cortes C, Wilk S, Roques BP, Fournie-Zaluski MC. Investigation of the active site of aminopeptidase A using a series of new thiol-containing inhibitors. J Med Chem. 1994;37(9):1339–46.

    Article  PubMed  CAS  Google Scholar 

  7. Fournie-Zaluski MC, et al. Potent and systemically active aminopeptidase N inhibitors designed from active-site investigation. J Med Chem. 1992;35(7):1259–66.

    Article  PubMed  CAS  Google Scholar 

  8. Reaux A, et al. Aminopeptidase A inhibitors as potential central antihypertensive agents. Proc Natl Acad Sci USA. 1999;96(23):13415–20.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  9. Reaux A, Fournie-Zaluski MC, Llorens-Cortes C. Angiotensin III: a central regulator of vasopressin release and blood pressure. Trends Endocrinol Metab. 2001;12(4):157–62.

    Article  PubMed  CAS  Google Scholar 

  10. Fournie-Zaluski MC, Fassot C, Valentin B, Djordjijevic D, Reaux-Le Goazigo A, Corvol P, et al. Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: a potential treatment of salt-dependent hypertension. Proc Natl Acad Sci USA. 2004;101(20):7775–80.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  11. Rozenfeld R, Iturrioz X, Maigret B, Llorens-Cortes C. Contribution of molecular modeling and site-directed mutagenesis to the identification of two structural residues, Arg-220 and Asp-227, in aminopeptidase A. J Biol Chem. 2002;277(32):29242–52.

    Article  PubMed  CAS  Google Scholar 

  12. Fournie-Zaluski MC, Coric P, Turcaud S, Lucas E, Noble F, Maldonado R, et al. “Mixed inhibitor-prodrug” as a new approach toward systemically active inhibitors of enkephalin-degrading enzymes. J Med Chem. 1992;35(13):2473–81.

    Article  PubMed  CAS  Google Scholar 

  13. Bodineau L, Frugière A, Marc Y, Inguimbert N, Fassot C, Balavoine F, et al. Orally active aminopeptidase A inhibitors reduce blood pressure: a new strategy for treating hypertension. Hypertension. 2008;51(5):1318–25.

    Article  PubMed  CAS  Google Scholar 

  14. Marc Y, Gao J, Balavoine F, Michaud A, Roques BP, Llorens-Cortes C. Central antihypertensive effects of orally active aminopeptidase A inhibitors in spontaneously hypertensive rats. Hypertension. 2012;60(2):411–8.

    Article  PubMed  CAS  Google Scholar 

  15. Marc Y, Llorens-Cortes C. The role of the brain renin-angiotensin system in hypertension: implications for new treatment. Prog Neurobiol. 2011;95(2):89–103.

    Article  PubMed  CAS  Google Scholar 

  16. Morgenthaler NG, Struck J, Jochberger S, Dünser MW. Copeptin: clinical use of a new biomarker. Trends Endocrinol Metab. 2008;19(2):43–9.

    Article  PubMed  CAS  Google Scholar 

  17. Evans WE, Schentag JJ, Jusko WJ. Applied pharmacokinetics: principles of therapeutic drug monitoring. 3rd ed. Baltimore: Lippincott Williams & Wilkins; 1992.

    Google Scholar 

  18. Wuerzner G, Azizi M. Renin inhibition with aliskiren. Clin Exp Pharmacol Physiol. 2008;35(4):426–30.

    Article  PubMed  CAS  Google Scholar 

  19. Uchino H, Kanai Y, Kim DK, Wempe MF, Chairoungdua A, Morimoto E, et al. Transport of amino acid-related compounds mediated by L-type amino acid transporter 1 (LAT1): insights into the mechanisms of substrate recognition. Mol Pharmacol. 2002;61(4):729–37.

    Google Scholar 

  20. Azizi M, Bissery A, Bura-Riviere A, Menard J. Dual renin-angiotensin system blockade restores blood pressure-renin dependency in individuals with low renin concentrations. J Hypertens. 2003;21(10):1887–95.

    Article  PubMed  CAS  Google Scholar 

  21. Lachurié ML, Azizi M, Guyene TT, Alhenc-Gelas F, Ménard J. Angiotensin-converting enzyme gene polymorphism has no influence on the circulating renin-angiotensin-aldosterone system or blood pressure in normotensive subjects. Circulation. 1995;91(12):2933–42.

    Article  PubMed  Google Scholar 

  22. De Mota N, Iturrioz X, Claperon C, Bodineau L, Fassot C, Roques BP, et al. Human brain aminopeptidase A: biochemical properties and distribution in brain nuclei. J Neurochem. 2008;106(1):416–28.

    Article  PubMed  CAS  Google Scholar 

  23. Ma TK, Kam KK, Yan BP, Lam YY. Renin-angiotensin-aldosterone system blockade for cardiovascular diseases: current status. Br J Pharmacol. 2010;160(6):1273–92.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  24. Volpe M, Pontremoli R, Borghi C. Direct renin inhibition: from pharmacological innovation to novel therapeutic opportunities. High Blood Press Cardiovasc Prev. 2011;18(3):93–105.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was sponsored by Quantum Genomics SA, France. The authors thank Biotrial’s staff at the Clinical Unit, in particular Dr. Pascale Koussignian and Dr. Didier Chassard for their work during the entire conduct of the study, and Bertin Pharma’s staff for the analysis of the plasma and urinary pharmacokinetic samples. The research leading to these results has received funding from the French Agence Nationale de la Recherche (BiotecS-ANR-08-BIOT-004), from the Institut National de la Santé et de la Recherche Médicale (INSERM) and Collège de France.

Conflict of interest

FB is a full-time employee of Quantum Genomics SA and holds stock options in the company. CL-C, MA, DB, NDM and BR have no conflict of interest.

Author Contributions

Fabrice Balavoine, Michel Azizi, Bernard Roques and Catherine Llorens-Cortes wrote the manuscript.

Fabrice Balavoine, Michel Azizi, Bernard Roques and Catherine Llorens-Cortes designed the research.

Fabrice Balavoine, Michel Azizi and Catherine Llorens-Cortes analysed the data.

Damien Bergerot, Nadia De Mota and Remi Patouret performed the experiments.

Author information

Authors and Affiliations

  1. Quantum Genomics SA, Bât. L’Odyssée, 2-12 chemin des femmes, 91300, Massy, France

    Fabrice Balavoine

  2. Université Paris-Descartes, 75270, Paris, France

    Michel Azizi

  3. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, 75015, Paris, France

    Michel Azizi

  4. INSERM, Clinical Investigation Centre 9201, 75015, Paris, France

    Michel Azizi & Damien Bergerot

  5. Laboratory of Central Neuropeptides and Regulations of Body Fluid Homeostasis and Cardiovascular Functions, INSERM U1050, CIRB, Collège de France, 75231, Paris, France

    Nadia De Mota & Catherine Llorens-Cortes

  6. INSERM U1022, Université Paris-Descartes, 75270, Paris, France

    Rémi Patouret & Bernard P. Roques

Authors
  1. Fabrice Balavoine
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michel Azizi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Damien Bergerot
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nadia De Mota
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rémi Patouret
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bernard P. Roques
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Catherine Llorens-Cortes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fabrice Balavoine.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Balavoine, F., Azizi, M., Bergerot, D. et al. Randomised, Double-Blind, Placebo-Controlled, Dose-Escalating Phase I Study of QGC001, a Centrally Acting Aminopeptidase A Inhibitor Prodrug. Clin Pharmacokinet 53, 385–395 (2014). https://doi.org/10.1007/s40262-013-0125-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-013-0125-y

Keywords

Search

Navigation