European Journal of Clinical Pharmacology

, Volume 69, Issue 9, pp 1673–1682 | Cite as

A microdose study of 14C-AR-709 in healthy men: pharmacokinetics, absolute bioavailability and concentrations in key compartments of the lung

  • G. Lappin
  • M. J. Boyce
  • T. Matzow
  • S. Lociuro
  • M. Seymour
  • S. J. Warrington
Pharmacokinetics and Disposition



To explore, in a microdose (phase-0) study, the pharmacokinetics, bioavailability and concentrations in key compartments of the lung, of AR-709, a novel diaminopyrimidine antibiotic for the treatment of respiratory infection.


Four healthy men each received two single, 100 μg microdoses of 14C-AR-709, 7 days apart: the first was administered intravenously (IV), the second orally. Plasma pharmacokinetics of 14C and unchanged AR-709 were obtained by high-performance liquid chromatography and accelerator mass spectrometry (AMS). Next, 15 healthy men received a single, 100 μg microdose of 14C-AR-709 IV. Plasma, bronchoalveolar lavage fluid, alveolar macrophages and bronchial mucosal biopsy samples were analysed by AMS.


After IV administration, clearance of AR-709 was 496 mL/min, volume of distribution was 1,700 L and the absolute oral bioavailability was 2.5 %. Excretion in urine was negligible. At 8–12 h after IV dosing, 14C concentrations in lung samples were 15- (bronchial mucosa) to 200- (alveolar macrophages) fold higher than in plasma. In alveolar macrophages, 14C was still mostly associated with AR-709 at 12 h after dosing.


The results of this microdose study indicate that AR-709 attains concentrations appreciably higher within the lung than in plasma. Its low oral bioavailability however, precludes oral administration. Although IV administration would appear to be an effective route of administration, this would limit the use of AR-709 to a clinical setting and would therefore be economically unsustainable. If further clinical development were to be undertaken, therefore, an alternative route of administration would be necessary.


Microdose Diaminopyrimidine antibiotic Accelerator mass spectrometry Bronchial alveolar lavage Pharmacokinetics 


  1. 1.
    Musher DM (1992) Infections caused by streptococcus pneumoniae: clinical spectrum, pathogenesis, immunity, and treatment. Clin Infect Dis 14(4):801–807PubMedCrossRefGoogle Scholar
  2. 2.
    Mukhija S, Bandera M, Parisi S, Rigo S, Lieb S, Lociuro S, Gillessen D, Islam K (2006) AR709—an investigational diaminopyrimidine: inhibition, binding and mode of action. In: 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. San Fransisco, Abstr F1-1955Google Scholar
  3. 3.
    Jansen WT, Verel A, Verhoef J, Milatovic D (2008) In vitro activity of AR-709 against Streptococcus pneumoniae. Antimicrob Agents Chemother 52(3):1182–1183PubMedCrossRefGoogle Scholar
  4. 4.
    Ressner RA, Moore MR, Jorgensen JH (2008) Activity of the diaminopyrimidine AR-709 against recently collected multidrug-resistant isolates of invasive Streptococcus pneumoniae from North America. Antimicrob Agents Chemother 52(3):1147–1149PubMedCrossRefGoogle Scholar
  5. 5.
    Smith K, Ednie LM, Appelbaum PC, Hawser S, Lociuro S (2008) Antistreptococcal activity of AR-709 compared to that of other agents. Antimicrob Agents Chemother 52(6):2279–2282PubMedCrossRefGoogle Scholar
  6. 6.
    McKenney D, Murphy T, Little S, Gordon L, Islam K, Lociuro S (2007) Efficacy of AR-709 in pneumococcal murine pneumonia. In: 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. ChicagoGoogle Scholar
  7. 7.
    Lappin G (2010) Microdosing: current and the future. Bioanalysis 2(3):509–517PubMedCrossRefGoogle Scholar
  8. 8.
    Lappin G, Garner RC (2003) Big physics, small doses: the use of AMS and PET in human microdosing of development drugs. Nat Rev Drug Discov 2(3):233–240PubMedCrossRefGoogle Scholar
  9. 9.
    Li RC, Zhu M, Schentag JJ (1999) Achieving an optimal outcome in the treatment of infections. The role of clinical pharmacokinetics and pharmacodynamics of antimicrobials. Clin Pharmacokinet 37(1):1–16PubMedCrossRefGoogle Scholar
  10. 10.
    Committee for Medicinal Products for Human Use (CPMP)/International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (2009) ICH Topic M3 Note for Guidance on non-clinical safety pharmacology studies for human pharmaceuticals. CPMP/ICH/286/95. CPMP/ICH, London/GenevaGoogle Scholar
  11. 11.
    Lappin G, Wagner C, Langer O, Merbel VD (2009) New ultrasensitive detection technologies and techniques for use in microdosing studies. Bioanalysis 1(2):357–366PubMedCrossRefGoogle Scholar
  12. 12.
    The BAL Cooperative Group Steering Committee (1990) Bronchoalveolar lavage constituents in healthy individuals, idiopathic pulmonary fibrosis, and selected comparison groups. Am Rev Respir Dis 141:S166–S202Google Scholar
  13. 13.
    Turteltaub KW, Felton JS, Gledhill BL, Vogel JS, Southon JR, Caffee MW, Finkel RC, Nelson DE, Proctor ID, Davis JC (1990) Accelerator mass spectrometry in biomedical dosimetry: relationship between low-level exposure and covalent binding of heterocyclic amine carcinogens to DNA. Proc Natl Acad Sci USA 87(14):5288–5292PubMedCrossRefGoogle Scholar
  14. 14.
    Gunnarsson M, Leide-Svegborn S, Stenstrom K, Skog G, Nilsson LE, Hellborg R, Mattsson S (2002) No radiation protection reasons for restrictions on 14C urea breath tests in children. Br J Radiol 75(900):982–986PubMedGoogle Scholar
  15. 15.
    Committee for Medicinal Products for Human Use (2004) Position paper on non-clinical safety studies to support clinical trials with a single microdose. Position paper CPMP/SWP/2599. European Medicines Agency, LondonGoogle Scholar
  16. 16.
    Albert A, Brown DJ (1954) Purine studies part I. Stability to acid and alkali. Solubility, ionization, comparison with pteridines. J Chem Soc 2060–2071Google Scholar
  17. 17.
    Bernatek E, Hvatum M (1960) On the stability of ozonides. Acta Chem Scand 14:836–840CrossRefGoogle Scholar
  18. 18.
    Wenkert E, Alonso ME, Gottlib HE, Sanchez EL, Pellicciari R, Cogolli P (1977) Reactions of ethyl diazoacetate with thianaphthene, indoles and benzofuran. J Org Chem 42(24):3945–3949CrossRefGoogle Scholar
  19. 19.
    Lappin G, Simpson M, Shishikura Y, Garner C (2008) High-performance liquid chromatography accelerator mass spectrometry: correcting for losses during analysis by internal standardization. Anal Biochem 378:93–95PubMedCrossRefGoogle Scholar
  20. 20.
    Klech H, Pohl W (1989) Report of the European Society of Pneumology Task Group on BAL. Technical recommendations and guidelines for bronchoalveolar lavage (BAL). Eur Respir J 2(561–585)Google Scholar
  21. 21.
    Rennard SI, Basset G, Lecossier D, O’Donnell KM, Pinkston P, Martin PG, Crystal RG (1986) Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution. J Appl Physiol 60:532–538PubMedGoogle Scholar
  22. 22.
    Lappin G, Seymour M, Young G, Higton D, Hill HM (2011) An AMS method to determine analyte recovery from pharmacokinetic studies with concomitant extravascular and intravenous administration. Bioanalysis 3(4):407–410PubMedCrossRefGoogle Scholar
  23. 23.
    Lappin G, Garner RC (2003) Ultra-sensitive detection of radiolabelled drugs and their metabolites using accelerator mass spectrometry. In: Wilson I (ed) Handbook of analytical separations, vol 4. Bioanalytical separations. Elsevier, Amsterdam, pp 331–349CrossRefGoogle Scholar
  24. 24.
    Lappin G, Garner RC (2004) Current perspectives of 14C-isotope measurement in biomedical accelerator mass spectrometry. Anal Biochem 378(2):356–364Google Scholar
  25. 25.
    Salehpour M, Possnert G, Bryhni H (2008) Subattomole sensitivity in biological accelerator mass spectrometry. Anal Chem 80(10):3515–3521PubMedCrossRefGoogle Scholar
  26. 26.
    Rowland M (2012) Microdosing: a critical assessment of human data. J Pharm Sci 101(11):4067–4074PubMedCrossRefGoogle Scholar
  27. 27.
    Rowland M, Benet LZ (2011) Clinical trials and translational medicine commentaries. J Pharm Sci 100:4047–4049Google Scholar
  28. 28.
    Lappin G, Noveck R, Burt T (2013) Microdosing and drug development: past, present and future. Expert Opin Drug Metab Toxicol 9 (7):in pressGoogle Scholar
  29. 29.
    Benet LZ, Broccatelli F, Oprea TI (2011) BDDCS applied to over 900 drugs. AAPS J 13(4):519–547PubMedCrossRefGoogle Scholar
  30. 30.
    Lappin G, Shishikura Y, Jochemsen R, Weaver RJ, Gesson C, Brian Houston J, Oosterhuis B, Bjerrum OJ, Grynkiewicz G, Alder J, Rowland M, Garner C (2011) Comparative pharmacokinetics between a microdose and therapeutic dose for clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen), and phenobarbital in human volunteers. Eur J Pharm Sci 43:141–150PubMedCrossRefGoogle Scholar
  31. 31.
    Conte JE Jr, Golden JA, Kipps J, Zurlinden E (2004) Steady-state plasma and intrapulmonary pharmacokinetics and pharmacodynamics of cethromycin. Antimicrob Agents Chemother 48(9):3508–3515PubMedCrossRefGoogle Scholar
  32. 32.
    Periti P, Mazzei T, Mini E, Novelli A (1989) Clinical pharmacokinetic properties of the macrolide antibiotics. Effects of age and various pathophysiological states (Part II). Clin Pharmacokinet 16(5):261–282PubMedCrossRefGoogle Scholar
  33. 33.
    Hii JT, Duff HJ, Burgess ED (1991) Clinical pharmacokinetics of propafenone. Clin Pharmacokinet 21(1):1–10PubMedCrossRefGoogle Scholar
  34. 34.
    Zanni GR, Wick JY (2006) Microdosing: the new pharmacokinetic paradigm? Consult Pharm 21(10):756–776PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • G. Lappin
    • 1
  • M. J. Boyce
    • 2
  • T. Matzow
    • 2
  • S. Lociuro
    • 3
  • M. Seymour
    • 4
  • S. J. Warrington
    • 2
  1. 1.School of PharmacyUniversity of LincolnLincolnUK
  2. 2.Hammersmith Medicines ResearchLondonUnited Kingdom
  3. 3.MaroggiaSwitzerland
  4. 4.Xceleron Inc.GermantownUSA

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