Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1990 Nov;34(11):2228–2233. doi: 10.1128/aac.34.11.2228

Safety and pharmacokinetics of rimantadine small-particle aerosol.

R L Atmar 1, S B Greenberg 1, J M Quarles 1, S Z Wilson 1, B Tyler 1, S Feldman 1, R B Couch 1
PMCID: PMC172027  PMID: 2073113

Abstract

The safety and pharmacokinetics of rimantadine administered by small-particle aerosol were assessed in healthy adults and adults with acute influenza virus infection. Aerosolized rimantadine delivered at a concentration of 40 micrograms/liter of air was associated with nasal burning and irritation in normal volunteers. A concentration of 20 micrograms/liter of air was well tolerated for up to 12 h by normal volunteers and was not associated with any changes in pulmonary function, as measured by routine spirometry, plethysmography, or diffusion capacity of carbon monoxide. Mean peak levels of drug in serum were approximately 10-fold lower after 12 h of aerosol administration than they were after oral administration of 200 mg (29.7 versus 255 ng/ml, respectively), while mean nasal wash levels were approximately 100-fold higher (6,650 versus 66.6 ng/ml, respectively). Elimination half-lives were similar after both aerosol and oral administration (24.1 and 25.2 h, respectively), and rimantadine urinary excretion was less than 1% per 24 h in both groups. Twenty micrograms of aerosolized rimantadine per liter of air given 12 h daily for 3 days to nine adults with acute influenza virus infection was well tolerated. Levels in plasma after 12 h of aerosol inhalation were similar to those in normal volunteers, but were higher at the end of the third treatment than they were at the end of the first treatment (88.3 versus 47.9 ng/ml, respectively). Thus, rimantadine delivered via small-particle aerosol at a dose of 20 micrograms/liter of air was well tolerated in normal volunteers and in those with acute influenza and was associated with high local concentrations.

Full text

PDF
2231

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baxter B. D., Couch R. B., Greenberg S. B., Kasel J. A. Maintenance of viability and comparison of identification methods for influenza and other respiratory viruses of humans. J Clin Microbiol. 1977 Jul;6(1):19–22. doi: 10.1128/jcm.6.1.19-22.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Belshe R. B., Smith M. H., Hall C. B., Betts R., Hay A. J. Genetic basis of resistance to rimantadine emerging during treatment of influenza virus infection. J Virol. 1988 May;62(5):1508–1512. doi: 10.1128/jvi.62.5.1508-1512.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Burlington D. B., Meiklejohn G., Mostow S. R. Anti-influenza A activity of combinations of amantadine and ribavirin in ferret tracheal ciliated epithelium. J Antimicrob Chemother. 1983 Jan;11(1):7–14. doi: 10.1093/jac/11.1.7. [DOI] [PubMed] [Google Scholar]
  4. Burlington D. B., Meiklejohn G., Mostow S. R. Anti-influenza A virus activity of amantadine hydrochloride and rimantadine hydrochloride in ferret tracheal ciliated epithelium. Antimicrob Agents Chemother. 1982 May;21(5):794–799. doi: 10.1128/aac.21.5.794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dolin R., Reichman R. C., Madore H. P., Maynard R., Linton P. N., Webber-Jones J. A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection. N Engl J Med. 1982 Sep 2;307(10):580–584. doi: 10.1056/NEJM198209023071002. [DOI] [PubMed] [Google Scholar]
  6. Fenton R. J., Bessell C., Spilling C. R., Potter C. W. The effects of peroral or local aerosol administration of 1-aminoadamantane hydrochloride (amantadine hydrochloride) on influenza infections of the ferret. J Antimicrob Chemother. 1977 Sep;3(5):463–472. doi: 10.1093/jac/3.5.463. [DOI] [PubMed] [Google Scholar]
  7. Fukuda E. K., Rodriguez L. C., Choma N., Keigher N., De Grazia F., Garland W. A. Quantitative determination of rimantadine in human plasma and urine by GC-MS. Biomed Environ Mass Spectrom. 1987 Oct;14(10):549–553. doi: 10.1002/bms.1200141004. [DOI] [PubMed] [Google Scholar]
  8. Galegov G. A., Pushkarskaya N. L., Obrosova-Serova N. P., Zhdanov V. M. Combined action of ribovirin and rimantadine in experimental myxovirus infection. Experientia. 1977 Jul 15;33(7):905–906. doi: 10.1007/BF01951273. [DOI] [PubMed] [Google Scholar]
  9. Hall C. B., McBride J. T., Walsh E. E., Bell D. M., Gala C. L., Hildreth S., Ten Eyck L. G., Hall W. J. Aerosolized ribavirin treatment of infants with respiratory syncytial viral infection. A randomized double-blind study. N Engl J Med. 1983 Jun 16;308(24):1443–1447. doi: 10.1056/NEJM198306163082403. [DOI] [PubMed] [Google Scholar]
  10. Hayden F. G., Belshe R. B., Clover R. D., Hay A. J., Oakes M. G., Soo W. Emergence and apparent transmission of rimantadine-resistant influenza A virus in families. N Engl J Med. 1989 Dec 21;321(25):1696–1702. doi: 10.1056/NEJM198912213212502. [DOI] [PubMed] [Google Scholar]
  11. Hayden F. G., Cote K. M., Douglas R. G., Jr Plaque inhibition assay for drug susceptibility testing of influenza viruses. Antimicrob Agents Chemother. 1980 May;17(5):865–870. doi: 10.1128/aac.17.5.865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hayden F. G., Hall W. J., Douglas R. G., Jr Therapeutic effects of aerosolized amantadine in naturally acquired infection due to influenza A virus. J Infect Dis. 1980 May;141(5):535–542. doi: 10.1093/infdis/141.5.535. [DOI] [PubMed] [Google Scholar]
  13. Hayden F. G., Hoffman H. E., Spyker D. A. Differences in side effects of amantadine hydrochloride and rimantadine hydrochloride relate to differences in pharmacokinetics. Antimicrob Agents Chemother. 1983 Mar;23(3):458–464. doi: 10.1128/aac.23.3.458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hayden F. G., Minocha A., Spyker D. A., Hoffman H. E. Comparative single-dose pharmacokinetics of amantadine hydrochloride and rimantadine hydrochloride in young and elderly adults. Antimicrob Agents Chemother. 1985 Aug;28(2):216–221. doi: 10.1128/aac.28.2.216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hayden F. G., Monto A. S. Oral rimantadine hydrochloride therapy of influenza A virus H3N2 subtype infection in adults. Antimicrob Agents Chemother. 1986 Feb;29(2):339–341. doi: 10.1128/aac.29.2.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hayden F. G., Schlepushkin A. N., Pushkarskaya N. L. Combined interferon-alpha 2, rimantadine hydrochloride, and ribavirin inhibition of influenza virus replication in vitro. Antimicrob Agents Chemother. 1984 Jan;25(1):53–57. doi: 10.1128/aac.25.1.53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hayden F. G., Zylidnikov D. M., Iljenko V. I., Padolka Y. V. Comparative therapeutic effect of aerosolized and oral rimantadine HCl in experimental human influenza A virus infection. Antiviral Res. 1982 Aug;2(3):147–153. doi: 10.1016/0166-3542(82)90016-x. [DOI] [PubMed] [Google Scholar]
  18. Knight V., Bloom K., Wilson S. Z., Wilson R. K. Amantadine aerosol in humans. Antimicrob Agents Chemother. 1979 Nov;16(5):572–578. doi: 10.1128/aac.16.5.572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Knight V., McClung H. W., Wilson S. Z., Waters B. K., Quarles J. M., Cameron R. W., Greggs S. E., Zerwas J. M., Couch R. B. Ribavirin small-particle aerosol treatment of influenza. Lancet. 1981 Oct 31;2(8253):945–949. doi: 10.1016/s0140-6736(81)91152-1. [DOI] [PubMed] [Google Scholar]
  20. Knight V., Yu C. P., Gilbert B. E., Divine G. W. Estimating the dosage of ribavirin aerosol according to age and other variables. J Infect Dis. 1988 Aug;158(2):443–448. doi: 10.1093/infdis/158.2.443. [DOI] [PubMed] [Google Scholar]
  21. Rabinovich S., Baldini J. T., Bannister R. Treatment of influenza. The therapeutic efficacy of rimantadine HC1 in a naturally occurring influenza A2 outbreak. Am J Med Sci. 1969 May;257(5):328–335. doi: 10.1097/00000441-196905000-00005. [DOI] [PubMed] [Google Scholar]
  22. Rocci M. L., Jr, Jusko W. J. LAGRAN program for area and moments in pharmacokinetic analysis. Comput Programs Biomed. 1983 Jun;16(3):203–216. doi: 10.1016/0010-468x(83)90082-x. [DOI] [PubMed] [Google Scholar]
  23. Taber L. H., Knight V., Gilbert B. E., McClung H. W., Wilson S. Z., Norton H. J., Thurson J. M., Gordon W. H., Atmar R. L., Schlaudt W. R. Ribavirin aerosol treatment of bronchiolitis associated with respiratory syncytial virus infection in infants. Pediatrics. 1983 Nov;72(5):613–618. [PubMed] [Google Scholar]
  24. Thompson J., Fleet W., Lawrence E., Pierce E., Morris L., Wright P. A comparison of acetaminophen and rimantadine in the treatment of influenza A infection in children. J Med Virol. 1987 Mar;21(3):249–255. doi: 10.1002/jmv.1890210308. [DOI] [PubMed] [Google Scholar]
  25. Van Voris L. P., Betts R. F., Hayden F. G., Christmas W. A., Douglas R. G., Jr Successful treatment of naturally occurring influenza A/USSR/77 H1N1. JAMA. 1981 Mar 20;245(11):1128–1131. doi: 10.1001/jama.245.11.1128. [DOI] [PubMed] [Google Scholar]
  26. Walker J. S., Stephen E. L., Spertzel R. O. Small-particle aerosols of antiviral compounds in treatment of type A influenza pneumonia in mice. J Infect Dis. 1976 Jun;133 (Suppl):A140–A144. doi: 10.1093/infdis/133.supplement_2.a140. [DOI] [PubMed] [Google Scholar]
  27. Wilson S. Z., Gilbert B. E., Quarles J. M., Knight V., McClung H. W., Moore R. V., Couch R. B. Treatment of influenza A (H1N1) virus infection with ribavirin aerosol. Antimicrob Agents Chemother. 1984 Aug;26(2):200–203. doi: 10.1128/aac.26.2.200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Wilson S. Z., Knight V., Wyde P. R., Drake S., Couch R. B. Amantadine and ribavirin aerosol treatment of influenza A and B infection in mice. Antimicrob Agents Chemother. 1980 Apr;17(4):642–648. doi: 10.1128/aac.17.4.642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Wingfield W. L., Pollack D., Grunert R. R. Therapeutic efficacy of amantadine HCl and rimantadine HCl in naturally occurring influenza A2 respiratory illness in man. N Engl J Med. 1969 Sep 11;281(11):579–584. doi: 10.1056/NEJM196909112811102. [DOI] [PubMed] [Google Scholar]
  30. Zlydnikov D. M., Kubar O. I., Kovaleva T. P., Kamforin L. E. Study of rimantadine in the USSR: a review of the literature. Rev Infect Dis. 1981 May-Jun;3(3):408–421. doi: 10.1093/clinids/3.3.408. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES