Skip to main content
SpringerLink
Log in

Clinical Pharmacokinetics of the Antiviral Nucleotide Analogues Cidofovir and Adefovir

  • Review Articles
  • Drug Disposition
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Cidofovir and adefovir are members of a new class of antiviral compounds. They are acyclic phosphonate analogues of deoxynucleoside monophosphates. Both compounds undergo intracellular activation to form diphosphates that are potent inhibitors of viral DNA polymerases. Cidofovir has broad spectrum antiviral activity against herpesviruses, papillomaviruses and poxviruses, whereas adefovir has potent activity against retroviruses and certain DNA viruses, including herpesviruses and hepadnaviruses. Intravenous cidofovir is approved for treatment of cytomegalovirus retinitis in patients with AIDS.

Cidofovir and adefovir are dianionic at physiological pH and have low oral bioavailability in animals and humans. After intravenous administration to HIV-infected patients, the pharmacokinetics of both drugs are independent of dose and are consistent with preclinical data. Systemic exposure is proportional to the intravenous dose and both drugs are cleared by the kidney and excreted extensively as unchanged drug in the urine. Intracellular activation of a small fraction (<10%) of the dose by cellular kinases leads to prolonged antiviral effects that are not easily predicted from conventional pharmacokinetic studies. The observed rate of elimination of cidofovir and adefovir from serum may not reflect the true duration of action of these drugs, since the antiviral effect is dependent on concentrations of the active phosphorylated metabolites that are present within cells. For both drugs, >90% of an intravenous dose is recovered unchanged in the urine over 24 hours. Metabolism does not contribute significantly to the total clearance of either drug. Concomitant oral probenecid decreases both the renal clearance of cidofovir and the incidence of nephrotoxicity, presumably by blocking its active tubular secretion. This is the basis of the clinical use of concomitant probenecid as a nephroprotectant during cidofovir therapy. Subcutaneous administration produces exposure equivalent to that following intravenous administration.

Drug interaction studies with cidofovir are ongoing, but there is no evidence of an interaction between zidovudine and either cidofovir or adefovir. Clearance of cidofovir in patients with renal impairment showed a linear relationship to creatinine clearance. The low oral bioavailability of adefovir has led to the development of an oral prodrug, adefovir dipivoxil, currently in development for the treatment of HIV and hepatitis B infections.

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

Similar content being viewed by others

References

  1. Bronson JJ, Ferrara LM, Hitchcock MJM, et al. (S)-1-(3-Hydroxy-2-(phosphonylmethoxy)propyl) cytosine (HPMPC): a potent antiherpesvirus agent. In: Lopez C, Mori R, Roizman B, et al., editors. Immunobiology and prophylaxis of human herpesvirus infections. New York: Plenum Press, 1990.

    Google Scholar 

  2. Balzarini J, Naesens L, Herdewijn P, et al. Marked in vivo anti-retrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine, a selective anti-human immunodeficiency virus agent. Proc Natl Acad Sci USA 1989; 86: 332–6.

    Article  PubMed  CAS  Google Scholar 

  3. Bronson JJ, Ho H-T, De Boeck H, et al. Biochemical pharmacology of acyclic nucleotide analogs. Ann NY Acad Sci 1990; 616: 398–407.

    Article  PubMed  CAS  Google Scholar 

  4. Safrin S. Treatment of acyclovir resistant herpes simplex virus infections in patients with AIDS. J Acquir Immune Defic Syndr 1992; 5 Suppl.: S29–32.

    PubMed  Google Scholar 

  5. Naesens L, Snoeck R, Andrei G, et al. HPMPC (cidofovir), PMEA (adefovir) and related acyclic nucleoside phosphonate analogues: a review of their pharmacology and clinical potential in the treatment of viral infections. Antiviral Chem Chemother 1997; 8 (1): 1–23.

    CAS  Google Scholar 

  6. Ho H-T, Woods KL, Bronson JJ, et al. Intracellular metabolism of the antiherpes agent (S)-1-[3-hydroxy-2-phosphonylmethoxy)propyl]-cytosine. Mol Pharmacol 1992; 41: 197–202.

    PubMed  CAS  Google Scholar 

  7. Aduma P, Connelly MC, Srinivas RV, et al. Metabolic diversity and antiviral activities of acyclic nucleoside phosphonates. Mol Pharmacol 1995 47: 816–22.

    PubMed  CAS  Google Scholar 

  8. Lalezari JP, Stagg RJ, Kuppermann BD, et al. Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. Ann Intern Med 1997; 126: 257–63.

    PubMed  CAS  Google Scholar 

  9. Lalezari J, Schaker T, Feinberg J, et al. A randomized, doubleblind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. J Infect Dis 1997; 176: 892–8.

    Article  PubMed  CAS  Google Scholar 

  10. Kriesel J, Douglas J, Corey L, et al. A phase I/II study of cidofovir gel for refractory condyloma acuminatum in patients with HIV-infection [abstract no. 334]. Program and Abstracts of the 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–25: Washington, DC.

  11. Walker RE, Vogel SE, Jaffe HS, et al. A phase I/II study of PMEA in HIV-infected patients [abstract no. 522]. First National Conference on Humun Retroviruses and Related Infections; 1993 Dec 12–16; 148.

  12. Cundy KC, Petty BG, Flaherty J, et al. Clinical pharmacokinetics of cidofovir in HIV-infected patients. Antimicrob Agents Chemother 1995; 39: 1247–52.

    Article  PubMed  CAS  Google Scholar 

  13. Snoeck R, DeWit S, Rossi C, et al. Treatment of progressive multifocal leukoencephalopathy (PML) with cidofovir in an AIDS patient [abstract]. Antiviral Res 1996; 30: A51.

    Google Scholar 

  14. Eisenberg EJ, Cundy KC. HPLC determination of cytosine containing compounds by precolumn fluorescence derivatization with phenacyl bromide: application to antiviral nucleosides and nucleotides. J Chomatogr Biomed Appl 1996; 679: 119–27.

    Article  CAS  Google Scholar 

  15. Russell JW, Marrero D, Whiterock VJ, et al. Determination of 9-[2-phosphonylmethoxy)-ethyl]adenine in rat urine by high-performance liquid chromatography with fluorescence detection. J Chromatogr 1991; 572: 321–6.

    Article  PubMed  CAS  Google Scholar 

  16. Naesens L, Balzarini J, De Clercq E. Acyclic adenine nucleoside phosphonates in plasma determined by high-performance liquid chromatography with fluorescence detection. Clin Chem 1992; 38: 480–5.

    PubMed  CAS  Google Scholar 

  17. Cundy KC, Barditch-Crovo P, Walker RE, et al. Clinical pharmacokinetics of adefovir in human immunodeficiency virus type 1-infected patients. Antimicrob Agents Chemother 1995; 39: 2401–5.

    Article  PubMed  CAS  Google Scholar 

  18. Naesens L, Balzarini J, De Clercq E. Pharmacokinetics in mice of the antiretrovirus agent 9-(2-phosphonylmethoxyethyl) adenine. Drug Metab Dispos 1992; 20: 747–52.

    PubMed  CAS  Google Scholar 

  19. Cundy KC, Bidgood AM, Lynch G, et al. Pharmacokinetics, bioavailability, metabolism and tissue distribution of cidofovir (HPMPC) and cyclic HPMPC in rats. Drug Metab Dispos 1996; 24: 745–52.

    PubMed  CAS  Google Scholar 

  20. Shaw J-P, Louie MS, Krishnamurthy K, et al. Pharmacokinetics and metabolism of selected prodrugs of PMEA in rats. Drug Metab Dispos 1997; 25: 362–6.

    PubMed  CAS  Google Scholar 

  21. Cundy KC, Lynch G, Lee WA. Bioavailability and metabolism of cidofovir following topical administration to rabbits. Antiviral Res 1997; 35: 113–22.

    Article  PubMed  CAS  Google Scholar 

  22. Kern ER, Palmer J, Vogt PE, et al. Efficacy and pharmacokinetics of topical HPMPC in a genital herpes model [abstract]. Antiviral Res 1995; 26: A341.

    Google Scholar 

  23. Cundy KC, Marshburn J, Nakamura C, et al. Oral formulations of adefovir dipivoxil: in vitro dissolution and in vivo bioavailability in dogs. J Pharm Sci 1997; 86: 1334–8.

    Article  PubMed  CAS  Google Scholar 

  24. Cundy KC, Shaw J-P, Lee WA. Oral, subcutaneous and intramuscular bioavailabilities of the antiviral nucleotide analog 9-(2-phosphonylmethoxyethyl)adenine in cynomolgus monkeys. Antimicrob Agents Chemother 1994; 38: 365–8.

    Article  PubMed  CAS  Google Scholar 

  25. Cundy KC, Li Z-H, Hitchcock MJM, et al. Pharmacokinetics of cidofovir in monkeys: evidence for a prolonged elimination phase representing phosphorylated drug. Drug Metab Dispos 1996; 24: 738–44.

    PubMed  CAS  Google Scholar 

  26. Wachsman M, Petty BG, Cundy KC, et al. Pharmacokinetics, safety and bioavailability of cidofovir in HIV-infected subjects. Antiviral Res 1996; 29: 153–61.

    Article  PubMed  CAS  Google Scholar 

  27. Lalezari JP, Drew WL, Glutzer E, et al. HPMPC: results of a phase I/II study of a novel antiviral nucleotide analogue. J Infect Dis 1995; 171: 788–96.

    Article  PubMed  CAS  Google Scholar 

  28. Lalezari J, Holland G, Stagg R, et al. A randomized controlled study of cidofovir (CDV) for relapsing cytomegalovirus retinitis (CMV-R) in patients with AIDS [abstract]. Proceedings and Abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1995 Sep 17–20: San Francisco.

  29. Cundy KC, Li Z-H, Lee WA. Effect of probenecid on the distribution, metabolism and excretion of cidofovir in rabbits. Drug Metab Dispos 1996; 24: 315–21.

    PubMed  CAS  Google Scholar 

  30. Balzarini J, Naesens L, Slachmuylders J, et al. 9-(2-Phosphonylmethoxyethyl)adenine (PMEA) effectively inhibits retrovirus replication in vitro and simian immunodeficiency virus infection in rhesus monkeys. AIDS 1991; 5: 21–8.

    Article  PubMed  CAS  Google Scholar 

  31. Lacy SA, Hitchcock MJM, Lee WA, et al. Effect of oral probenecid coadministration on the chronic toxicity and pharmacokinetics of intravenous cidofovir in cynomolgus monkeys. Toxicol Sci 1997; 44: 97–106.

    Article  Google Scholar 

  32. Dudley MN, Graham KK, Kaul S, et al. Pharmacokinetics of stavudine in patients with AIDS or AIDS-related complex. J Infect Dis 1992; 166: 480–5.

    Article  PubMed  CAS  Google Scholar 

  33. Gilead Sciences Inc. Vistide® package insert. Foster City (CA): Gilead Sciences Inc., 1998.

    Google Scholar 

  34. Sadler M, Morris-Jones S, Nelson M, et al. Successful treatment of cytomegalovirus encephalitis in an AIDS patient using cidofovir. AIDS 1997; 11: 1293–4.

    PubMed  CAS  Google Scholar 

  35. Blick G, Garton T, Hopkins U, et al. Successful use of cidofovir in treating AIDS-related cytomegalovirus retinitis, encephalitis, and esophagitis. J Acquir Immune Defic Syndr Hum Retrovir 1997; 15: 84–5.

    Article  CAS  Google Scholar 

  36. Cihlar T, Chen M. Identification of enzymes catalyzing two-step phosphorylation of cidofovir and the effect of cytomegalovirus infection on their activities in host cells. Mol Pharmacol 1996; 50: 1502–10.

    PubMed  CAS  Google Scholar 

  37. Cihlar T, Votruba I, Horska K, et al. Metabolism of 1-(S)-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) in human embryonic lung cells. Collect Czech Chem Commun 1992; 57: 661–72.

    Article  CAS  Google Scholar 

  38. Merta A, Votruba I, Jindrich J, et al. Phosphorylation of 9-(2-phosphonylmethyoxyethyl)adenine and 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)adenine by AMP (dAMP) kinase from L1210 cells. Biochem Pharmacol 1992; 44: 2067–77.

    Article  PubMed  CAS  Google Scholar 

  39. Balzarini J, De Clercq E. 5-Phosphoribosyl-1-pyrophosphate synthetase converts the nucleotide phosphonates 9-(3-hydroxy-1-phosphonylmethoxypropyl)adenine and 9-(2-phosphonylmethoxyethyl)-adenine directly to their antivirally active diphosphate derivatives. J Biol Chem 1991; 266: 8686–9.

    PubMed  CAS  Google Scholar 

  40. Fridland A. Cellular pharmacology of the antiviral agents PMPA and PMEA in vitro and in vivo [abstract]. 12th World AIDS Conference; 1998 Jun 28–Jul 3: Geneva.

  41. Eisenberg EJ, Lynch GR, Bidgood AM, et al. Isolation and identification of a metabolite of cidofovir from rat kidney. J Pharm Biomed Anal 1998; 16: 1349–56.

    Article  PubMed  CAS  Google Scholar 

  42. Tune BM. Relationship between the transport and toxicity of cephalosporins in the kidney. J Infect Dis 1975; 132: 189–94.

    Article  PubMed  CAS  Google Scholar 

  43. Shaw J-P, Cundy KC. Biological screens of PMEA prodrugs. Pharm Res 1993; 10 (Suppl.): S294.

    Google Scholar 

  44. Starrett Jr JE, Tortolani DR, Russell J, et al. Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9-[2-(phosphonomethoxy)ethyl]-adenine (PMEA). J Med Chem 1994; 37: 1857–64.

    Article  PubMed  CAS  Google Scholar 

  45. Cundy KC, Fishback JA, Shaw J-P, et al. Oral bioavailability of the antiretroviral agent 9-(2-phosphonylmethoxyethyl) adenine (PMEA) from three formulations of the prodrug bis(pivaloyloxymethyl)PMEA in fasted male cynomolgus monkeys. Pharm Res 1994; 11: 839–43.

    Article  PubMed  CAS  Google Scholar 

  46. Barditch-Crovo P, Cundy KC, Hellmann N, et al. Anti-HIV activity, safety and pharmacokinetics of adefovir dipivoxil (9-[2-(bispivaloyloxymethyl)phosphonylmethoxyethyl]adenine) in HIV-infected patients. J Infect Dis 1996; 176: 406–13.

    Article  Google Scholar 

  47. Gilson RJC, Murray-Lyon IM, Nelson MR, et al. Extended treatment with adefovir dipivoxil in patients with chronic hepatitis B virus infection [abstract]. 49th Annual Meeting of the American Association for the Study of Liver Disease; 1998 Nov 6–10: Chicago.

  48. Aspe E, Guy RH, Lee WA, et al. Optimization of in vitro flux through hairless mouse skin of cidofovir, a potent nucleotide analog. J Pharm Sci 1995; 84: 750–4.

    Article  PubMed  CAS  Google Scholar 

  49. Gordon YZ, Naesens L, De Clercq E, et al. Treatment of adenoviral conjunctivitis with topical cidofovir [letter]. Cornea 1996; 15: 546.

    Article  PubMed  CAS  Google Scholar 

  50. Wu WH, Rivkees D, McWilliams W, et al. Pharmacokinetics and mass balance of 14C-cidofovir in the rabbit [abstract]. Pharm Res 1997; 14 Suppl. 1; S–363.

    Google Scholar 

  51. Hosoya K, Lee VHL. Cidofovir transport in the pigmented rabbit conjunctiva. Curr Eye Res 1995; 119: 466–76.

    Google Scholar 

  52. Kirsch LS, Arevalo JF, De Clercq E, et al. Phase I/II study of intravitreal cidofovir for the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol 1995; 119: 466–76.

    PubMed  CAS  Google Scholar 

  53. Cundy KC, Lynch G, Shaw J-P, et al. Distribution and metabolism of intravitreal cidofovir and cyclic HPMPC in rabbits. Curr Eye Res 1996; 15: 569–76.

    Article  PubMed  CAS  Google Scholar 

  54. Hitchcock MJM, Lacy SA, Lindsey JR, et al. The cyclic congener of cidofovir has reduced nephrotoxicity in three species [abstract]. Antiviral Res 1995; 26: A358.

    Article  Google Scholar 

  55. Cunningham RF, Israili ZH, Dayton PG. Clinical pharmacokinetics of probenecid. Clin Pharmacokinet 1981; 6: 135–51.

    Article  PubMed  CAS  Google Scholar 

  56. Jacobs C, Kaubisch S, Halsey J, et al. The use of probenecid as a chemoprotector against cisplatin nephrotoxicity. Cancer 1991; 67: 1518–24.

    Article  PubMed  CAS  Google Scholar 

  57. Brody SR, Humphreys M, Gambertoglio JG, et al. An open label study of the pharmacokinetics of intravenous cidofovir in patients with varying degrees of renal insufficiency [abstract]. Clin Pharmacol Ther 1997; 61: 149.

    Google Scholar 

  58. Lush RM, Nguyen B-Y, Cundy KC, et al. The pharmacokinetics of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and zidovudine (AZT) when administered in combination. J Appl Ther 1996; 1: 13–8.

    CAS  Google Scholar 

  59. Martin MA, Kane C. Nursing considerations in the use of cidofovir for CMV retinitis in patients with AIDS: report of a roundtable meeting. J Assoc Nurse AIDS Care 1997; 8: 66–74.

    Article  CAS  Google Scholar 

  60. Lalezari JP. Cidofovir: a new therapy for cytomegalovirus retinitis. J Acquir Immune Defic Syndr Hum Retrovir 1997; 14 Suppl. 1: S22–6.

    Article  CAS  Google Scholar 

  61. Lalezari JP, Kuppermann BD. Clinical experience with cidofovir in the treatment of cytomegalovirus retinitis. J Acquir Immune Defic Syndr Hum Retrovir 1997; 14 Suppl. 1: S27–31.

    Article  CAS  Google Scholar 

  62. Palau LA, Tufty GT, Pankey GA. Recurrent iritis after intravenous administration of cidofovir. Clin Infect Dis 1997; 25: 337–8.

    Article  PubMed  CAS  Google Scholar 

  63. Kahn J, Lagakos S, Weng D, et al. Multi-center, randomized, double-blind placebo controlled study of the efficacy and safety of adefovir dipivoxil (ADV) when added to standard antiretroviral therapy (ART) [abstract]. 38th Annual Meeting of the Interscience Congress on Antimicrobial Agents and Chemotherapy; 1998 Sep 24–27: San Diego.

Download references

Author information

Authors and Affiliations

  1. Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California, 94404, USA

    Kenneth C. Cundy

Authors
  1. Kenneth C. Cundy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenneth C. Cundy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cundy, K.C. Clinical Pharmacokinetics of the Antiviral Nucleotide Analogues Cidofovir and Adefovir. Clin Pharmacokinet 36, 127–143 (1999). https://doi.org/10.2165/00003088-199936020-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-199936020-00004

Keywords

Search

Navigation