title: Liposomal Amphotericin B (AmBisome(®)): A Review of the Pharmacokinetics, Pharmacodynamics, Clinical Experience and Future Directions.
abstract: Liposomal amphotericin B (AmBisome(®); LAmB) is a unique lipid formulation of amphotericin B. LAmB is a standard of care for a wide range of medically important opportunistic fungal pathogens. LAmB has a significantly improved toxicity profile compared with conventional amphotericin B deoxycholate (DAmB). Despite nearly 20 years of clinical use, the pharmacokinetics and pharmacodynamics of this agent, which differ considerably from DAmB, remain relatively poorly understood and underutilized in the clinical setting. The molecular pharmacology, preclinical and clinical pharmacokinetics, and clinical experience with LAmB for the most commonly encountered fungal pathogens are reviewed. In vitro, experimental animal models and human clinical trial data are summarized, and novel routes of administration and dosing schedules are discussed. LAmB is a formulation that results in reduced toxicity as compared with DAmB while retaining the antifungal effect of the active agent. Its long terminal half-life and retention in tissues suggest that single or intermittent dosing regimens are feasible, and these should be actively investigated in both preclinical models and in clinical trials. Significant gaps remain in knowledge of pharmacokinetics and pharmacodynamics in special populations such as neonates and children, pregnant women and obese patients.
authors.affiliation: Institute for Infection and Immunity, St. George's University of London, London, UK. nstone@sgul.ac.uk.
authors.forename: Neil R H
authors.initials: NR
authors.lastname: Stone
authors.affiliation: Institute for Infection and Immunity, St. George's University of London, London, UK.
authors.forename: Tihana
authors.initials: T
authors.lastname: Bicanic
authors.affiliation: Department of Haematology, Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: Rahuman
authors.initials: R
authors.lastname: Salim
authors.affiliation: Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, 1.09 Sherrington Building, University of Liverpool, Liverpool, UK.
authors.forename: William
authors.initials: W
authors.lastname: Hope
mesh_terms: D000666:Amphotericin B / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002986:Clinical Trials as Topic; D003840:Deoxycholic Acid / Q000493:pharmacokinetics / Q000494:pharmacology; D004338:Drug Combinations; D006207:Half-Life; D006801:Humans; D014018:Tissue Distribution
chemical_list: D004338:Drug Combinations; C068538:liposomal amphotericin B; D003840:Deoxycholic Acid; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination
references.citation: Biochim Biophys Acta. 1982 Feb 23;685(2):219-24
references.pmid: 7059605
references.citation: J Antimicrob Chemother. 1991 Oct;28 Suppl B:39-48
references.pmid: 1778891
references.citation: Antimicrob Agents Chemother. 1995 Sep;39(9):1954-8
references.pmid: 8540697
references.citation: Antimicrob Agents Chemother. 1995 Aug;39(8):1885-7
references.pmid: 7486941
references.citation: Thorax. 1995 Dec;50(12):1321-3
references.pmid: 8553311
references.citation: Antimicrob Agents Chemother. 1996 May;40(5):1214-8
references.pmid: 8723469
references.citation: J Aerosol Med. 1996 Spring;9(1):111-22
references.pmid: 10160201
references.citation: Leuk Lymphoma. 1997 Feb;24(5-6):491-9
references.pmid: 9086439
references.citation: Biochemistry. 1997 Apr 22;36(16):4959-68
references.pmid: 9125518
references.citation: Antimicrob Agents Chemother. 2006 Mar;50(3):935-42
references.pmid: 16495254
references.citation: J Antimicrob Chemother. 2006 Apr;57(4):724-31
references.pmid: 16446374
references.citation: Antimicrob Agents Chemother. 2006 Apr;50(4):1567-9
references.pmid: 16569887
references.citation: J Antimicrob Chemother. 2006 Jun;57(6):1153-60
references.pmid: 16627591
references.citation: Antimicrob Agents Chemother. 2006 Jun;50(6):2122-31
references.pmid: 16723574
references.citation: Ann Oncol. 2006 Aug;17(8):1306-12
references.pmid: 16766594
references.citation: Microbiol Immunol. 2006;50(8):579-86
references.pmid: 16924142
references.citation: Clin Infect Dis. 2006 Oct 1;43(7):917-24
references.pmid: 16941377
references.citation: Antimicrob Agents Chemother. 2006 Oct;50(10):3418-23
references.pmid: 17005824
references.citation: Bone Marrow Transplant. 2007 Mar;39(5):301-6
references.pmid: 17262059
references.citation: Chemotherapy. 2007;53(2):142-7
references.pmid: 17310120
references.citation: J Antimicrob Chemother. 2007 May;59(5):941-51
references.pmid: 17400589
references.citation: Clin Infect Dis. 2007 May 15;44(10):1289-97
references.pmid: 17443465
references.citation: Lancet. 2007 May 5;369(9572):1519-27
references.pmid: 17482982
references.citation: Clin Ther. 2007 Sep;29(9):1980-6
references.pmid: 18035197
references.citation: Int J Antimicrob Agents. 2008 Feb;31(2):135-41
references.pmid: 18162375
references.citation: Clin Infect Dis. 2008 Feb 1;46(3):327-60
references.pmid: 18177225
references.citation: J Antimicrob Chemother. 2008 Feb;61(2):235-7
references.pmid: 18065413
references.citation: Antimicrob Agents Chemother. 2008 Apr;52(4):1573-6
references.pmid: 18227182
references.citation: Clin Infect Dis. 2008 May 1;46(9):1401-8
references.pmid: 18419443
references.citation: Clin Microbiol Infect. 2008 May;14 Suppl 4:25-36
references.pmid: 18430127
references.citation: J Antimicrob Chemother. 2014 Sep;69(9):2522-6
references.pmid: 24891430
references.citation: J Clin Pharm Ther. 2014 Dec;39(6):584-608
references.pmid: 25203631
references.citation: Antimicrob Agents Chemother. 2015 May;59(5):2735-45
references.pmid: 25712363
references.citation: Antimicrob Agents Chemother. 2012 Aug;56(8):4439-49
references.pmid: 22687510
references.citation: Pharm Res. 1999 Nov;16(11):1694-701
references.pmid: 10571274
references.citation: J Infect Dis. 2000 Jul;182(1):274-82
references.pmid: 10882607
references.citation: Antimicrob Agents Chemother. 2000 Sep;44(9):2327-32
references.pmid: 10952575
references.citation: Am J Physiol Heart Circ Physiol. 2000 Sep;279(3):H1319-28
references.pmid: 10993799
references.citation: Clin Infect Dis. 2000 Nov;31(5):1155-63
references.pmid: 11073745
references.citation: Pharm Res. 2000 Dec;17(12):1494-502
references.pmid: 11303959
references.citation: Transplantation. 2001 Apr 15;71(7):910-3
references.pmid: 11349726
references.citation: Antimicrob Agents Chemother. 2001 Aug;45(8):2354-7
references.pmid: 11451696
references.citation: J Antimicrob Chemother. 2002 Feb;49 Suppl 1:21-30
references.pmid: 11801577
references.citation: N Engl J Med. 2002 Jan 24;346(4):225-34
references.pmid: 11807146
references.citation: Mycoses. 2001 Dec;44(11-12):455-63
references.pmid: 11820258
references.citation: Antimicrob Agents Chemother. 2002 Mar;46(3):828-33
references.pmid: 11850268
references.citation: Antimicrob Agents Chemother. 2002 Mar;46(3):834-40
references.pmid: 11850269
references.citation: Ann Intern Med. 2002 Jul 16;137(2):105-9
references.pmid: 12118965
references.citation: Antimicrob Agents Chemother. 2002 Nov;46(11):3634-6
references.pmid: 12384379
references.citation: Clin Infect Dis. 2003 May 15;36(10):1213-20
references.pmid: 12746764
references.citation: Clin Infect Dis. 2003 Jun 1;36(11):1500-1
references.pmid: 12766850
references.citation: Antimicrob Agents Chemother. 1997 Jun;41(6):1275-80
references.pmid: 9174183
references.citation: Clin Infect Dis. 1997 Jul;25(1):112-8
references.pmid: 9243045
references.citation: Br J Haematol. 1997 Sep;98(3):711-8
references.pmid: 9332329
references.citation: AIDS. 1997 Oct;11(12):1463-71
references.pmid: 9342068
references.citation: Antimicrob Agents Chemother. 1998 Apr;42(4):899-902
references.pmid: 9559804
references.citation: Antimicrob Agents Chemother. 1998 Sep;42(9):2391-8
references.pmid: 9736569
references.citation: Br J Haematol. 1998 Oct;103(1):205-12
references.pmid: 9792309
references.citation: Clin Infect Dis. 1998 Dec;27(6):1406-12
references.pmid: 9868651
references.citation: N Engl J Med. 1999 Mar 11;340(10):764-71
references.pmid: 10072411
references.citation: Bone Marrow Transplant. 1999 Jan;23(2):163-8
references.pmid: 10197802
references.citation: J Antimicrob Chemother. 2005 Feb;55(2):229-33
references.pmid: 15649998
references.citation: Clin Infect Dis. 2005 Aug 1;41(3):301-7
references.pmid: 16007524
references.citation: Antimicrob Agents Chemother. 2005 Dec;49(12):4895-902
references.pmid: 16304150
references.citation: Transpl Infect Dis. 2005 Sep-Dec;7(3-4):126-32
references.pmid: 16390401
references.citation: Med Mal Infect. 2008 Jun;38 Suppl 2:S90-1
references.pmid: 18598882
references.citation: Pediatr Infect Dis J. 2008 Aug;27(8):762-4
references.pmid: 18664989
references.citation: Curr Clin Pharmacol. 2007 Jan;2(1):37-58
references.pmid: 18690854
references.citation: Pediatr Infect Dis J. 2008 Sep;27(9):820-6
references.pmid: 18679151
references.citation: Antimicrob Agents Chemother. 2008 Nov;52(11):4178-80
references.pmid: 18725439
references.citation: J Heart Lung Transplant. 2009 Feb;28(2):170-5
references.pmid: 19201343
references.citation: J Antimicrob Chemother. 2009 Jul;64(1):101-8
references.pmid: 19398459
references.citation: J Antimicrob Chemother. 2009 Aug;64(2):383-7
references.pmid: 19491205
references.citation: Clin Infect Dis. 2009 Dec 1;49(11):1721-8
references.pmid: 19886800
references.citation: Clin Infect Dis. 2010 Feb 1;50(3):291-322
references.pmid: 20047480
references.citation: J Control Release. 2010 Jan 25;141(2):208-15
references.pmid: 19815038
references.citation: N Engl J Med. 2010 Feb 11;362(6):504-12
references.pmid: 20147716
references.citation: Antimicrob Agents Chemother. 2010 Mar;54(3):1298-304
references.pmid: 20038620
references.citation: J Antimicrob Chemother. 2012 Mar;67(3):715-22
references.pmid: 21937481
references.citation: Clin Infect Dis. 2012 Jun;54(12):1774-7
references.pmid: 22491505
references.citation: Antimicrob Agents Chemother. 1998 Feb;42(2):263-8
references.pmid: 9527770
references.citation: J Antimicrob Chemother. 1991 Oct;28 Suppl B:63-71
references.pmid: 1778893
references.citation: AIDS. 1993 Jun;7(6):829-35
references.pmid: 8363759
references.citation: J Antimicrob Chemother. 1993 Sep;32(3):465-72
references.pmid: 8262869
references.citation: J Infect Dis. 1994 Feb;169(2):356-68
references.pmid: 8106769
references.citation: J Antimicrob Chemother. 1993 Nov;32(5):723-39
references.pmid: 8125837
references.citation: Antimicrob Agents Chemother. 1994 Apr;38(4):713-8
references.pmid: 8031034
references.citation: J Pharm Sci. 1994 Jul;83(7):1006-10
references.pmid: 7965656
references.citation: Bone Marrow Transplant. 1994;14 Suppl 5:S3-7
references.pmid: 7703928
references.citation: J Med Vet Mycol. 1994 Dec;32(6):467-71
references.pmid: 7738729
references.citation: Antimicrob Agents Chemother. 2010 Apr;54(4):1633-5
references.pmid: 20086161
references.citation: J Heart Lung Transplant. 2010 May;29(5):523-30
references.pmid: 20061165
references.citation: Clin Infect Dis. 2010 Jul 15;51(2):225-32
references.pmid: 20536366
references.citation: Antimicrob Agents Chemother. 2010 Aug;54(8):3432-41
references.pmid: 20439615
references.citation: Antimicrob Agents Chemother. 2010 Sep;54(9):3884-94
references.pmid: 20606065
references.citation: PLoS Negl Trop Dis. 2010;4(12):e913
references.pmid: 21151883
references.citation: Lancet. 2011 Feb 5;377(9764):477-86
references.pmid: 21255828
references.citation: J Med Toxicol. 2011 Mar;7(1):12-5
references.pmid: 21057910
references.citation: Antimicrob Agents Chemother. 2012 Jan;56(1):536-43
references.pmid: 22083471
references.citation: Antimicrob Agents Chemother. 2012 Oct;56(10):5303-8
references.pmid: 22869566
references.citation: Diagn Microbiol Infect Dis. 2013 Jul;76(3):361-7
references.pmid: 23774005
references.citation: J Infect Dis. 2013 Jul 15;208(2):351-61
references.pmid: 23599314
references.citation: Drugs. 2013 Jun;73(9):919-34
references.pmid: 23729001
references.citation: N Engl J Med. 2013 Jun 27;368(26):2522-3
references.pmid: 23802521
references.citation: Expert Opin Drug Saf. 2013 Nov;12(6):881-95
references.pmid: 23931455
references.citation: Clin Microbiol Rev. 2014 Jan;27(1):68-88
references.pmid: 24396137
references.citation: PLoS Negl Trop Dis. 2014;8(1):e2613
references.pmid: 24454970
references.citation: Pediatr Pulmonol. 2014 Jun;49(6):574-80
references.pmid: 23843366
references.citation: Clin Infect Dis. 2003 Sep 15;37(6):800-4
references.pmid: 12955641
references.citation: J Biol Chem. 2003 Sep 26;278(39):37561-8
references.pmid: 12860979
references.citation: J Antimicrob Chemother. 2003 Nov;52(5):813-9
references.pmid: 14563893
references.citation: Antimicrob Agents Chemother. 2004 May;48(5):1727-32
references.pmid: 15105127
references.citation: N Engl J Med. 2004 Sep 30;351(14):1391-402
references.pmid: 15459300
references.citation: J Mol Biol. 1965 Aug;13(1):238-52
references.pmid: 5859039
references.citation: Biochim Biophys Acta. 1973 Jul 6;311(3):330-48
references.pmid: 4729825