title: Meta-analysis of inter-patient pharmacokinetic variability of liposomal and non-liposomal anticancer agents.
abstract: A meta-analysis was conducted to evaluate the inter-patient pharmacokinetic (PK) variability of liposomal and small molecule (SM) anticancer agents. Inter-patient PK variability of 9 liposomal and SM formulations of the same drug was evaluated. PK variability was measured as coefficient of variance (CV%) of area under the plasma concentration versus time curve (AUC) and the fold-difference between AUCmax and AUCmin (AUC range). CV% of AUC and AUC ranges were 2.7-fold (P<0.001) and 16.7-fold (P=0.13) greater, respectively, for liposomal compared with SM drugs. There was an inverse linear relationship between the clearance (CL) of liposomal agents and PK variability with a lower CL associated with greater PK variability (R(2)=0.39). PK variability of liposomal agents was greater when evaluated from 0-336 h compared with 0-24h. PK variability of liposomes is significantly greater than SM. The factors associated with the PK variability of liposomal agents need to be evaluated.
  
  
  BACKGROUND
  In this meta-analysis, the inter-patient pharmacokinetic variability of 9 liposomal and small molecule anti-cancer agents was studied. The authors determined that several parameters are in favor of the liposomal formulation; however, the PK variability of the formulation was higher compared with small molecule agents, the reason for which remains to be determined in future studies.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina (UNC) Eshelman School of Pharmacy, Chapel Hill, NC, USA; Translational Oncology and Nanoparticle Drug Development Initiative (TOND(2)I) Lab, UNC, Chapel Hill, NC, USA.
authors.forename: Ryan F
authors.initials: RF
authors.lastname: Schell
authors.affiliation: Translational Oncology and Nanoparticle Drug Development Initiative (TOND(2)I) Lab, UNC, Chapel Hill, NC, USA; Duquesne University Mylan School of Pharmacy.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Sidone
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina (UNC) Eshelman School of Pharmacy, Chapel Hill, NC, USA; Translational Oncology and Nanoparticle Drug Development Initiative (TOND(2)I) Lab, UNC, Chapel Hill, NC, USA.
authors.forename: Whitney P
authors.initials: WP
authors.lastname: Caron
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina (UNC) Eshelman School of Pharmacy, Chapel Hill, NC, USA; Translational Oncology and Nanoparticle Drug Development Initiative (TOND(2)I) Lab, UNC, Chapel Hill, NC, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Walsh
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina (UNC) Eshelman School of Pharmacy, Chapel Hill, NC, USA; Translational Oncology and Nanoparticle Drug Development Initiative (TOND(2)I) Lab, UNC, Chapel Hill, NC, USA.
authors.forename: Taylor F
authors.initials: TF
authors.lastname: White
authors.affiliation: Department of Mathematics, Carlow University, Pittsburgh, Pennsylvania.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Zamboni
authors.affiliation: The Translational Genomics Research Institute (TGen), Phoenix, AZ, USA.
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina (UNC) Eshelman School of Pharmacy, Chapel Hill, NC, USA; Translational Oncology and Nanoparticle Drug Development Initiative (TOND(2)I) Lab, UNC, Chapel Hill, NC, USA; Molecular Therapeutics, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA; UNC GLP Bioanalytical Facility, Chapel Hill, NC, USA; Institute for Pharmacogenomics and Individualized Therapy (IPIT), Chapel Hill, NC, USA; Carolina Center of Cancer Nanotechnology Excellence (C-CCNE), Chapel Hill, NC, USA; North Carolina Biomedical Innovation Network (NC BIN), Chapel Hill, NC, USA. Electronic address: zamboni@email.unc.edu.
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D002166:Camptothecin
keywords: CKD-602; Liposomes; Pharmacokinetic; S-CKD602; Sampling schema; Variability
references.citation: J Clin Pharmacol. 1996 Jan;36(1):55-63
references.pmid: 8932544
references.citation: Cancer Chemother Pharmacol. 2002 Mar;49(3):201-10
references.pmid: 11935212
references.citation: Anticancer Drugs. 2000 Feb;11(2):123-7
references.pmid: 10789595
references.citation: J Liposome Res. 2012 Sep;22(3):177-92
references.pmid: 22332871
references.citation: Clin Pharmacokinet. 1997 Apr;32(4):324-43
references.pmid: 9113440
references.citation: Toxicol Appl Pharmacol. 2008 May 15;229(1):121-34
references.pmid: 18355886
references.citation: Pharmacol Rev. 1999 Dec;51(4):691-743
references.pmid: 10581328
references.citation: Curr Drug Deliv. 2007 Oct;4(4):297-305
references.pmid: 17979650
references.citation: Cancer. 2000 Sep 1;89(5):1037-47
references.pmid: 10964334
references.citation: Br J Cancer. 2006 Oct 9;95(7):822-8
references.pmid: 16969346
references.citation: Eur J Cancer. 2004 May;40(8):1170-8
references.pmid: 15110880
references.citation: Cancer Chemother Pharmacol. 1998;41(5):347-52
references.pmid: 9523729
references.citation: Nat Rev Cancer. 2005 Jun;5(6):447-58
references.pmid: 15928675
references.citation: J Pharm Sci. 2008 Nov;97(11):4696-740
references.pmid: 18351638
references.citation: Biochim Biophys Acta. 2005 Jun 1;1711(1):25-32
references.pmid: 15904660
references.citation: Eur J Cancer. 2004 Dec;40(18):2748-52
references.pmid: 15571957
references.citation: Mol Pharm. 2008 Jul-Aug;5(4):505-15
references.pmid: 18672949
references.citation: N Engl J Med. 2005 May 26;352(21):2211-21
references.pmid: 15917386
references.citation: Cancer Res. 1995 Sep 1;55(17):3752-6
references.pmid: 7641188
references.citation: Cancer Chemother Pharmacol. 2012 Jan;69(1):43-50
references.pmid: 21590446
references.citation: J Control Release. 1998 Apr 30;53(1-3):275-9
references.pmid: 9741935
references.citation: J Control Release. 2012 Nov 10;163(3):322-34
references.pmid: 22989535
references.citation: Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2150-7
references.pmid: 16609028
references.citation: Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11460-4
references.pmid: 1763060
references.citation: Br J Clin Pharmacol. 2003 Oct;56(4):370-7
references.pmid: 12968981
references.citation: Invest New Drugs. 2012 Feb;30(1):282-9
references.pmid: 20809205
references.citation: J Clin Pharmacol. 2006 Jul;46(7):727-37
references.pmid: 16809798
references.citation: Cancer Chemother Pharmacol. 2004 Apr;53(4):329-36
references.pmid: 14673619
references.citation: Ther Drug Monit. 2010 Feb;32(1):50-2
references.pmid: 19927044
references.citation: Biochim Biophys Acta. 1992 Aug 14;1113(2):171-99
references.pmid: 1510996
references.citation: Clin Pharmacol Ther. 2012 May;91(5):802-12
references.pmid: 22472987
references.citation: Curr Drug Metab. 2010 Feb;11(2):129-41
references.pmid: 20359289
references.citation: Cancer Chemother Pharmacol. 2008 Apr;61(4):695-702
references.pmid: 17549475
references.citation: Curr Opin Immunol. 2006 Feb;18(1):49-53
references.pmid: 16338128
references.citation: Clin Cancer Res. 2009 Feb 15;15(4):1466-72
references.pmid: 19190127
references.citation: Antimicrob Agents Chemother. 2006 Mar;50(3):935-42
references.pmid: 16495254
references.citation: Biochim Biophys Acta. 2002 Apr 12;1561(2):188-201
references.pmid: 11997119
references.citation: Clin Pharmacol Ther. 2009 Nov;86(5):519-26
references.pmid: 19675541
references.citation: Cancer Treat Rev. 1997 May;23(3):153-69
references.pmid: 9251720
references.citation: Cancer. 2001 May 1;91(9):1826-33
references.pmid: 11335910
references.citation: Cancer Chemother Pharmacol. 2012 Nov;70(5):699-705
references.pmid: 22941375
references.citation: Br J Cancer. 2001 Apr 20;84(8):1029-35
references.pmid: 11308249
references.citation: Cancer Res. 1994 Feb 15;54(4):987-92
references.pmid: 8313389
references.citation: Methods Mol Biol. 2008;433:159-75
references.pmid: 18679623
references.citation: Clin Cancer Res. 2005 Dec 1;11(23):8230-4
references.pmid: 16322279
references.citation: Nat Rev Drug Discov. 2005 Feb;4(2):145-60
references.pmid: 15688077