title: Allometric scaling of pegylated liposomal anticancer drugs.
abstract: Pegylated liposomal formulations contain lipid conjugated to polyethylene glycol. The disposition of encapsulated drug is dictated by the composition of the liposome, thus altering the pharmacokinetic (PK) profile of the drug. Allometric scaling is based on a power-log relationship between body weight (W) and drug clearance (CL) among mammals and has been used to compare the disposition of nonliposomal drugs across species. The objectives of this study were to use allometric scaling to: (1) compare the disposition of pegylated liposomal drugs across speciesand determine the best scaling model and (2) predict PK parameters of pegylated liposomal drugs in humans. The PK of pegylated liposomal CKD-602 (S-CKD602), doxorubicin (Doxil®), and cisplatin (SPI-077) were compared. PK studies ofS-CKD602, Doxil®, and SPI-077 were performed at the maximum tolerated dose (MTD) in male and female mice, rats, dogs and patients with refractory solid tumors. The allometric equation used to evaluate the relationship between W and CL in each species was CL = a(W)(m) (a = empirical coefficient; m = allometric exponent). Substitution of physiological variables other than body weight, such as factors representative of the mononuclear phagocyte system (MPS) were evaluated. Dedrick Plots and Maximum Life-Span Potential (MLP) were used to determine scaling feasibility. Standard allometry demonstrated a relationship between clearance of S-CKD602, Doxil®, and SPI-077 and body, spleen, liver, and kidney weights, total monocyte count, and spleen and liver blood flow. However, using scaling to predict CL of these agents in humans often resulted in differences >30%. Despite a strong correlation between body weight and MPS-associated variables with CL among preclinical species, the use of the equations did not predict CL. Thus, new methods of allometric scaling and measures of MPS function need to be developed.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Suite 1013, CB 7361, Chapel Hill, NC 27599-7361, USA.
authors.forename: Whitney P
authors.initials: WP
authors.lastname: Caron
authors.forename: Harvey
authors.initials: H
authors.lastname: Clewell
authors.forename: Robert
authors.initials: R
authors.lastname: Dedrick
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: Whitney L
authors.initials: WL
authors.lastname: Davis
authors.forename: Ning
authors.initials: N
authors.lastname: Yu
authors.forename: Margaret
authors.initials: M
authors.lastname: Tonda
authors.forename: Jan H
authors.initials: JH
authors.lastname: Schellens
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D001835:Body Weight; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D002945:Cisplatin / Q000097:blood / Q000493:pharmacokinetics*; D017321:Clinical Trials, Phase I as Topic; D004285:Dogs; D004317:Doxorubicin / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D008297:Male; D051379:Mice; D008962:Models, Theoretical; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D012984:Software; D013045:Species Specificity; D013997:Time Factors
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D008081:Liposomes; C422270:SPI-77, liposomal; C116963:belotecan; D011092:Polyethylene Glycols; D004317:Doxorubicin; D002945:Cisplatin; D002166:Camptothecin