PMID- 31113837
OWN - NLM
STAT- MEDLINE
DCOM- 20191230
LR  - 20200801
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 370
IP  - 2
DP  - 2019 Aug
TI  - Preclinical Pharmacokinetics of Fosciclopirox, a Novel Treatment of Urothelial 
      Cancers, in Rats and Dogs.
PG  - 148-159
LID - 10.1124/jpet.119.257972 [doi]
AB  - Pharmacokinetic studies in rats and dogs were performed to characterize the in 
      vivo performance of a novel prodrug, fosciclopirox. Ciclopirox olamine (CPX-O) is 
      a marketed topical antifungal agent with demonstrated in vitro and in vivo 
      preclinical anticancer activity in several solid tumor and hematologic 
      malignancies. The oral route of administration for CPX-O is not feasible due to 
      low bioavailability and dose-limiting gastrointestinal toxicities. To enable 
      parenteral administration, the phosphoryl-oxymethyl ester of ciclopirox (CPX), 
      fosciclopirox (CPX-POM), was synthesized and formulated as an injectable drug 
      product. In rats and dogs, intravenous CPX-POM is rapidly and completely 
      metabolized to its active metabolite, CPX. The bioavailability of the active 
      metabolite is complete following CPX-POM administration. CPX and its inactive 
      metabolite, ciclopirox glucuronide (CPX-G), are excreted in urine, resulting in 
      delivery of drug to the entire urinary tract. The absolute bioavailability of CPX 
      following subcutaneous administration of CPX-POM is excellent in rats and dogs, 
      demonstrating the feasibility of this route of administration. These studies 
      confirmed the oral bioavailability of CPX-O is quite low in rats and dogs 
      compared with intravenous CPX-POM. Given its broad-spectrum anticancer activity 
      in several solid tumor and hematologic cancers and renal elimination, CPX-POM is 
      being developed for the treatment of urothelial cancer. The safety, dose 
      tolerance, pharmacokinetics, and pharmacodynamics of intravenous CPX-POM are 
      currently being characterized in a United States multicenter first-in-human Phase 
      1 clinical trial in patients with advanced solid tumors (NCT03348514).
CI  - Copyright (c) 2019 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Weir, Scott J
AU  - Weir SJ
AUID- ORCID: 0000-0002-8020-434X
AD  - University of Kansas Cancer Center, Kansas City, Kansas (S.J.W., R.W., A.E.B., 
      G.A.R., R.A.J., M.J.B., S.A., J.A.T.); Institute for Advancing Medical Innovation 
      (S.J.W., R.W., A.E.B., M.J.B.) and Departments of Cancer Biology (S.J.W., P.R., 
      S.A.), Pharmacology, Toxicology, and Therapeutics (S.J.W., G.A.R.) Pathology 
      (R.A.J.), and Urology (J.A.T.), University of Kansas Medical Center, Kansas City, 
      Kansas; Biotechnology Innovation and Optimization Center, University of Kansas, 
      Lawrence, Kansas (K.S., K.H., L.R., M.T., M.J.B.); School of Pharmacy, Istanbul 
      Kemerburgaz University, Istanbul, Turkey (M.T.); CicloMed LLC, Kansas City, 
      Missouri (T.H.); Navigator LSA, Wilmington, North Carolina (M.J.M.); Alba 
      BioPharm Advisors Inc., Durham, North Carolina (W.M.); and The Gnomon Group, 
      Carrboro, North Carolina (M.D.) sweir@kumc.edu.
FAU - Wood, Robyn
AU  - Wood R
AD  - University of Kansas Cancer Center, Kansas City, Kansas (S.J.W., R.W., A.E.B., 
      G.A.R., R.A.J., M.J.B., S.A., J.A.T.); Institute for Advancing Medical Innovation 
      (S.J.W., R.W., A.E.B., M.J.B.) and Departments of Cancer Biology (S.J.W., P.R., 
      S.A.), Pharmacology, Toxicology, and Therapeutics (S.J.W., G.A.R.) Pathology 
      (R.A.J.), and Urology (J.A.T.), University of Kansas Medical Center, Kansas City, 
      Kansas; Biotechnology Innovation and Optimization Center, University of Kansas, 
      Lawrence, Kansas (K.S., K.H., L.R., M.T., M.J.B.); School of Pharmacy, Istanbul 
      Kemerburgaz University, Istanbul, Turkey (M.T.); CicloMed LLC, Kansas City, 
      Missouri (T.H.); Navigator LSA, Wilmington, North Carolina (M.J.M.); Alba 
      BioPharm Advisors Inc., Durham, North Carolina (W.M.); and The Gnomon Group, 
      Carrboro, North Carolina (M.D.).
FAU - Schorno, Karl
AU  - Schorno K
AD  - University of Kansas Cancer Center, Kansas City, Kansas (S.J.W., R.W., A.E.B., 
      G.A.R., R.A.J., M.J.B., S.A., J.A.T.); Institute for Advancing Medical Innovation 
      (S.J.W., R.W., A.E.B., M.J.B.) and Departments of Cancer Biology (S.J.W., P.R., 
      S.A.), Pharmacology, Toxicology, and Therapeutics (S.J.W., G.A.R.) Pathology 
      (R.A.J.), and Urology (J.A.T.), University of Kansas Medical Center, Kansas City, 
      Kansas; Biotechnology Innovation and Optimization Center, University of Kansas, 
      Lawrence, Kansas (K.S., K.H., L.R., M.T., M.J.B.); School of Pharmacy, Istanbul 
      Kemerburgaz University, Istanbul, Turkey (M.T.); CicloMed LLC, Kansas City, 
      Missouri (T.H.); Navigator LSA, Wilmington, North Carolina (M.J.M.); Alba 
      BioPharm Advisors Inc., Durham, North Carolina (W.M.); and The Gnomon Group, 
      Carrboro, North Carolina (M.D.).
FAU - Brinker, Amanda E
AU  - Brinker AE
AUID- ORCID: 0000-0003-1134-0572
AD  - University of Kansas Cancer Center, Kansas City, Kansas (S.J.W., R.W., A.E.B., 
      G.A.R., R.A.J., M.J.B., S.A., J.A.T.); Institute for Advancing Medical Innovation 
      (S.J.W., R.W., A.E.B., M.J.B.) and Departments of Cancer Biology (S.J.W., P.R., 
      S.A.), Pharmacology, Toxicology, and Therapeutics (S.J.W., G.A.R.) Pathology 
      (R.A.J.), and Urology (J.A.T.), University of Kansas Medical Center, Kansas City, 
      Kansas; Biotechnology Innovation and Optimization Center, University of Kansas, 
      Lawrence, Kansas (K.S., K.H., L.R., M.T., M.J.B.); School of Pharmacy, Istanbul 
      Kemerburgaz University, Istanbul, Turkey (M.T.); CicloMed LLC, Kansas City, 
      Missouri (T.H.); Navigator LSA, Wilmington, North Carolina (M.J.M.); Alba 
      BioPharm Advisors Inc., Durham, North Carolina (W.M.); and The Gnomon Group, 
      Carrboro, North Carolina (M.D.).
FAU - Ramamoorthy, Prabhu
AU  - Ramamoorthy P
AUID- ORCID: 0000-0002-1963-6004
AD  - University of Kansas Cancer Center, Kansas City, Kansas (S.J.W., R.W., A.E.B., 
      G.A.R., R.A.J., M.J.B., S.A., J.A.T.); Institute for Advancing Medical Innovation 
      (S.J.W., R.W., A.E.B., M.J.B.) and Departments of Cancer Biology (S.J.W., P.R., 
      S.A.), Pharmacology, Toxicology, and Therapeutics (S.J.W., G.A.R.) Pathology 
      (R.A.J.), and Urology (J.A.T.), University of Kansas Medical Center, Kansas City, 
      Kansas; Biotechnology Innovation and Optimization Center, University of Kansas, 
      Lawrence, Kansas (K.S., K.H., L.R., M.T., M.J.B.); School of Pharmacy, Istanbul 
      Kemerburgaz University, Istanbul, Turkey (M.T.); CicloMed LLC, Kansas City, 
      Missouri (T.H.); Navigator LSA, Wilmington, North Carolina (M.J.M.); Alba 
      BioPharm Advisors Inc., Durham, North Carolina (W.M.); and The Gnomon Group, 
      Carrboro, North Carolina (M.D.).
FAU - Heppert, Kathy
AU  - Heppert K
AD  - University of Kansas Cancer Center, Kansas City, Kansas (S.J.W., R.W., A.E.B., 
      G.A.R., R.A.J., M.J.B., S.A., J.A.T.); Institute for Advancing Medical Innovation 
      (S.J.W., R.W., A.E.B., M.J.B.) and Departments of Cancer Biology (S.J.W., P.R., 
      S.A.), Pharmacology, Toxicology, and Therapeutics (S.J.W., G.A.R.) Pathology 
      (R.A.J.), and Urology (J.A.T.), University of Kansas Medical Center, Kansas City, 
      Kansas; Biotechnology Innovation and Optimization Center, University of Kansas, 
      Lawrence, Kansas (K.S., K.H., L.R., M.T., M.J.B.); School of Pharmacy, Istanbul 
      Kemerburgaz University, Istanbul, Turkey (M.T.); CicloMed LLC, Kansas City, 
      Missouri (T.H.); Navigator LSA, Wilmington, North Carolina (M.J.M.); Alba 
      BioPharm Advisors Inc., Durham, North Carolina (W.M.); and The Gnomon Group, 
      Carrboro, North Carolina (M.D.).
FAU - Rajewski, Lian
AU  - Rajewski L
AD  - University of Kansas Cancer Center, Kansas City, Kansas (S.J.W., R.W., A.E.B., 
      G.A.R., R.A.J., M.J.B., S.A., J.A.T.); Institute for Advancing Medical Innovation 
      (S.J.W., R.W., A.E.B., M.J.B.) and Departments of Cancer Biology (S.J.W., P.R., 
      S.A.), Pharmacology, Toxicology, and Therapeutics (S.J.W., G.A.R.) Pathology 
      (R.A.J.), and Urology (J.A.T.), University of Kansas Medical Center, Kansas City, 
      Kansas; Biotechnology Innovation and Optimization Center, University of Kansas, 
      Lawrence, Kansas (K.S., K.H., L.R., M.T., M.J.B.); School of Pharmacy, Istanbul 
      Kemerburgaz University, Istanbul, Turkey (M.T.); CicloMed LLC, Kansas City, 
      Missouri (T.H.); Navigator LSA, Wilmington, North Carolina (M.J.M.); Alba 
      BioPharm Advisors Inc., Durham, North Carolina (W.M.); and The Gnomon Group, 
      Carrboro, North Carolina (M.D.).
FAU - Tanol, Mehmet
AU  - Tanol M
AD  - University of Kansas Cancer Center, Kansas City, Kansas (S.J.W., R.W., A.E.B., 
      G.A.R., R.A.J., M.J.B., S.A., J.A.T.); Institute for Advancing Medical Innovation 
      (S.J.W., R.W., A.E.B., M.J.B.) and Departments of Cancer Biology (S.J.W., P.R., 
      S.A.), Pharmacology, Toxicology, and Therapeutics (S.J.W., G.A.R.) Pathology 
      (R.A.J.), and Urology (J.A.T.), University of Kansas Medical Center, Kansas City, 
      Kansas; Biotechnology Innovation and Optimization Center, University of Kansas, 
      Lawrence, Kansas (K.S., K.H., L.R., M.T., M.J.B.); School of Pharmacy, Istanbul 
      Kemerburgaz University, Istanbul, Turkey (M.T.); CicloMed LLC, Kansas City, 
      Missouri (T.H.); Navigator LSA, Wilmington, North Carolina (M.J.M.); Alba 
      BioPharm Advisors Inc., Durham, North Carolina (W.M.); and The Gnomon Group, 
      Carrboro, North Carolina (M.D.).
FAU - Ham, Tammy
AU  - Ham T
AD  - University of Kansas Cancer Center, Kansas City, Kansas (S.J.W., R.W., A.E.B., 
      G.A.R., R.A.J., M.J.B., S.A., J.A.T.); Institute for Advancing Medical Innovation 
      (S.J.W., R.W., A.E.B., M.J.B.) and Departments of Cancer Biology (S.J.W., P.R., 
      S.A.), Pharmacology, Toxicology, and Therapeutics (S.J.W., G.A.R.) Pathology 
      (R.A.J.), and Urology (J.A.T.), University of Kansas Medical Center, Kansas City, 
      Kansas; Biotechnology Innovation and Optimization Center, University of Kansas, 
      Lawrence, Kansas (K.S., K.H., L.R., M.T., M.J.B.); School of Pharmacy, Istanbul 
      Kemerburgaz University, Istanbul, Turkey (M.T.); CicloMed LLC, Kansas City, 
      Missouri (T.H.); Navigator LSA, Wilmington, North Carolina (M.J.M.); Alba 
      BioPharm Advisors Inc., Durham, North Carolina (W.M.); and The Gnomon Group, 
      Carrboro, North Carolina (M.D.).
FAU - McKenna, Michael J
AU  - McKenna MJ
AD  - University of Kansas Cancer Center, Kansas City, Kansas (S.J.W., R.W., A.E.B., 
      G.A.R., R.A.J., M.J.B., S.A., J.A.T.); Institute for Advancing Medical Innovation 
      (S.J.W., R.W., A.E.B., M.J.B.) and Departments of Cancer Biology (S.J.W., P.R., 
      S.A.), Pharmacology, Toxicology, and Therapeutics (S.J.W., G.A.R.) Pathology 
      (R.A.J.), and Urology (J.A.T.), University of Kansas Medical Center, Kansas City, 
      Kansas; Biotechnology Innovation and Optimization Center, University of Kansas, 
      Lawrence, Kansas (K.S., K.H., L.R., M.T., M.J.B.); School of Pharmacy, Istanbul 
      Kemerburgaz University, Istanbul, Turkey (M.T.); CicloMed LLC, Kansas City, 
      Missouri (T.H.); Navigator LSA, Wilmington, North Carolina (M.J.M.); Alba 
      BioPharm Advisors Inc., Durham, North Carolina (W.M.); and The Gnomon Group, 
      Carrboro, North Carolina (M.D.).
FAU - McCulloch, William
AU  - McCulloch W
AD  - University of Kansas Cancer Center, Kansas City, Kansas (S.J.W., R.W., A.E.B., 
      G.A.R., R.A.J., M.J.B., S.A., J.A.T.); Institute for Advancing Medical Innovation 
      (S.J.W., R.W., A.E.B., M.J.B.) and Departments of Cancer Biology (S.J.W., P.R., 
      S.A.), Pharmacology, Toxicology, and Therapeutics (S.J.W., G.A.R.) Pathology 
      (R.A.J.), and Urology (J.A.T.), University of Kansas Medical Center, Kansas City, 
      Kansas; Biotechnology Innovation and Optimization Center, University of Kansas, 
      Lawrence, Kansas (K.S., K.H., L.R., M.T., M.J.B.); School of Pharmacy, Istanbul 
      Kemerburgaz University, Istanbul, Turkey (M.T.); CicloMed LLC, Kansas City, 
      Missouri (T.H.); Navigator LSA, Wilmington, North Carolina (M.J.M.); Alba 
      BioPharm Advisors Inc., Durham, North Carolina (W.M.); and The Gnomon Group, 
      Carrboro, North Carolina (M.D.).
FAU - Dalton, Michael
AU  - Dalton M
AD  - University of Kansas Cancer Center, Kansas City, Kansas (S.J.W., R.W., A.E.B., 
      G.A.R., R.A.J., M.J.B., S.A., J.A.T.); Institute for Advancing Medical Innovation 
      (S.J.W., R.W., A.E.B., M.J.B.) and Departments of Cancer Biology (S.J.W., P.R., 
      S.A.), Pharmacology, Toxicology, and Therapeutics (S.J.W., G.A.R.) Pathology 
      (R.A.J.), and Urology (J.A.T.), University of Kansas Medical Center, Kansas City, 
      Kansas; Biotechnology Innovation and Optimization Center, University of Kansas, 
      Lawrence, Kansas (K.S., K.H., L.R., M.T., M.J.B.); School of Pharmacy, Istanbul 
      Kemerburgaz University, Istanbul, Turkey (M.T.); CicloMed LLC, Kansas City, 
      Missouri (T.H.); Navigator LSA, Wilmington, North Carolina (M.J.M.); Alba 
      BioPharm Advisors Inc., Durham, North Carolina (W.M.); and The Gnomon Group, 
      Carrboro, North Carolina (M.D.).
FAU - Reed, Gregory A
AU  - Reed GA
AD  - University of Kansas Cancer Center, Kansas City, Kansas (S.J.W., R.W., A.E.B., 
      G.A.R., R.A.J., M.J.B., S.A., J.A.T.); Institute for Advancing Medical Innovation 
      (S.J.W., R.W., A.E.B., M.J.B.) and Departments of Cancer Biology (S.J.W., P.R., 
      S.A.), Pharmacology, Toxicology, and Therapeutics (S.J.W., G.A.R.) Pathology 
      (R.A.J.), and Urology (J.A.T.), University of Kansas Medical Center, Kansas City, 
      Kansas; Biotechnology Innovation and Optimization Center, University of Kansas, 
      Lawrence, Kansas (K.S., K.H., L.R., M.T., M.J.B.); School of Pharmacy, Istanbul 
      Kemerburgaz University, Istanbul, Turkey (M.T.); CicloMed LLC, Kansas City, 
      Missouri (T.H.); Navigator LSA, Wilmington, North Carolina (M.J.M.); Alba 
      BioPharm Advisors Inc., Durham, North Carolina (W.M.); and The Gnomon Group, 
      Carrboro, North Carolina (M.D.).
FAU - Jensen, Roy A
AU  - Jensen RA
AD  - University of Kansas Cancer Center, Kansas City, Kansas (S.J.W., R.W., A.E.B., 
      G.A.R., R.A.J., M.J.B., S.A., J.A.T.); Institute for Advancing Medical Innovation 
      (S.J.W., R.W., A.E.B., M.J.B.) and Departments of Cancer Biology (S.J.W., P.R., 
      S.A.), Pharmacology, Toxicology, and Therapeutics (S.J.W., G.A.R.) Pathology 
      (R.A.J.), and Urology (J.A.T.), University of Kansas Medical Center, Kansas City, 
      Kansas; Biotechnology Innovation and Optimization Center, University of Kansas, 
      Lawrence, Kansas (K.S., K.H., L.R., M.T., M.J.B.); School of Pharmacy, Istanbul 
      Kemerburgaz University, Istanbul, Turkey (M.T.); CicloMed LLC, Kansas City, 
      Missouri (T.H.); Navigator LSA, Wilmington, North Carolina (M.J.M.); Alba 
      BioPharm Advisors Inc., Durham, North Carolina (W.M.); and The Gnomon Group, 
      Carrboro, North Carolina (M.D.).
FAU - Baltezor, Michael J
AU  - Baltezor MJ
AD  - University of Kansas Cancer Center, Kansas City, Kansas (S.J.W., R.W., A.E.B., 
      G.A.R., R.A.J., M.J.B., S.A., J.A.T.); Institute for Advancing Medical Innovation 
      (S.J.W., R.W., A.E.B., M.J.B.) and Departments of Cancer Biology (S.J.W., P.R., 
      S.A.), Pharmacology, Toxicology, and Therapeutics (S.J.W., G.A.R.) Pathology 
      (R.A.J.), and Urology (J.A.T.), University of Kansas Medical Center, Kansas City, 
      Kansas; Biotechnology Innovation and Optimization Center, University of Kansas, 
      Lawrence, Kansas (K.S., K.H., L.R., M.T., M.J.B.); School of Pharmacy, Istanbul 
      Kemerburgaz University, Istanbul, Turkey (M.T.); CicloMed LLC, Kansas City, 
      Missouri (T.H.); Navigator LSA, Wilmington, North Carolina (M.J.M.); Alba 
      BioPharm Advisors Inc., Durham, North Carolina (W.M.); and The Gnomon Group, 
      Carrboro, North Carolina (M.D.).
FAU - Anant, Shrikant
AU  - Anant S
AD  - University of Kansas Cancer Center, Kansas City, Kansas (S.J.W., R.W., A.E.B., 
      G.A.R., R.A.J., M.J.B., S.A., J.A.T.); Institute for Advancing Medical Innovation 
      (S.J.W., R.W., A.E.B., M.J.B.) and Departments of Cancer Biology (S.J.W., P.R., 
      S.A.), Pharmacology, Toxicology, and Therapeutics (S.J.W., G.A.R.) Pathology 
      (R.A.J.), and Urology (J.A.T.), University of Kansas Medical Center, Kansas City, 
      Kansas; Biotechnology Innovation and Optimization Center, University of Kansas, 
      Lawrence, Kansas (K.S., K.H., L.R., M.T., M.J.B.); School of Pharmacy, Istanbul 
      Kemerburgaz University, Istanbul, Turkey (M.T.); CicloMed LLC, Kansas City, 
      Missouri (T.H.); Navigator LSA, Wilmington, North Carolina (M.J.M.); Alba 
      BioPharm Advisors Inc., Durham, North Carolina (W.M.); and The Gnomon Group, 
      Carrboro, North Carolina (M.D.).
FAU - Taylor, John A 3rd
AU  - Taylor JA 3rd
AD  - University of Kansas Cancer Center, Kansas City, Kansas (S.J.W., R.W., A.E.B., 
      G.A.R., R.A.J., M.J.B., S.A., J.A.T.); Institute for Advancing Medical Innovation 
      (S.J.W., R.W., A.E.B., M.J.B.) and Departments of Cancer Biology (S.J.W., P.R., 
      S.A.), Pharmacology, Toxicology, and Therapeutics (S.J.W., G.A.R.) Pathology 
      (R.A.J.), and Urology (J.A.T.), University of Kansas Medical Center, Kansas City, 
      Kansas; Biotechnology Innovation and Optimization Center, University of Kansas, 
      Lawrence, Kansas (K.S., K.H., L.R., M.T., M.J.B.); School of Pharmacy, Istanbul 
      Kemerburgaz University, Istanbul, Turkey (M.T.); CicloMed LLC, Kansas City, 
      Missouri (T.H.); Navigator LSA, Wilmington, North Carolina (M.J.M.); Alba 
      BioPharm Advisors Inc., Durham, North Carolina (W.M.); and The Gnomon Group, 
      Carrboro, North Carolina (M.D.).
LA  - eng
SI  - ClinicalTrials.gov/NCT03348514
GR  - P30 CA168524/CA/NCI NIH HHS/United States
GR  - R01 CA190291/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190521
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Prodrugs)
RN  - 19W019ZDRJ (Ciclopirox)
SB  - IM
MH  - Animals
MH  - Biological Availability
MH  - Ciclopirox/*metabolism
MH  - Dogs
MH  - Male
MH  - Prodrugs/metabolism/*pharmacokinetics/*pharmacology/therapeutic use
MH  - Rats
MH  - Urologic Neoplasms/*drug therapy/*pathology
MH  - Urothelium/*drug effects
PMC - PMC6614794
EDAT- 2019/05/23 06:00
MHDA- 2019/12/31 06:00
PMCR- 2020/08/01
CRDT- 2019/05/23 06:00
PHST- 2019/03/11 00:00 [received]
PHST- 2019/05/08 00:00 [accepted]
PHST- 2019/05/23 06:00 [pubmed]
PHST- 2019/12/31 06:00 [medline]
PHST- 2019/05/23 06:00 [entrez]
PHST- 2020/08/01 00:00 [pmc-release]
AID - jpet.119.257972 [pii]
AID - JPET_257972 [pii]
AID - 10.1124/jpet.119.257972 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2019 Aug;370(2):148-159. doi: 10.1124/jpet.119.257972. Epub 
      2019 May 21.