PT  - JOURNAL ARTICLE
AU  - Scott J. Weir
AU  - Robyn Wood
AU  - Karl Schorno
AU  - Amanda E. Brinker
AU  - Prabhu Ramamoorthy
AU  - Kathy Heppert
AU  - Lian Rajewski
AU  - Mehmet Tanol
AU  - Tammy Ham
AU  - Michael J. McKenna
AU  - William McCulloch
AU  - Michael Dalton
AU  - Gregory A. Reed
AU  - Roy A. Jensen
AU  - Michael J. Baltezor
AU  - Shrikant Anant
AU  - John A. Taylor III
TI  - Preclinical Pharmacokinetics of Fosciclopirox, a Novel Treatment of Urothelial Cancers, in Rats and Dogs
AID  - 10.1124/jpet.119.257972
DP  - 2019 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 148--159
VI  - 370
IP  - 2
4099  - http://jpet.aspetjournals.org/content/370/2/148.short
4100  - http://jpet.aspetjournals.org/content/370/2/148.full
SO  - J Pharmacol Exp Ther2019 Aug 01; 370
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).