Weir, Scott J.Wood, RobynSchorno, KarlBrinker, Amanda E.Ramamoorthy, PrabhuHeppert, KathyTaylor, John A., IIITanol, Mehmet2021-05-152021-05-1520190022-35651521-0103https://doi.org/10.1124/jpet.119.257972https://hdl.handle.net/20.500.12939/938Brinker, Amanda/0000-0003-1134-0572; Weir, Scott/0000-0002-8020-434XPharmacokinetic 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.eninfo:eu-repo/semantics/openAccessFosciclopiroxCiclopiroxCiclopirox GlucuronidePharmacokineticsDrug MetabolismExcretionBladder CancerAllometric ScalingArticle10.1124/jpet.119.2579723702148159311138372-s2.0-85069296748Q2WOS:000477702600002Q2