Preclinical Pharmacokinetics of Fosciclopirox, a Novel Treatment of Urothelial Cancers, in Rats and Dogs

Abstract

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-inhuman Phase 1 clinical trial in patients with advanced solid tumors (NCT03348514).

CPX Targeting DJ-1 Triggers ROS-induced Cell Death and Protective Autophagy in Colorectal Cancer

“…For example, Andrew M. Davidoff et al delivered CPX via a subcutaneously implanted, continuous release pump to treat neuroblastomas 11. More importantly, John A. Taylor III et al designed and synthesized the phosphoryl-oxymethyl ester of CPX, fosciclopirox (CPX-POM) which has higher oral bioavailability and is able to be metabolized rapidly and completely to the active CPX when intravenously injected 41. The safety, dose tolerance, pharmacokinetics and pharmacodynamics of intravenous CPX-POM are currently being characterized in a United States multi-center first-in-human Phase 1 clinical trial in patients with advanced solid tumors (NCT03348514).…”

Effects of the antifungal agent ciclopirox in HPV‐positive cancer cells: Repression of viral E6/E7 oncogene expression and induction of senescence and apoptosis

“…A clinical study applying CPX olamine in an oral formulation in patients with hematological malignancies was discontinued due to the low bioavailability upon oral administration and dose‐limiting gastrointestinal toxicity. Recently, a clinical trial in bladder cancer patients was initiated, administrating a phosphoryl–oxymethyl ester of CPX (fosciclopirox) by intravenous injection …”

“…Recently, a clinical trial in bladder cancer patients was initiated, administrating a phosphoryl-oxymethyl ester of CPX (fosciclopirox) by intravenous injection. 50,51 The systemic application of iron chelators has been associated with severe side effects. 52 Notably, however, and in contrast to most other clinically used iron chelators, CPX can be applied topically, and is used since decades for the treatment of fungal infections of the skin and mucosa with an excellent pharmacological safety profile.…”

Iron: An Essential Element of Cancer Metabolism

“…Ciclopirox olamine is a fungicide that initially showed promising effects in different mouse models [280][281][282][283] and in human hematological malignancies but showed a very poor pharmacokinetic profile (low solubility and rapid metabolism and clearance) [284]. A prodrug was consequently developed and was shown to be effective in urothelial cancers in rats and dog and is now under a phase I clinical trial for advanced solid tumors [285] (NCT03348514). Similar to DFP, tachpyridine also depletes intracellular iron while inducing oxidative stress [286].…”