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

Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.

Figures

Fig. 1.

Chemical structure of fosciclopirox ((6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yl) oxy) methyl phosphate heptahydrate (CPX-POM).

Fig. 2.

Mean ± S.D. plasma CPX concentration-time profiles following single dose intravenous administration of 17.5 mg/kg CPX-POM and 13 mg/kg CPX-O to male Sprague-Dawley rats. Data are presented on rectilinear (A) and semilogarithmic (B) plots as mean ± S.D., n = 6 per treatment group. CPX, ciclopirox; CPX-O, ciclopirox olamine; CPX-POM, fosciclopirox; hr, hour; IV, intravenous.

Fig. 3.

Mean ± S.D. plasma CPX concentration-time rectilinear profiles following a single dose intravenous administration of 5.4 mg/kg CPX-POM and 4.0 mg/kg CPX-O to male beagle dogs. Plasma CPX concentration-time profiles following single dose administration of 5.4 mg/kg intravenous CPX-POM and 4.0 mg/kg CPX-O to 4 male beagle dogs in a complete crossover fashion. Data are presented on rectilinear (A) and semilogarithmic (B) plots as mean ± S.D. CPX, ciclopirox; CPX-O, ciclopirox olamine; CPX-POM, fosciclopirox; hr, hour; IV, intravenous.

Fig. 4.

Mean ± S.D. plasma CPX concentration-time rectilinear profiles following administration of 47 mg/kg intravenous CPX-POM, 70.6 mg/kg subcutaneous CPX-POM, and 38.8 mg/kg CPX-O to 6 rats per treatment group. Plasma CPX concentration-time profiles following single dose administration of 47 mg/kg intravenous CPX-POM, 71 mg/kg subcutaneous CPX-POM, and 39 mg/kg CPX-O to male Sprague-Dawley rats. Data are presented on rectilinear (A) and semilogarithmic (B) plots as mean ± S.D., n = 6 per treatment group. CPX, ciclopirox; CPX-O, ciclopirox olamine; CPX-POM, fosciclopirox; hr, hour; IV, intravenous; PO, oral; SC, subcutaneous.

Fig. 5.

Mean ± S.D. plasma CPX concentration-time rectilinear profiles following intravenous administration of 7.3 mg/kg CPX-POM, SC administration of 21.8 mg/kg SC CPX-POM, and 12.2 mg/kg oral CPX-O to four male beagle dogs. Plasma CPX concentration-time profiles following single dose administration of 7.3 mg/kg intravenous CPX-POM, 21.8 mg/kg SC CPX-POM, and 12.2 mg/kg oral CPX-O to four male beagle dogs in a complete crossover fashion. Data are presented on rectilinear (A) and semilogarithmic (B) plots as mean ± S.D. CPX, ciclopirox; CPX-O, ciclopirox olamine; CPX-POM, fosciclopirox; hr, hour; IV, intravenous; PO, oral; SC, subcutaneous.