Abstract 4346: Improved pharmacokinetic properties of the purified S-enantiomer of the alkylphospholipid Edelfosine compared to the racemic mixture: Potential orally available novel anticancer agent active against pancreatic cancer
Authors: Michael Ahrweiler, Wolfgang Meyer, Daniel Perrissoud, Axel Zander
Journal: Cancer Research (2025)

Abstract Edelfosine, an alkylphospholipid anticancer drug, has been extensively investigated, but the racemic mixture used in these studies has not been approved for human commercial use. This drug acts by integrating into lipid rafts in cell membranes, including mitochondria and the ER. The mechanism of action involves CD95-mediated apoptosis, AKT3/PI3K inhibition, phospholipase C and protein kinase C inhibition, as well as interference with cholesterol and phosphatidylcholine metabolism. Edelfosine is preferentially taken up by malignant cells, its efficacy in numerous xenograft studies, including metastatic breast and prostate cancer models, as well as in phase 2 clinical trials has been convincingly demonstrated. In patients, it is generally well-tolerated; the reported main adverse event was dose-dependent, but reversible gastrointestinal toxicity. We purified the S and R enantiomers from the racemic mixture and assessed the pharmacokinetic (PK) and pharmacodynamic (PD) differences between them (R-CP201 and S-CP201) in rodents using a validated LC-MS/MS bioanalytical method. Following a single-dose i.v. administration (20 mg/kg) in male rats (N=5), S-CP201 showed a favorable half-life (t1/2 alpha and beta: 1.8 and 8.0 hours) vs R-CP201 (2.1 and 18.2 hours). Cmax values were similar (∼42 µg/mL); but AUClast was higher for S-CP201 (172.6 µg*h/mL vs. 149.3 µg*h/mL for R-CP201). This trend persisted with oral administration (150 mg/kg), where AUClast was 54.2 µg*h/mL for S-CP201 compared to 46.3 µg*h/mL for R-CP201. In another study, single doses of each enantiomer (10 mg/kg orally, 2.5 mg/kg i.v.) were given to male rats (N=8). Systemic exposure, expressed as AUClast, was lower for R-CP201 (i.v.: 43.0 µg*h/mL; oral: 49.4 µg*h/mL) than S-CP201 (i.v.: 50.6 µg*h/mL; oral: 63.7 µg*h/mL). Absolute oral bioavailability (F) was 33.2% for S-CP201 and 29.1% for R-CP201. Daily doses of 10 mg/kg S-CP201 or R-CP201 were given to male rats (N=4) for 5 days. After 5 days, AUClast values were 115.5 µg*h/mL for R-CP201 and 159.0 µg*h/mL for S-CP201, with respective Cmax values of 1.9 µg/mL and 2.6 µg/mL. A single-dose PK study of Edelfosine (20 and 40 mg/kg orally; 5 mg/kg i.v.) and its enantiomers (10 and 20 mg/kg orally; 2.5 mg/kg i.v.) in male mice showed comparable relative bioavailability for Edelfosine and S-CP201 (∼45%), but lower for R-CP201 (∼35%). Also, no interconversion between the enantiomers was observed in rat plasma. S-CP201 demonstrated in vitro efficacy across diverse tumor cell lines and showed superior tumor reduction in a PDX pancreatic cancer study in mice (57% vs. 33%). No major toxicity was detected for S-CP201 in rats and mice. These results confirm PK and PD advantages and acceptable tolerability of S-CP201 and support its further development as an anticancer agent is warranted. Citation Format: Michael Ahrweiler, Wolfgang Meyer, Daniel Perrissoud, Axel Zander. Improved pharmacokinetic properties of the purified S-enantiomer of the alkylphospholipid Edelfosine compared to the racemic mixture: Potential orally available novel anticancer agent active against pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4346.