Abstract 758: Comparative pharmacokinetics for 4-demethyl-4-cholesteryloxy- carbonylpenclomedine (DM-CHOC-PEN) in humans
Authors: Weiner Roy S. , Ware Marcus L. , Bastian Gerard , Urien Saik , Rodgers Andrew H. , Morgan Lee Roy 
Published: August 2012

4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a polychlorinated pyridine cholesteryl carbonate, which is active vs. intracranially (IC) implanted human xenograft models - U251 and D54 glioblastoma and MX-1 breast cancer (%LTS/CR): +29/25 and +20/17, resp. and has a MOA via alkylation of DNA @ N7 - guanine (CCP, 64, 829, 2009). DM-CHOC-PEN's preclinical rodent single IV dose toxicity studies documented the following landmark values: for mice - LD10/50 136/385 mg/kg; & for rats - LD10 100 mg/kg. DM-CHOC-PEN is metabolized to 4-demethyl-PEN (DM-PEN) and cholesterol. The DLT in rats was hypercholesteremia - 2nd to release of cholesterol from the oxycarbonate moiety. The LDL-cholesterol was increased 30 fold at doses of 200 and 300 mg/kg, which returned to normal values - predominantly as the HDL-cholesterol by Day 15. Plasma and erythrocyte DM-CHOC-PEN and metabolites DM-PEN/cholesterol were assayed vs. time by HPLC. Overall, PK values in rats revealed the following profile for DM-CHOC-PEN @ 100 mg/kg: AUC o-t = 1.05 mg (h/L), T1/2β = 0.51 (h), T1/2β = 2.48 (h) & CL = 3.04 (L/h) [a two compartment model]. The AUC was linear for 100, 200, 300 mg/kg doses. There were no differences between males and females. For the Phase I clinical trial (IND 68,876), the calculated (from mice) initial single dose for DM-CHOC-PEN was 39 mg/m2 administrated IV q 21-days with 40% dose escalations q 3-cycles until SLTs were identified. To date, doses of 39, 55, 70 mg/m2 have been administered to patients without toxicity. DM-CHOC-PEN PK modeling revealed a central compartment (cpt) which released the drug into a peripheral compartment (pct) with CL - 0.141L/h, T1/2 α - 0.63 h & Tα - 24.1 h. DM-CHOC-PEN & DM-PEN showed an important rebound phenomenon @ ∼ 50 hours post-infusion with Trelease 26.7h (for both).Same phenomenon is observed in rbcs (estimation using Monolix 3.2). DM-CHOC-PEN and DM-PEN were detected for 3 and 15 days, resp., bound to rbcs (after 70 mg/m2); DM-CHOC-PEN was also detected in the urine (Cmax=17.5 µg/mL) until day 15. Similar to rats, the total lipid profiles (cholesterol and triglycerides) for the patients were erratic during the 3-h IV infusion period (2o to the lipid emulsion vehicle) and then returned to pre-treatment values after 24 h; triglycerides most significantly affected. In 1-patient, DM-CHOC-PEN could be identified in sarcoma tissue metastatic to the spine in 190 ng/g quantities, which was obtained 21-days post IV infusion with 39 mg/m2. Five (5) patients have been treated to date; no hematological, neurotoxic or psychological alterations have been identified. Thus, DM-CHOC-PEN is well tolerated with manageable toxicities to date; the trial continues. An update on patient responses/toxicities will be presented. Comparative PK profiles of DM-CHOC PEN and metabolite in plasma, RBC and urine are analyzed and will be presented here. Supported by NCI/SBIR grant - 1R43CA132257.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 758. doi:1538-7445.AM2012-758