Bioavailablility of penclomedine and systemic exposure to 4-O-demethylpenclomedine in patients receiving oral and intravenous penclomedine

Purpose: Oral administration of penclomedine was investigated based on prec linical studies indicating that an oral schedule of penclomedine treatment may prevent the neurotoxicity observed in phase I studies of an intravenous (i.v.) formulation, possibly by reducing maximum plasma concentrations (C- max) of the neurotoxic parent species. Methods: Penclomedine was administer ed i.v. (200 mg/m(2)) and orally (250 mg/m(2)) in alternate sequences to pa tients with solid tumor malignancies. Plasma concentrations of parent drug and the principal metabolite, 4-O-demethylpenclomedine, were determined by a reversed-phase HPLC assay. Results: Penclomedine was detectable in the pl asma of all patients within 1 h of oral penclomedine treatment and C-max wa s reached within 1 to 4 h. Consistent with the hypothesis that an oral sche dule of administration may circumvent neurotoxicity, a paired data analysis demonstrated a significant reduction in C-max values following oral admini stration (P=0.017). However the magnitude of this reduction was highly vari able. Similarly an extensive range in the relative exposure to both parent drug and metabolite were observed. The bioavailability of penclomedine rang ed from 28% to 98% (median 73%). Conclusions: Oral penclomedine does produc e systemic exposure, but substantial interpatient variability in absorption and systemic exposure is present which may limit the clinical role of the oral route of administration.