Preclinical toxicology and pharmacokinetics of intravenous lipid emulsion fenretinide

C159

Purpose: Fenretinide (4-HPR) is a cytotoxic retinoid active against a variety of human tumor cell lines. Poor bioavailability of the NCI capsule formulation may limit clinical activity. We developed an intravenous emulsion formulation of 4-HPR delivered in egg phospholipids, glycerin, alcohol and soybean oil, and conducted IND-directed toxicology. Pharmacokinetics (PK) and bioavailability in beagle dogs was compared between intravenous emulsion 4-HPR, oral capsule 4-HPR, and intravenous 4-HPR in NCI Diluent-12 [cremophor EL: ethanol: saline (12.5:12.5:75)]. Results: In a single-dose 1-hr bolus infusion PK study of emulsion 4-HPR and diluent-12, at 1 mg/kg 4-HPR in beagle dogs, the values of C_max, t_1/2Beta, Vdss, and Cl were 5.6 μM, 25.3 hr, 3.5 L/kg, and 0.096 L/hr/kg for emulsion 4-HPR and 6.6 μM, 34.7 hr, 4.24 L/kg and 0.85 L/hr for diluent-12 4-HPR. Dogs receiving a single oral 10 mg/kg dose of 4-HPR capsules displayed a 4-HPR C_max of 3.1 μM and AUC of 70.2 μM*hr; mean oral bioavailability in dogs of capsule 4-HPR was ~ 16%. Minimal toxicity occurred in dogs given a continuous intravenous (c.i.v.) infusion of emulsion 4-HPR as two 7-day courses (separated by 1-week) at 0, 25, and 50 mg/kg/day. Toxicities observed were increased WBC, neutrophil, monocyte counts, and ALT, anemia, decreased total protein, albumin, sodium, potassium, chloride, lesions in ear, and mild pulmonary inflammation. By contrast, an extreme hypersensitivity response to the vehicle was seen in dogs given identical c.i.v. infusion doses of Diluent-12 4-HPR. The mean (± SD) plasma levels in dogs after 7 days of c.i.v emulsion 4-HPR were 4-HPR = 38.3 ± 4.4, 4-MPR = 40.9 ± 8.2 μM (25 mg/kg/day) and 4-HPR = 144.7 ± 34.9, 4-MPR = 162.0 ± 42.9 μM (50 mg/kg/day), significantly higher (P = 0.0003) than the 13.3 ± 3.4 μM 4-HPR plasma levels at day 7 in dogs treated with oral 4-HPR capsules at 70 mg/kg/day divided t.i.d. The highest tissue concentration on day 22 in dogs receiving c.i.v. emulsion 4-HPR was found in kidney cortex, with progressively lower concentrations in the liver, adrenal gland, lung, and lymph nodes ranging from 16.8 to 5.8 μg/g at 25 mg/kg/day and 35.2 to 16.1 μg/g at 50 mg/kg/day. Fischer rats also tolerated a 5-day c.i.v. infusion of emulsion 4-HPR at 61 mg/kg/day; mean plasma concentrations at the end of a 120-hr infusion in rats were 4-HPR = 49.3 ± 16.5 and 4-MPR = 1.8 ± 0.2 μM. Conclusions: (1) Intravenous 4-HPR emulsion achieved significantly higher 4-HPR plasma levels than a higher oral dose of 4-HPR capsules and emulsion 4-HPR was better tolerated than Diluent-12 4-HPR. (2) A clinical entry dose of 4 mg/kg/day (80 mg/ m²/day) was calculated based on one-third of the 'toxic dose low' in dogs from both i.v. formulations. Phase I trials of intravenous emulsion 4-HPR in adults and children are in progress.