(W0930-02-08) Toxicokinetics of VLX-1005, a Selective Inhibitor of 12-lipoxygenase, following Intravenous Infusion in Rats and Dogs

Purpose: To assess the toxicokinetics (TK) of VLX-1005 in rats and dogs following once daily 1-hour intravenous infusion for 14 days. VLX-1005 is a small molecule, first-in-class selective inhibitor of 12-lipoxygenase, a key enzyme in the arachidonic acid pathway which plays an important role in cardiovascular biology, diabetes, and many inflammatory diseases. VLX-1005 was granted an orphan drug designation by FDA for thrombosis prophylaxis in patients with heparin-induced thrombocytopenia.

Methods: Male and female Sprague-Dawley rats (n=3 or 6/TK group) and Beagle dogs (n=4 or 6/group) received once daily 1-hour intravenous infusion of VLX-1005 at 0, 20, 40, or 80 mg/kg/day for 14 days. The 20 mg/kg male dog dose group was inadvertently administered 10 mg/kg on Day 1 and was included in the toxicokinetic analysis, along with the replacement group that was dosed at 20 mg/kg on Day 1 only. Blood samples were collected at predetermined times on Days 1 and 14 and plasma was assayed for VLX-1005 by validated HPLC-MS/MS assays with a calibration range of 2.00 to 4,000 ng/mL for both species. The TK parameters were determined by model independent methods.

Results: The highest VLX-1005 plasma concentrations were observed at the end of infusion (1 h) in both species. VLX-1005 was not detected in vehicle control animals. In rats, Day 1 VLX-1005 values for the C_max in males were 95,700, 144,000 and 238,000 ng/mL, AUC_(0-24) were 214,000, 334,000 and 638,000 ng·h/mL and T_1/2 were 2.73, 3.05 and 3.34 h for the doses of 20, 40 and 80 mg/kg, respectively. In females, the values for the C_max were 154,000, 231,000 and 289,000 ng/mL, AUC_(0-24) were 382,000, 559,000 and 1,010,000 ng·h/mL and T_1/2 were 3.74, 3.62 and 3.25 h for the respective doses. Day 14 C_max values in males were 109,000, 171,000 and 215,000 ng/mL, AUC_(0-24) were 239,000, 371,000 and 560,000 ng·h/mL for doses of 20, 40 and 80 mg/kg/day, respectively. The values for the T_1/2 were 20.0 and 31.4 h for the doses of 40 and 80 mg/kg/day, respectively. The T_1/2 for the 20 mg/kg/day dose was not calculated since the R² of the terminal phase of concentration-time profiles was < 0.75. In females, Day 14 values for the C_max were 135,000, 169,000 and 259,000 ng/mL, AUC_(0-24) were 311,000, 388,000 and 705,000 ng·h/mL and T_1/2 were 15.5, 21.6 and 37.1 h for doses of 20, 40 and 80 mg/kg/day, respectively. In dogs, Day 1 VLX-1005 mean C_max values in males were 62,400, 108,000, 178,000 and 319,000 ng/mL, AUC_(0-24) were 111,000, 238,000, 481,000 and 1,290,000 ng·h/mL and T_1/2 were 6.53, 4.55, 3.24 and 2.69 h for the doses of 10, 20, 40 and
80 mg/kg, respectively. In females, the mean C_max values were 114,000, 210,000 and 331,000 ng/mL, AUC_(0-24) were 260,000, 648,000 and 1,520,000 ng·h/mL and T_1/2 were 3.58, 2.65 and 2.69 h for the doses of 20, 40 and 80 mg/kg. Day 14 values for the mean C_max in males were 108,000, 160,000 and 252,000 ng/mL, AUC_(0-24) were 213,000, 495,000 and 1,170,000 ng·h/mL and T_1/2 were 4.45, 4.40 and 3.29 h for the doses of 20, 40 and 80 mg/kg/day, respectively. In females, Day 14 values for the mean C_max were 102,000, 180,000 and 268,000 ng/mL, AUC_(0-24) were 237,000, 566,000 and 1,180,000 ng·h/mL and T_1/2 were 4.12, 3.78 and 3.26 h for doses of 20, 40 and 80 mg/kg/day, respectively. In both rats and dogs, the TK exposure on Day 14 appeared to be similar to that of Day 1 indicating no accumulation of
VLX-1005 following repeated daily dosing for 14 days. In addition, there was no apparent sex-related difference in VLX-1005 TK on both days.

Conclusion: In both rats and dogs, VLX-1005 TK exposure increased with increasing dose, and did not exhibit sex-related differences or accumulation.