Pharmacokinetics (PK) and pharmacodynamics (PD) of TTI-101, a STAT3 inhibitor that blocks muscle proteolysis in rats with chronic kidney disease.

Loss of muscle proteins increases the morbidity and mortality of patients with chronic kidney disease (CKD) and there are no reliable preventive treatments. We uncovered a STAT3, CEBPδ to myostatin signaling pathway that activates muscle protein degradation in mice with CKD or cancer; we also identified a small molecule inhibitor of STAT3 (TTI-101) that blocks this pathway. To evaluate TTI-101 as a treatment of CKD-induced cachexia, we measured TTI-101 pharmacokinetics (PK) and pharmacodynamics (PD) in control and CKD rats that were orally administrated TTI-101or its diluent. Two groups of gavage-fed rats, sham-operated, control rats and CKD rats were studied. Plasma was collected serially (0, 0.25, 0.5, 1, 2, 4, 8 and 24 hr.) following TTI-101 administration (at oral doses of 0, 10, 30, or 100 mg/kg). Plasma levels of TTI-101 were measured by LC-MS/MS and PK results analyzed with the PKsolver program. Plasma TTI-101 levels increased linearly with doses; the maximum plasma concentrations (C) and time to maximal (T) plasma levels (~1 hour) were similar in sham-operated, control and CKD rats. Notably, gavage treatment of TTI-101 for 3 days produced TTI-101 muscle levels in sham-control and CKD rats that were not significantly different. CKD rats that received TTI-101 for 7 days had suppression of activated STAT3 and improved muscle grip strength; there also was a trend for increasing body and muscle weights. TTI-101 was tolerated at doses of 100 mg/kg/day for 7 days. These results with TTI-101 in rats warrants its development as a treatment of cachexia in humans.