Moving beyond Binary Predictions of Human Drug-Induced Liver Injury (DILI) toward Contrasting Relative Risk Potential.

The hepatic risk matrix (HRM) was developed and used to differentiate lead clinical and back-up drug candidates against competitor/marketed drugs within the same pharmaceutical class for their potential to cause human drug-induced liver injury (DILI). The hybrid HRM scoring system blends physicochemical properties (Rule of Two Model: dose and lipophilicity or Partition Model: dose, ionization state, lipophilicity, and fractional carbon bond saturation) with common toxicity mechanisms (cytotoxicity, mitochondrial dysfunction, and bile salt export pump (BSEP) inhibition) that promote DILI. HRM scores are based on bracketed safety margins (<1, 1-10, 10-100, and >100× clinical ).

Immunologic effects of chronic administration of tofacitinib, a Janus kinase inhibitor, in cynomolgus monkeys and rats - Comparison of juvenile and adult responses.

Tofacitinib, an oral Janus kinase (JAK) inhibitor for treatment of rheumatoid arthritis, targets JAK1, JAK3, and to a lesser extent JAK2 and TYK2. JAK1/3 inhibition impairs gamma common chain cytokine receptor signaling, important in lymphocyte development, homeostasis and function. Adult and juvenile cynomolgus monkey and rat studies were conducted and the impact of tofacitinib on immune parameters (lymphoid tissues and lymphocyte subsets) and function (T-dependent antibody response (TDAR), mitogen-induced T cell proliferation) assessed.