Pharmacokinetics of TD-8236, a Lung-Selective pan-JAK Inhibitor, Following Single-Dose Administration in Mice, Rats, and Dogs

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Rationale: Janus kinases (JAKs) play a central role in signaling the pro-inflammatory effects of multiple cytokines. TD-8236 is a pan-JAK inhibitor designed for delivery to the lungs for treatment of inflammatory lung conditions. By selectively retaining a targeted JAK inhibitor in the lungs, maximal local anti-inflammatory activity may be achieved while minimizing the potential for systemic JAK-mediated effects. The objective of these studies was to define the lung and plasma pharmacokinetics of TD-8236 following oral aspiration (OA), inhalation (IH), and oral (PO) administration to mice, rats, and dogs. Methods: TD-8236 was administered as a single-dose solution via OA dosing to male Balb/c mice (0.4 mg/kg) and male Sprague-Dawley rats (0.4 mg/kg). TD-8236 dry powder formulations were administered as a single dose via inhalation to male Sprague-Dawley rats (0.2 -2 mg/kg) and male beagle dogs (1 mg/kg). TD-8236 was administered via single-dose PO administration to male Sprague-Dawley rats (0.5 mg/kg) and male beagle dogs (5 mg/kg). Lung and plasma concentrations of TD-8236 were determined using LC/MS/MS. Results: TD-8236 lung concentrations in mice and rats following single-dose OA solution administration were substantially elevated relative to plasma concentrations at 24 hours post-dose demonstrating the intrinsic lung duration and retention of TD-8236. Administration of dry powder formulations in rats and dogs also was associated with properties consistent with lung selectivity. TD-8236 lung to plasma ratios after dry powder inhalation dosing exceeded 7,000-fold in rat and dog with high lung concentrations maintained 24 hours post-dose. The plasma concentration profile following inhalation dosing in rats and dogs declined rapidly and was characterized by low absolute TD-8236 concentrations. Oral bioavailability of TD-8236 was negligible (< 1%) in both rats and dogs. Conclusions: TD-8236 exhibits a lung-selective pharmacokinetic profile after inhalation dosing characterized by low systemic plasma exposures and sustained lung retention. The preclinical TD-8236 PK profile supports once-daily clinical evaluation of this inhaled, lung-selective, JAK inhibitor in patients with inflammatory lung conditions, including moderate to severe asthma.

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