Abstract Rationale Rentosertib (INS018₀55) is a novel TNIK inhibitor developed using generative AI platforms for the treatment of idiopathic pulmonary fibrosis. To reduce risk of potential adverse effects with systemic exposure and to maximize exposure in fibrotic lung tissue, we developed an aerosolized, inhalable form of rentosertib. We analyzed tissue-specific pharmacokinetics in rats to assess the effectiveness of aerosolized administration. Methods Aerosol generation and characterization A PARI compression atomizer generated aerosol from rentosertib solution. Mass aerodynamic diameter (MMAD) and fine particle fraction (FPF, 4 µm) was calculated by cascade impactor, and concentration was determined by HPLC. Pharmacokinetics and lung tissue distribution in healthy rats Male Sprague-Dawley rats (n = 72, 6-9 weeks old) were randomly assigned to three groups, each receiving 0. 357 mg/kg (“low”), 1. 042 mg/kg (“medium”), and 2. 256 mg/kg (“high”) aerosolized rentosertib using the HRH-LMNE1628 oro-nasal exposure system (Beijing Huironghe Technology). Blood samples and lung tissue were collected from 30 min to 12. 5 hr after the start of administration (n = 3/timepoint/concentration). Rentosertib was quantified in plasma and lung tissue by LC-MS/MS. Pharmacokinetics in fibrotic lungs Lung fibrosis was induced in 8-9-week-old male Sprague-Dawley rats via intratracheal bleomycin hydrochloride (n = 72, 1. 5 mg/kg). Starting on day 7, animals were administered aerosolized rentosertib at 0. 040 mg/kg, 0. 136 mg/kg, 0. 485 mg/kg, or 2. 575 mg/kg over 30 minutes once-daily for 21 days. Blood and lung tissue was collected on day 28 immediately after dosing (n = 3/group). Results MMAD of aerosols ranged from 2. 652-2. 77 µm, with FPF 79. 7-85. 0%. Across all doses in healthy rats (low, medium, high), mean plasma Cmax was 4. 40 ng/mL, 12. 49 ng/mL, and 27. 68 ng/mL; left/right lung Cmax was 296. 60/332. 58 ng/g, 823. 32/1343. 28 ng/g, and 1488. 92/1790. 62 ng/g, respectively; plasma AUClast was 1. 58 h*ng/mL, 9. 70 h*ng/mL, and 27. 00 h*ng/mL, and left/right lung AUClast was 213. 04/215. 98 h*ng/g, 664. 36/622. 70 h*ng/g, and 1379. 55/1064. 88 h*ng/g, respectively. The ratio of left lung to plasma AUClast for the three doses was 134. 84, 68. 49, and 51. 09, respectively; the ratio of right lung to plasma AUClast was 136. 70, 64. 20, and 39. 44, respectively. In the bleomycin-induced fibrosis model, the ratio of rentosertib concentration in lung to plasma ranged from 36. 9-77. 2. No clinical abnormalities were observed in any study animal. Conclusions Inhaled delivery of rentosertib was effective and resulted in lung exposure 36. 9-136. 70-fold greater than in plasma, suggesting inhalable formulation and delivery effectively limits systemic exposure while maximizing exposure in tissues affected by fibrosis, and informing dosage in future human trials. This abstract is funded by: Insilico Medicine
Satler et al. (Fri,) studied this question.