Abstract Rationale IKT-001, an investigational prodrug of imatinib under evaluation to treat pulmonary arterial hypertension (PAH), was designed to release free imatinib in the systemic circulation while avoiding direct gastrointestinal exposure to improve tolerability. Nonclinical studies demonstrated intestinal luminal and enterocyte stability of IKT-001 with rapid and complete bioconversion to imatinib in plasma. A three-part, single-dose study was conducted to assess IKT-001 safety, tolerability, and imatinib pharmacokinetics (PK) in healthy participants. Methods This open-label, three-part study examined IKT-001 safety, tolerability, and PK relative to imatinib mesylate. Safety and tolerability assessments included adverse event (AE) reporting, electrocardiograms (ECGs), and clinical laboratory parameters. Plasma imatinib PK parameters were estimated by noncompartmental analysis. Part A was a fixed-sequence design where participants received a 300-, 400-, 500-, or 600-mg oral dose of IKT-001 followed by a single 400-mg oral dose of imatinib for comparison. Part B was a randomized, crossover design where participants received single oral doses of IKT-001 600 mg and imatinib 400 mg to assess the relative bioavailability of imatinib from IKT-001. Based on the results of Part A, Part C was a fixed-sequence design where participants received an oral dose of IKT-001 800 mg followed by an oral dose of imatinib 600 mg to assess relative bioavailability at a high IKT-001 dose. Results Sixty-five of 66 enrolled participants completed the study. IKT-001 was well tolerated; AEs, including mostly gastrointestinal and musculoskeletal effects, were mild. There were no remarkable observations for clinical laboratory parameters, vital signs, and ECGs. In Part A, imatinib exposures increased proportionally over the IKT-001 300-600-mg dose range. Imatinib absorption rate from IKT-001 administration appeared to be slower than imatinib. Imatinib terminal half-life and oral clearance were similar between the two compounds. In Part B, the geometric mean ratio of imatinib area under the curve (AUC; 90% confidence interval), was 115% (111-119%), and IKT-001 600 mg produced slightly greater systemic imatinib exposure compared with imatinib 400 mg. In Part C, the geometric mean imatinib AUCinf after IKT-001 800 mg was 6.8% lower compared with imatinib 600 mg. Conclusions Single doses of IKT-001 were well tolerated and exposures were dose proportional over a 300- to 800-mg dose range. Systemic exposure of imatinib following oral IKT-001 administration was comparable to imatinib tablets; the relative bioavailability of imatinib from IKT-001 after adjusting for molar dose equivalents was near complete (98%). This abstract is funded by: Inhibikase Therapeutics, Inc.
Adams et al. (Fri,) studied this question.