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제목	Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BI 685509, a Soluble Guanylate Cyclase Activator, in Healthy Chinese and Japanese Males: a Randomised, Single-Blind, Placebo-Controlled Multiple Rising Dose Trial
저자	In-Jin Jang
출판정보	2024; 2024(1):
키워드
초록	Objectives: BI 685509 is a novel, potent, soluble guanylate cyclase activator in development for diabetic nephropathy. This trial investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of BI 685509 in healthy Chinese and Japanese males following administration of multiple rising doses (MRDs). Methods: This was a randomised, placebo-controlled, single-blind, Phase I trial. Healthy Chinese or Japanese males aged 20–45 years were randomised 3:1 within each ethnicity to one of three BI 685509 dose groups (DGs; DG1, daily dose 0.5/1.0 mg; DG2, 2.5/5.0 mg; DG3, 1.0/3.0/6.0/9.0 mg) or placebo. Treatment was administered orally for 15 days: a single dose on Day 1 followed by multiple doses on Days 4–17. The primary endpoint was the number of participants with of treatment-emergent adverse events (TEAEs). Secondary endpoints were pharmacokinetic parameters: AUC0–24, Cmax, AUCτ,steady state (SS), Cmax,SS. Results: In total, 72 participants received trial medication across all DGs (n=36, Chinese; n=36, Japanese). Baseline characteristics were generally similar between ethnicities. Overall, 70.8% of participants had a TEAE (BI 685509, 38/54 [70.4%]; placebo, 13/18 [72.2%]). The most common TEAE across ethnicities and treatment groups was orthostatic hypotension (Tables 1 and 2). There were no TEAEs leading to discontinuation of trial medication, severe AEs, protocol-specified AEs of special interest, serious AEs or deaths. Investigator-defined treatment-related AEs (TRAEs) occurred in 21/27 (77.8%) Chinese participants and 15/27 (55.6%) Japanese participants. All TRAEs were mild and resolved by the end of the trial. BI 685509 exposure (AUC and Cmax) increased in a dose-proportional manner. BI 685509 plasma concentrations reached SS during the multiple dosing periods. No dose-dependent effect on plasma and urine cGMP levels was observed. These results were consistent across both ethnicities. Conclusions: MRDs of BI 685509 were well tolerated in healthy Chinese and Japanese males. These results support further clinical investigation of BI 685509.
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