A dose-escalation study of HP501, a highly selective URAT1 inhibitor, in male Chinese patients with hyperuricemia.

HP501 is a highly selective renal urate transporter 1 (URAT1) inhibitor used for treating hyperuricemia. This study aimed to evaluate the tolerability, pharmacokinetics, and pharmacodynamics of HP501 in male Chinese patients. Patients with hyperuricemia were sequentially assigned to receive oral doses of HP501 (30, 50, 60, 90, and 120 mg) as a single dose on Day 1 and as once-daily doses from Days 4 to 13. Safety, pharmacokinetic, and pharmacodynamic data were collected. Multiple oral doses of HP501 were well-tolerated in all the cohorts. The most common adverse events (≥ 10% of patients) of any grade regardless of drug relationship were gout flare (14 patients, 25.93%), diarrhea (12 patients, 22.22%), elevated ALT (8 patients, 14.81%), hypertriglyceridemia (7 patients, 12.96%), dry mouth (7 patients, 12.96%) and oral ulcer (7 patients, 12.96%). All adverse events were mild or moderate. The Cmax and exposure (AUC) of HP501 was approximately dose-proportional between 30 and 120 mg. A dose-dependent serum uric acid (UA)-lowering effect was observed in the dose range of 30 to 60 mg and the serum UA lowering effect was similar between 90 and 120 mg on day 13, indicating that the maximal serum UA lowering effect of HP501 was achieved at 90 mg in the patients with hyperuricemia. In conclusion, the tolerability, pharmacokinetics, and pharmacodynamics supported 90 mg HP501 for subsequent clinical studies of this highly selective URAT1 inhibitor.Clinical Trial registration: No. CTR20212259 ( http://www.chinadrugtrials.org.cn/ ) was registered in September 2021, and No. CTR20222257 was registered in September 2022.

Choline phosphate lipid as an intra-crosslinker in liposomes for drug and antibody delivery under guard.

Liposomes are used to deliver therapeutics in vivo because of their good biocompatibility, efficient delivery, and ability to protect the therapeutics from degradation. However, the instability of liposomes will cause the therapeutics to lose protection and become ineffective. To deliver therapeutics to the target under guard, we synthesized and used a bio-membrane mimetic choline phosphate lipid (CP-lip) to intra-crosslink liposomes to highly improve their stability. We found that when the ratio of PC-lip to CP-lip is 1 : 2, the intra-crosslinked liposome (PC-CP-lipo) showed higher stability, better biocompatibility and improved anti-protein adsorption than other common liposomes. We used doxorubicin (Dox) loaded PC-CP-lipo to treat melanoma and the tumor inhibition ratio could reach 86.3%. After the combined Dox@PC-CP-lipo treatment with PD-L1 antibody to block the immune checkpoints, the tumor suppression rate could reach 94.4%, and 60% of the mice did not suffer from tumor rechallenge. The method of using a CP-lip to intra-crosslink liposomes is applicable to all liposomes, solving the key problem of liposome disintegration, thus enhancing the protection of drugs and antibodies by liposomes in vivo.