Pharmacokinetics of LBPT and its primary metabolites, as well as tolerability in the first-in-human study

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Abstract

Background:

LBPT is a novel platelet-activating factor (PAF) receptor antagonist that is developed for the treatment of rheumatoid arthritis. The purpose of this first-in-human study was to evaluate the tolerability and safety of LBPT, to investigate the pharmacokinetics of LBPT and its primary metabolites, as well as to assess the food effect on the pharmacokinetics in healthy Chinese subjects.

Materials and Methods:

LBPT was evaluated in 2 clinical studies. The first study was a double blind, placebo-controlled and ascending dose study. Eighty-five healthy Chinese subjects received oral dose of 2, 4, 6, 8, 15, 25, 50, 75, 100, 125, 150, 225, 300, 400 or 500 mg of LBPT or placebo. The pharmacokinetics of LBPT and its primary metabolites were investigated in the last 4 dose cohorts. The tolerability was evaluated by monitoring adverse events (AEs), physical examinations, 12-lead electrocardiograms (ECG) and laboratory tests. The second study was an open-label, 2-period cross-over study with a washout interval of 3 days. Twelve subjects received 300 mg of LBPT after an overnight fasting or a high-fat breakfast. The pharmacokinetics of LBPT in subjects under fasted and fed conditions were compared.

Results:

LBPT was well tolerated up to 500 mg-dose and there were no serious AEs in the study. The incidence and severity of AEs were closely related to dose. Following single oral administration of 225, 300, 400 and 500 mg of LBPT, plasma Cmax was reached at 0.5 h and the mean t1/2 was 0.6–1.6 h. Plasma exposure increased with dose escalation but proportionality was not observed. LBPT was eliminated in forms of metabolites and 20–40% of the given dose was recovered in urine. Compared with the subjects under fasting conditions, AUC and Cmax were lower and tmax was delayed in the fed subjects.

Conclusion:

LBPT was well tolerated in healthy subjects with a pattern of dose-related AEs. The pharmacokinetics was non-linear and was impacted by food intake.

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