Pharmacokinetics and pharmacodynamics of HTD1801 (berberine ursodeoxycholate, BUDCA) in patients with hyperlipidemia

Abstract

Background: Reduction in elevated serum cholesterol concentrations is important in the management of individuals at risk of atherosclerotic cardiovascular disease (ASCVD), such as myocardial infarction and thrombotic stroke. Although HMGCoA reductase inhibitors ("statins") are frequently used for this purpose, a significant proportion of patients remain at increased residual risk of ASCVD as they do not adequately address some of the associated co-morbidities such as diabetes and fatty liver disease.

Methods: A double-blind, randomized, placebo-controlled, dose ranging study was carried out that compared three doses of berberine ursodeoxycholate (BUDCA) to placebo in a cohort of subjects with a history of hypercholesterolemia and serum LDL cholesterol levels above 2.59 mmol/L (> 99.9 mg/dL). BUDCA was administered in two divided doses each day for 28 days. The primary endpoints of the study were safety and tolerability of this new compound, as well as its effect in lowering serum lipid and lipoprotein concentrations.

Results: A total of 50 subjects were enrolled into three dose cohorts in this study. BUDCA was generally well tolerated, even at doses of 2000 mg per day (the highest dose group); there were no significant adverse effects reported and this highest dose was associated with significant reductions in LDL cholesterol. By day 28 and with the highest dose of BUDCA, there were significant reductions in the serum concentrations of total cholesterol by 8.2% (P = 0.0004) and LDL cholesterol by 10.4% (P = 0.0006), but no significant changes in triglyceride and HDL cholesterol concentrations.

Conclusions: BUDCA is a new single molecular entity that has a significant but modest effect in safely lowering serum LDL-cholesterol concentrations in individuals with a history of hypercholesterolemia. It has a potential use for treating hypercholesterolemia in individuals who cannot take statins, and possibly as adjunctive to other agents, such as ezetimibe or bempedoic acid.

Trial registration: The study was registered on Clinicaltrials.gov ( NCT03381287 ).

Keywords: Berberine; Hyperlipidemia; Pharmacokinetics; Ursodeoxycholic acid.

Conflict of interest statement

The following authors have potentially competing interests:

AMD is a consultant to HighTide and Chief Medical Officer.

GFW: Research grants and consultancy fees from Amgen, Sanofi, Regeneron, Arrowhead and Novartis.

PL: Consultant to HighTide.

LL, MY, RB: employees of HighTide Therapeutics.

Figures

Fig. 1

Study overview and randomization scheme

Fig. 2

Percentage change in serum lipids at day 28. Marked parameters were statistically significantly different from baseline (*P = 0.0006; ** P = 0.0004; *** P = 0.0006)

Fig. 3

a Average (+/−SE) plasma berberine concentration-time profiles (linear plot) after single- (day 1) and multiple-dose administration of HTD1801 in the group receiving the highest dose (1000 mg BID). b Average (+/−SE) plasma berberine concentration-time profiles (log-linear plot) after single- (day 1) and multiple-dose administration of HTD1801 in the group receiving the highest dose (1000 mg BID)

Fig. 4

a Average (+/−SE) plasma UDCA concentration-time profiles (linear plot) after single- (day 1) and multiple-dose administration of HTD1801 in the group receiving the highest dose (1000 mg BID). b Average (+/−SE) plasma UDCA concentration-time profiles (log-linear plot) after single- (day 1) and multiple-dose administration of HTD1801 in the group receiving the highest dose (1000 mg BID)