Single and Multiple Dose Pharmacokinetics, Pharmacodynamics and Safety of the Novel Lipoprotein-Associated Phospholipase A2 Enzyme Inhibitor Darapladib in Healthy Chinese Subjects: An Open Label Phase-1 Clinical Trial

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Abstract

Background and Objectives

Darapladib is a lipoprotein-associated phospholipase A ₂ (Lp-PLA ₂) inhibitor. This study evaluated the pharmacokinetics, pharmacodynamics and safety of darapladib in healthy Chinese subjects.

Methods

Twenty-four subjects received darapladib 160 mg orally, approximately 1 hour after a standard breakfast, as a single dose and once daily for 28 days. Non-compartmental methods were used to determine the single and multiple dose pharmacokinetics of darapladib and its metabolite SB-553253. Repeat dose Lp-PLA ₂ activity and safety were evaluated.

Results

Systemic exposure (AUC _(0-T), Cmax geometric mean (CVb%)) of darapladib was higher after multiple-dosing (519 ng.h/mL (33.3%), 34.4 ng/mL (49.9%)) compared to single-dose administration (153 ng.h/mL (69.0%), 17.9 ng/mL (55.2%). The steady-state accumulation ratio was less than unity (Rs = 0.80), indicating time-dependent pharmacokinetics of darapladib. Darapladib steady-state was reached by Day 14 of once daily dosing. Systemic exposure to SB-553253 was lower than darapladib with median (SB-553253: darapladib) ratios for AUC _(0-τ) of 0.0786 for single dose and 0.0532 for multiple dose administration. On Day 28, pre-dose and maximum inhibition of Lp-PLA ₂ activity was approximately 70% and 75% relative to the baseline value, respectively and was dependent of darapladib concentration. The most common adverse events (≥ 21% subjects) were abnormal faeces, abnormal urine odour, diarrhoea and nasopharyngitis.

Conclusion

Darapladib 160 mg single and repeat doses were profiled in healthy Chinese subjects. Single dose systemic exposure to darapladib in healthy Chinese subjects was consistent with that observed previously in Western subjects whereas steady-state systemic exposure was approximately 65% higher in Chinese than Western subjects. The Lp-PLA ₂ activity and adverse event profile were similar in healthy Chinese and previous reports in Western subjects. Ethnic-specific dose adjustment of darapladib is not considered necessary for the Chinese population.

Trial Registration

ClinicalTrials.gov NCT02000804

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Most cited references 3

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Lp-PLA2 Inhibitors for the Reduction of Cardiovascular Events

Dylan L Steen, Michelle L. O'Donoghue (2013)

Evidence suggests that inflammation plays a central role in the pathogenesis of atherosclerosis (Libby, Nature 420:868–874, 2002). Inflammation is a physiologic process with highly regulated and often redundant mechanisms to balance pro-inflammatory and anti-inflammatory responses. The complexity of these networks has made it challenging to identify those specific pathways or key enzymes that contribute directly to atherogenesis and could act as a valuable therapeutic target. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a member of the phospholipase A2 family of enzymes and is believed to contribute to atherosclerotic plaque progression and instability by promoting inflammation. A large number of epidemiologic studies have demonstrated that elevated levels of Lp-PLA2 are associated with an increased risk of cardiovascular events across diverse patient populations, independent of established risk factors including low-density lipoprotein cholesterol. Further, a growing number of preclinical and genetic studies support a causal role for Lp-PLA2 in atherosclerosis. The development of a novel therapeutic agent that directly inhibits the Lp-PLA2 enzyme has provided a unique opportunity to directly test the hypothesis that inhibition of this inflammatory enzyme will translate into improved clinical outcomes. In this article, we will review the evidence to support the notion that Lp-PLA2 is causally implicated in the pathobiology of atherogenesis and discuss the potential utility of inhibiting this enzyme as a therapeutic target.

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The role of lipoprotein-associated phospholipase A2 (Lp-PLA₂) in cardiovascular disease.

John Lekakis, Ignatios Ikonomidis, Maria Anastasiou-Nana … (2011)

Lipoprotein-associated Phospholipase A2 (Lp-PLA(2)) is an enzyme that belongs to the A2 Phospholipase superfamily and is produced by inflammatory cells that are involved in the process of atherogenesis. Even though there is controversy in current bibliography whether Lp-PLA(2) exerts proatherogenic or anti-atherogenic properties, the weight of evidence suggests a pro-atherogenic role for this protein. Lp-PLA(2) is detected in human atherosclerotic lesions and elevated Lp-PLA(2) levels are associated with an increased risk of cardiovascular events and adverse events in patients with coronary artery disease independently of traditional risk factors and other markers of inflammation. It has been recently shown that direct pharmacological inhibition of Lp-PLA(2) activity exerts beneficiary effects on the atherosclerotic process. This finding is most interesting since it could offer a novel target for therapeutic intervention in patients suffering from cardiovascular disease. The purpose of this review article is to report on the role of Lp-PLA(2) in cardiovascular diseases and to enlighten the putative pathophysiologic mechanisms by which this protein exerts its effect on cardiovascular function. Additionally, the pharmacological interventions that influence Lp-PLA(2) activity and may offer a new approach for the treatment of atherosclerosis will be analyzed.

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Disposition and metabolism of darapladib, a lipoprotein-associated phospholipase A2 inhibitor, in humans.

Mehul Dave, Mike Nash, Graeme Young … (2014)

The absorption, metabolism, and excretion of darapladib, a novel inhibitor of lipoprotein-associated phospholipase A2, was investigated in healthy male subjects using [(14)C]-radiolabeled material in a bespoke study design. Disposition of darapladib was compared following single i.v. and both single and repeated oral administrations. The anticipated presence of low circulating concentrations of drug-related material required the use of accelerator mass spectrometry as a sensitive radiodetector. Blood, urine, and feces were collected up to 21 days post radioactive dose, and analyzed for drug-related material. The principal circulating drug-related component was unchanged darapladib. No notable metabolites were observed in plasma post-i.v. dosing; however, metabolites resulting from hydroxylation (M3) and N-deethylation (M4) were observed (at 4%-6% of plasma radioactivity) following oral dosing, indicative of some first-pass metabolism. In addition, an acid-catalyzed degradant (M10) resulting from presystemic hydrolysis was also detected in plasma at similar levels of ∼5% of radioactivity post oral dosing. Systemic exposure to radioactive material was reduced within the repeat dose regimen, consistent with the notion of time-dependent pharmacokinetics resulting from enhanced clearance or reduced absorption. Elimination of drug-related material occurred predominantly via the feces, with unchanged darapladib representing 43%-53% of the radioactive dose, and metabolites M3 and M4 also notably accounting for ∼9% and 19% of the dose, respectively. The enhanced study design has provided an increased understanding of the absorption, distribution, metabolism and excretion (ADME) properties of darapladib in humans, and substantially influenced future work on the compound.

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Author and article information

Contributors

Eng-Huat Tan: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 14 October 2015

Publication date Collection: 2015

Volume: 10

Issue: 10

Electronic Location Identifier: e0139862

Affiliations

[1 ]Phase I Clinical Research Unit, Shanghai Xuhui Central Hospital, Shanghai, China

[2 ]Clinical Pharmacology Modeling and Simulation, GSK Medicines Research Centre, Stevenage, United Kingdom

[3 ]Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America

[4 ]China Medicine Development, GlaxoSmithKline (China) R&D Company Limited, Shanghai, China

[5 ]Ethnopharmacology, GlaxoSmithKline, Sydney, Australia

National Cancer Centre, SINGAPORE

Author notes

Competing Interests: DT, MM, WZ and AG are GlaxoSmithKline employees and own GSK stock. HZ is a GSK employee. CH, QC, YML and YL have no conflicts of interests to declare. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Conceived and designed the experiments: CH QC YML WZ HZ YL. Performed the experiments: CH QC YML YL. Analyzed the data: DT WZ HZ. Contributed reagents/materials/analysis tools: DT MM WZ HZ AG. Wrote the paper: DT MM WZ HZ AG. Principal author of the manuscript: DT. Critical review and approval the final version of manuscript: CH DT MM QC YML WZ HZ AG YL.

* E-mail: yliu@ 123456shxh-centerlab.com (YL); debra.j.tompson@ 123456gsk.com (DT)

Article

Publisher ID: PONE-D-15-22267

DOI: 10.1371/journal.pone.0139862

PMC ID: 4605839

PubMed ID: 26465780

SO-VID: 5a5cf806-4f42-44cf-98ae-92638092f2b7

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

History

Date received : 26 May 2015

Date accepted : 15 September 2015

Page count

Figures: 4, Tables: 5, Pages: 15

Funding

This study was funded by GlaxoSmithKline (China) R&D Company Limited. GlaxoSmithKline (GSK) provided support in the form of salaries for authors DT, MM, WZ, HZ and AG. The role of GSK included study concept and design, funding of the participating center, analysis of data, development and funding of the final report and the manuscript.

Custom metadata

Data Availability Anonymized patient-level data underlying this study is available to independent researchers, subject to review by an independent panel, at ( www.clinicalstudydatarequest.com). To further protect the privacy of patients and individuals involved in our studies, GSK does not publically disclose subject level data.

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